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Farina I, Andreotti M, Pastori C, Bona R, Galluzzo CM, Amici R, Purificato C, Uberti-Foppa C, Riva A, Gauzzi MC, Lopalco L, Fantuzzi L. Modulation of CCR5 expression and R5 HIV-1 infection in primary macrophages exposed to sera from HESN, LTNP, and chronically HIV-1 infected people with or without natural antibodies to CCR5. Virus Res 2024; 350:199506. [PMID: 39638260 PMCID: PMC11669954 DOI: 10.1016/j.virusres.2024.199506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/07/2024]
Abstract
CCR5 is the main co-receptor for HIV-1 cell entry and it plays key roles in HIV-1 mucosal transmission. Natural anti-CCR5 antibodies were found in HIV-1-exposed seronegative and long-term non-progressor subjects, suggesting a role in controlling viral replication in vivo. We assessed the effect of sera containing or not natural anti-CCR5 antibodies, on membrane CCR5 level and HIV-1 infection in primary macrophages. Sera modulated CCR5 expression with a trend dependent on the donor/serum tested but independent on the presence or absence of anti-CCR5 antibodies. All sera strongly reduced HIV-1 DNA in all donor's macrophages and no correlation was observed between CCR5 and viral DNA levels. These results suggest that CCR5 expression level is not a major determinant of macrophage infection and that the observed modulation of CCR5 and HIV-1 DNA might depend on factors other than CCR5-reactive antibodies present in sera and/or intrinsic to the donors on which sera were tested.
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Affiliation(s)
- Iole Farina
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | - Mauro Andreotti
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | - Claudia Pastori
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Roberta Bona
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | | | - Roberta Amici
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | - Cristina Purificato
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
| | | | - Agostino Riva
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
| | | | - Lucia Lopalco
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Laura Fantuzzi
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy.
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Schriek AI, Aldon YLT, van Gils MJ, de Taeye SW. Next-generation bNAbs for HIV-1 cure strategies. Antiviral Res 2024; 222:105788. [PMID: 38158130 DOI: 10.1016/j.antiviral.2023.105788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Despite the ability to suppress viral replication using anti-retroviral therapy (ART), HIV-1 remains a global public health problem. Curative strategies for HIV-1 have to target and eradicate latently infected cells across the body, i.e. the viral reservoir. Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have the capacity to neutralize virions and bind to infected cells to initiate elimination of these cells. To improve the efficacy of bNAbs in terms of viral suppression and viral reservoir eradication, next generation antibodies (Abs) are being developed that address the current limitations of Ab treatment efficacy; (1) low antigen (Env) density on (reactivated) HIV-1 infected cells, (2) high viral genetic diversity, (3) exhaustion of immune cells and (4) short half-life of Abs. In this review we summarize and discuss preclinical and clinical studies in which anti-HIV-1 Abs demonstrated potent viral control, and describe the development of engineered Abs that could address the limitations described above. Next generation Abs with optimized effector function, avidity, effector cell recruitment and immune cell activation have the potential to contribute to an HIV-1 cure or durable control.
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Affiliation(s)
- A I Schriek
- Amsterdam UMC Location University of Amsterdam, Department of Medical Microbiology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands.
| | - Y L T Aldon
- Amsterdam UMC Location University of Amsterdam, Department of Medical Microbiology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
| | - M J van Gils
- Amsterdam UMC Location University of Amsterdam, Department of Medical Microbiology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands
| | - S W de Taeye
- Amsterdam UMC Location University of Amsterdam, Department of Medical Microbiology, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, the Netherlands.
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Characterization of Macrophage-Tropic HIV-1 Infection of Central Nervous System Cells and the Influence of Inflammation. J Virol 2022; 96:e0095722. [PMID: 35975998 PMCID: PMC9472603 DOI: 10.1128/jvi.00957-22] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
HIV-1 infection within the central nervous system (CNS) includes evolution of the virus, damaging inflammatory cascades, and the involvement of multiple cell types; however, our understanding of how Env tropism and inflammation can influence CNS infectivity is incomplete. In this study, we utilize macrophage-tropic and T cell-tropic HIV-1 Env proteins to establish accurate infection profiles for multiple CNS cells under basal and interferon alpha (IFN-α) or lipopolysaccharide (LPS)-induced inflammatory states. We found that macrophage-tropic viruses confer entry advantages in primary myeloid cells, including monocyte-derived macrophage, microglia, and induced pluripotent stem cell (iPSC)-derived microglia. However, neither macrophage-tropic or T cell-tropic HIV-1 Env proteins could mediate infection of astrocytes or neurons, and infection was not potentiated by induction of an inflammatory state in these cells. Additionally, we found that IFN-α and LPS restricted replication in myeloid cells, and IFN-α treatment prior to infection with vesicular stomatitis virus G protein (VSV G) Envs resulted in a conserved antiviral response across all CNS cell types. Further, using RNA sequencing (RNA-seq), we found that only myeloid cells express HIV-1 entry receptor/coreceptor transcripts at a significant level and that these transcripts in select cell types responded only modestly to inflammatory signals. We profiled the transcriptional response of multiple CNS cells to inflammation and found 57 IFN-induced genes that were differentially expressed across all cell types. Taken together, these data focus attention on the cells in the CNS that are truly permissive to HIV-1, further highlight the role of HIV-1 Env evolution in mediating infection in the CNS, and point to limitations in using model cell types versus primary cells to explore features of virus-host interaction. IMPORTANCE The major feature of HIV-1 pathogenesis is the induction of an immunodeficient state in the face of an enhanced state of inflammation. However, for many of those infected, there can be an impact on the central nervous system (CNS) resulting in a wide range of neurocognitive defects. Here, we use a highly sensitive and quantitative assay for viral infectivity to explore primary and model cell types of the brain for their susceptibility to infection using viral entry proteins derived from the CNS. In addition, we examine the ability of an inflammatory state to alter infectivity of these cells. We find that myeloid cells are the only cell types in the CNS that can be infected and that induction of an inflammatory state negatively impacts viral infection across all cell types.
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Nickoloff-Bybel EA, Festa L, Meucci O, Gaskill PJ. Co-receptor signaling in the pathogenesis of neuroHIV. Retrovirology 2021; 18:24. [PMID: 34429135 PMCID: PMC8385912 DOI: 10.1186/s12977-021-00569-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/11/2021] [Indexed: 12/13/2022] Open
Abstract
The HIV co-receptors, CCR5 and CXCR4, are necessary for HIV entry into target cells, interacting with the HIV envelope protein, gp120, to initiate several signaling cascades thought to be important to the entry process. Co-receptor signaling may also promote the development of neuroHIV by contributing to both persistent neuroinflammation and indirect neurotoxicity. But despite the critical importance of CXCR4 and CCR5 signaling to HIV pathogenesis, there is only one therapeutic (the CCR5 inhibitor Maraviroc) that targets these receptors. Moreover, our understanding of co-receptor signaling in the specific context of neuroHIV is relatively poor. Research into co-receptor signaling has largely stalled in the past decade, possibly owing to the complexity of the signaling cascades and functions mediated by these receptors. Examining the many signaling pathways triggered by co-receptor activation has been challenging due to the lack of specific molecular tools targeting many of the proteins involved in these pathways and the wide array of model systems used across these experiments. Studies examining the impact of co-receptor signaling on HIV neuropathogenesis often show activation of multiple overlapping pathways by similar stimuli, leading to contradictory data on the effects of co-receptor activation. To address this, we will broadly review HIV infection and neuropathogenesis, examine different co-receptor mediated signaling pathways and functions, then discuss the HIV mediated signaling and the differences between activation induced by HIV and cognate ligands. We will assess the specific effects of co-receptor activation on neuropathogenesis, focusing on neuroinflammation. We will also explore how the use of substances of abuse, which are highly prevalent in people living with HIV, can exacerbate the neuropathogenic effects of co-receptor signaling. Finally, we will discuss the current state of therapeutics targeting co-receptors, highlighting challenges the field has faced and areas in which research into co-receptor signaling would yield the most therapeutic benefit in the context of HIV infection. This discussion will provide a comprehensive overview of what is known and what remains to be explored in regard to co-receptor signaling and HIV infection, and will emphasize the potential value of HIV co-receptors as a target for future therapeutic development. ![]()
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Affiliation(s)
- E A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA
| | - L Festa
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, 240 S. 40th Street, Philadelphia, PA, 19104, USA
| | - O Meucci
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA.,Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - P J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA.
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Matt SM, Nickoloff-Bybel EA, Rong Y, Runner K, Johnson H, O'Connor MH, Haddad EK, Gaskill PJ. Dopamine Levels Induced by Substance Abuse Alter Efficacy of Maraviroc and Expression of CCR5 Conformations on Myeloid Cells: Implications for NeuroHIV. Front Immunol 2021; 12:663061. [PMID: 34093554 PMCID: PMC8170305 DOI: 10.3389/fimmu.2021.663061] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/26/2021] [Indexed: 12/12/2022] Open
Abstract
Despite widespread use of antiretroviral therapy (ART), HIV remains a major public health issue. Even with effective ART many infected individuals still suffer from the constellation of neurological symptoms now known as neuroHIV. These symptoms can be exacerbated by substance abuse, a common comorbidity among HIV-infected individuals. The mechanism(s) by which different types of drugs impact neuroHIV remains unclear, but all drugs of abuse increase central nervous system (CNS) dopamine and elevated dopamine increases HIV infection and inflammation in human myeloid cells including macrophages and microglia, the primary targets for HIV in the brain. Thus, drug-induced increases in CNS dopamine may be a common mechanism by which distinct addictive substances alter neuroHIV. Myeloid cells are generally infected by HIV strains that use the chemokine receptor CCR5 as a co-receptor, and our data indicate that in a subset of individuals, drug-induced levels of dopamine could interfere with the effectiveness of the CCR5 inhibitor Maraviroc. CCR5 can adopt distinct conformations that differentially regulate the efficiency of HIV entry and subsequent replication and using qPCR, flow cytometry, Western blotting and high content fluorescent imaging, we show that dopamine alters the expression of specific CCR5 conformations of CCR5 on the surface of human macrophages. These changes are not affected by association with lipid rafts, but do correlate with dopamine receptor gene expression levels, specifically higher levels of D1-like dopamine receptors. These data also demonstrate that dopamine increases HIV replication and alters CCR5 conformations in human microglia similarly to macrophages. These data support the importance of dopamine in the development of neuroHIV and indicate that dopamine signaling pathways should be examined as a target in antiretroviral therapies specifically tailored to HIV-infected drug abusers. Further, these studies show the potential immunomodulatory role of dopamine, suggesting changes in this neurotransmitter may also affect the progression of other diseases.
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Affiliation(s)
- Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Yi Rong
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Kaitlyn Runner
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Hannah Johnson
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Margaret H O'Connor
- Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, United States.,Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Elias K Haddad
- Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, United States.,Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
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Nishihara T, Tanaka J, Sekiya K, Nishikawa Y, Abe N, Hamada T, Kitamura S, Ikemune K, Ochi S, Choudhury ME, Yano H, Yorozuya T. Chronic constriction injury of the sciatic nerve in rats causes different activation modes of microglia between the anterior and posterior horns of the spinal cord. Neurochem Int 2020; 134:104672. [PMID: 31926989 DOI: 10.1016/j.neuint.2020.104672] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 12/28/2019] [Accepted: 01/06/2020] [Indexed: 01/20/2023]
Abstract
Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68+ phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms.
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Affiliation(s)
- Tasuku Nishihara
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Junya Tanaka
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Keisuke Sekiya
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Yuki Nishikawa
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan; Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Naoki Abe
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Taisuke Hamada
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Sakiko Kitamura
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Keizo Ikemune
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Shinichiro Ochi
- Department of Neuropsychiatry, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Mohammed E Choudhury
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Hajime Yano
- Department of Molecular and Cellular Physiology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
| | - Toshihiro Yorozuya
- Department of Anesthesia and Perioperative Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
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7
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Narasimhan V, Siddique RH, Hoffmann M, Kumar S, Choo H. Enhanced broadband fluorescence detection of nucleic acids using multipolar gap-plasmons on biomimetic Au metasurfaces. NANOSCALE 2019; 11:13750-13757. [PMID: 31140518 DOI: 10.1039/c9nr03178b] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Recent studies on metal-insulator-metal-based plasmonic antennas have shown that emitters could couple with higher-order gap-plasmon modes in sub-10-nm gaps to overcome quenching. However, these gaps are often physically inaccessible for functionalization and are not scalably manufacturable. Here, using a simple biomimetic batch-fabrication, a plasmonic metasurface is created consisting of closely-coupled nanodisks and nanoholes in a metal-insulator-metal arrangement. The quadrupolar mode of this system exhibits strong broadband resonance in the visible-near-infrared regime with minimal absorptive losses and effectively supresses quenching, making it highly suitable for broadband plasmon-enhanced fluorescence. Functionalizing the accessible insulator nanogap, analytes are selectively immobilized onto the plasmonic hotspot enabling highly-localized detection. Sensing the streptavidin-biotin complex, a 91-, 288-, 403- and 501-fold fluorescence enhancement is observed for Alexa Fluor 555, 647, 750 and 790, respectively. Finally, the detection of single-stranded DNA (gag, CD4 and CCR5) analogues of genes studied in the pathogenesis of HIV-1 between 10 pM-10 μM concentrations and then CD4 mRNA in the lysate of transiently-transfected cells with a 5.4-fold increase in fluorescence intensity relative to an untransfected control is demonstrated. This outcome promises the use of biomimetic Au metasurfaces as platforms for robust detection of low-abundance nucleic acids.
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Affiliation(s)
- Vinayak Narasimhan
- Department of Medical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
| | - Radwanul Hasan Siddique
- Department of Medical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
| | - Magnus Hoffmann
- Department of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Shailabh Kumar
- Department of Medical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
| | - Hyuck Choo
- Department of Medical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
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Borrajo A, Ranazzi A, Pollicita M, Bellocchi MC, Salpini R, Mauro MV, Ceccherini-Silberstein F, Perno CF, Svicher V, Aquaro S. Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage. MEDICINA (KAUNAS, LITHUANIA) 2019; 55:E297. [PMID: 31234437 PMCID: PMC6630780 DOI: 10.3390/medicina55060297] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/07/2019] [Accepted: 06/11/2019] [Indexed: 12/13/2022]
Abstract
Background and objectives: To enter the target cell, HIV-1 binds not only CD4 but also a co-receptor β-chemokine receptor 5 (CCR5) or α chemokine receptor 4 (CXCR4). Limited information is available on the impact of co-receptor usage on HIV-1 replication in monocyte-derived macrophages (MDM) and on the homeostasis of this important cellular reservoir. Materials and Methods: Replication (measured by p24 production) of the CCR5-tropic 81A strain increased up to 10 days post-infection and then reached a plateau. Conversely, the replication of the CXCR4-tropic NL4.3 strain (after an initial increase up to day 7) underwent a drastic decrease becoming almost undetectable after 10 days post-infection. The ability of CCR5-tropic and CXCR4-tropic strains to induce cell death in MDM was then evaluated. While for CCR5-tropic 81A the rate of apoptosis in MDM was comparable to uninfected MDM, the infection of CXCR4-tropic NL4.3 in MDM was associated with a rate of 14.3% of apoptotic cells at day 6 reaching a peak of 43.5% at day 10 post-infection. Results: This suggests that the decrease in CXCR4-tropic strain replication in MDM can be due to their ability to induce cell death in MDM. The increase in apoptosis was paralleled with a 2-fold increase in the phosphorylated form of p38 compared to WT. Furthermore, microarray analysis showed modulation of proapoptotic and cancer-related genes induced by CXCR4-tropic strains starting from 24 h after infection, whereas CCR5 viruses modulated the expression of genes not correlated with apoptotic-pathways. Conclusions: In conclusion, CXCR4-tropic strains can induce a remarkable depletion of MDM. Conversely, MDM can represent an important cellular reservoir for CCR5-tropic strains supporting the role of CCR5-usage in HIV-1 pathogenesis and as a pharmacological target to contribute to an HIV-1 cure.
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Affiliation(s)
- Ana Borrajo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
- Group of Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur)-Complexo Hospitalario Universitario de Vigo, SERGAS-UVigo, 36312 Vigo, Spain.
| | - Alessandro Ranazzi
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
| | - Michela Pollicita
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
| | - Maria Concetta Bellocchi
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
| | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
| | - Maria Vittoria Mauro
- Department of Microbiology and Virology, Complex Operative Unit (UOC), Hospital of Cosenza, 87100 Cosenza, Italy.
| | | | - Carlo Federico Perno
- Department of Microbiology and Clinic Microbiology, University of Milan, 20162 Milan, Italy.
| | - Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Roma, Italy.
| | - Stefano Aquaro
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
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Gisslén M, Heslegrave A, Veleva E, Yilmaz A, Andersson LM, Hagberg L, Spudich S, Fuchs D, Price RW, Zetterberg H. CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2018; 6:e512. [PMID: 30568991 PMCID: PMC6278890 DOI: 10.1212/nxi.0000000000000512] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 09/12/2018] [Indexed: 11/15/2022]
Abstract
Objective To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. Methods In this retrospective cross-sectional study, we measured concentrations of the macrophage/microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. Results CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4+ T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Conclusions Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4+ T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.
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Affiliation(s)
- Magnus Gisslén
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Amanda Heslegrave
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Elena Veleva
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Aylin Yilmaz
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Lars-Magnus Andersson
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Lars Hagberg
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Serena Spudich
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Dietmar Fuchs
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Richard W Price
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
| | - Henrik Zetterberg
- Department of Infectious Diseases (M.G., A.Y., L.-M.A., L.H.), Institute of Biomedicine, the Sahlgrenska Academy at University of Gothenburg, Sweden; Department of Molecular Neuroscience (A.H., E.V., H.Z.), UCL Institute of Neurology, Queen Square; UK Dementia Research Institute at UCL (A.H., E.V., H.Z.), London, United Kingdom; Department of Neurology and Center for Neuroepidemiology and Clinical Neurological Research (S.S.), Yale University, New Haven, CT; Division of Biological Chemistry (D.F.), Biocenter, Medical University of Innsbruck, Austria; Department of Neurology (R.W.P.), University of California San Francisco; Clinical Neurochemistry Laboratory (H.Z.), Sahlgrenska University Hospital; and Department of Psychiatry and Neurochemistry (H.Z.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden
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10
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The role of catecholamines in HIV neuropathogenesis. Brain Res 2018; 1702:54-73. [PMID: 29705605 DOI: 10.1016/j.brainres.2018.04.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 04/21/2018] [Accepted: 04/24/2018] [Indexed: 12/21/2022]
Abstract
The success of anti-retroviral therapy has improved the quality of life and lifespan of HIV + individuals, transforming HIV infection into a chronic condition. These improvements have come with a cost, as chronic HIV infection and long-term therapy have resulted in the emergence of a number of new pathologies. This includes a variety of the neuropathological and neurocognitive effects collectively known as HIVassociated neurocognitive disorders (HAND) or NeuroHIV. These effects persist even in the absence of viral replication, suggesting that they are mediated the long-term changes in the CNS induced by HIV infection rather than by active replication. Among these effects are significant changes in catecholaminergic neurotransmission, especially in dopaminergic brain regions. In HIV-infected individuals not treated with ARV show prominent neuropathology is common in dopamine-rich brain regions and altered autonomic nervous system activity. Even infected individuals on therapy, there is significant dopaminergic neuropathology, and elevated stress and norepinephrine levels correlate with a decreased effectiveness of antiretroviral drugs. As catecholamines function as immunomodulatory factors, the resultant dysregulation of catecholaminergic tone could substantially alter the development of HIVassociated neuroinflammation and neuropathology. In this review, we discuss the role of catecholamines in the etiology of HIV neuropathogenesis. Providing a comprehensive examination of what is known about these molecules in the context of HIV-associated disease demonstrates the importance of further studies in this area, and may open the door to new therapeutic strategies that specifically ameliorate the effects of catecholaminergic dysregulation on NeuroHIV.
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11
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In vivo characterization of macrophage-tropic simian immunodeficiency virus molecular clones in rhesus macaques. J Neurovirol 2018; 24:411-419. [PMID: 29594984 DOI: 10.1007/s13365-018-0628-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 02/20/2018] [Accepted: 03/02/2018] [Indexed: 02/06/2023]
Abstract
Macrophages are a major target of HIV/SIV infection and play an important role in pathogenesis by serving as viral reservoirs in the central nervous system. Previously, a unique early SIVmac251 envelope (Env) variant, deSIV147 was cloned from blood of a rhesus macaque with rapid disease progression and SIV-associated encephalitis. Here, we show that infectious molecular clone deSIV147 caused systemic infection in rhesus macaques following intravenous or intrarectal exposure. Next, we inoculated deSIV147 into macaques depleted of CD4+ T cells and found that animals were SIV-positive, with high plasma and CSF viral loads. These macaques also showed SIVp17-positive macrophages in brain, lymph nodes, colon, lung, and liver. Furthermore, accumulation of perivascular macrophages, multinucleated giant cells, and microgliosis was detected. These findings suggest that the neurotropic deSIV147 clone will be useful to study macrophage infection in HIV/SIV-associated neurocognitive disorders, gain insights into myeloid cell reservoirs in brain and other anatomical sites, as well as test strategies for eradication.
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12
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COPD monocytes demonstrate impaired migratory ability. Respir Res 2017; 18:90. [PMID: 28494757 PMCID: PMC5425971 DOI: 10.1186/s12931-017-0569-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 05/01/2017] [Indexed: 12/20/2022] Open
Abstract
Background Increased lung macrophage numbers in COPD may arise from upregulation of blood monocyte recruitment into the lungs. CCR5 is a monocyte chemokine receptor regulated by interleukin-6 (IL-6); the concentration of CCR5 ligands are known to be elevated in COPD lungs. The objective of this study was to investigate mechanisms of monocyte recruitment to the lung in COPD, including the role of CCR5 signalling. Methods Ninety one COPD patients, 29 smokers (S) and 37 non-smokers (NS) underwent sputum induction, plasma sampling (to measure IL-6 and soluble IL-6 receptor [sIL-6R] by immunoassay), monocyte characterization (by flow cytometry) and monocyte isolation for cell migration and quantitative polymerase chain reaction studies. Lung tissue was used for immunohistochemistry. Results Plasma IL-6 and sIL-6R levels were increased in COPD. Greater proportions of COPD CD14++CD16+ monocytes expressed CCR5 compared to controls. Monocyte stimulation with IL-6 and sIL-6R increased CCR5 gene expression. COPD monocytes demonstrated impaired migration towards sputum supernatant compared to NS (% migration, 4.4 vs 11.5, respectively; p < 0.05). Pulmonary microvessels showed reduced monocyte recruitment (% marginated cells) in COPD compared to NS, (9.3% vs 83.1%, respectively). The proportion of replicating Ki67+ alveolar macrophages was reduced in COPD compared to NS. All alveolar macrophages from COPD and S expressed the anti-apoptosis marker BCL2; this protein was not present in non-smokers or COPD ex-smokers. Conclusion COPD monocytes show decreased migratory ability despite increased CCR5 expression. Increased COPD lung macrophage numbers may be due to delayed apoptosis. Electronic supplementary material The online version of this article (doi:10.1186/s12931-017-0569-y) contains supplementary material, which is available to authorized users.
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13
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Chen NC, Partridge AT, Sell C, Torres C, Martín-García J. Fate of microglia during HIV-1 infection: From activation to senescence? Glia 2016; 65:431-446. [PMID: 27888531 DOI: 10.1002/glia.23081] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 09/12/2016] [Accepted: 09/20/2016] [Indexed: 12/14/2022]
Abstract
Microglia support productive human immunodeficiency virus type 1 (HIV-1) infection and disturbed microglial function could contribute to the development of HIV-associated neurocognitive disorders (HAND). Better understanding of how HIV-1 infection and viral protein exposure modulate microglial function during the course of infection could lead to the identification of novel therapeutic targets for both the eradication of HIV-1 reservoir and treatment of neurocognitive deficits. This review first describes microglial origins and function in the normal central nervous system (CNS), and the changes that occur during aging. We then critically discuss how HIV-1 infection and exposure to viral proteins such as Tat and gp120 affect various aspects of microglial homeostasis including activation, cellular metabolism and cell cycle regulation, through pathways implicated in cellular stress responses including p38 mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB). We thus propose that the functions of human microglia evolve during both healthy and pathological aging. Aging-associated dysfunction of microglia comprises phenotypes resembling cellular senescence, which could contribute to cognitive impairments observed in various neurodegenerative diseases. In addition, microglia seems to develop characteristics that could be related to cellular senescence post-HIV-1 infection and after exposure to HIV-1 viral proteins. However, despite its potential role as a component of HAND and likely other neurocognitive disorders, microglia senescence has not been well characterized and should be the focus of future studies, which could have high translational relevance. GLIA 2017;65:431-446.
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Affiliation(s)
- Natalie C Chen
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania.,MD/PhD Program, Drexel University College of Medicine, Philadelphia, Pennsylvania.,Molecular and Cell Biology and Genetics Graduate Program, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Andrea T Partridge
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania.,Microbiology and Immunology Graduate Program, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Christian Sell
- Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Claudio Torres
- Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Julio Martín-García
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania.,Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania
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14
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Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, Quintero-Fabián S, Pavón L. Immunomodulatory Effects Mediated by Dopamine. J Immunol Res 2016; 2016:3160486. [PMID: 27795960 PMCID: PMC5067323 DOI: 10.1155/2016/3160486] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/29/2016] [Accepted: 08/08/2016] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.
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Affiliation(s)
- Rodrigo Arreola
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Samantha Alvarez-Herrera
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Gilberto Pérez-Sánchez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Becerril-Villanueva
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Carlos Cruz-Fuentes
- Psychiatric Genetics Department, National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Enrique Octavio Flores-Gutierrez
- National Institute of Psychiatry “Ramón de la Fuente”, Clinical Research Branch, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - María Eugenia Garcés-Alvarez
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
| | - Dora Luz de la Cruz-Aguilera
- Laboratory of Neuroimmunoendocrinology, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Avenida Insurgentes Sur 3877, La Fama, Tlalpan, 14269 Mexico City, Mexico
| | - Emilio Medina-Rivero
- Unidad de Investigación y Desarrollo, Probiomed S.A. de C.V. Cruce de Carreteras Acatzingo-Zumpahuacán S/N, 52400 Tenancingo, MEX, Mexico
| | - Gabriela Hurtado-Alvarado
- Area of Neurosciences, Department of Biology of Reproduction, CBS, Universidad Autonoma Metropolitana, Unidad Iztapalapa, Avenida San Rafael Atlixco No. 186, Colonia Vicentina, Iztapalapa, 09340 Mexico City, Mexico
| | - Saray Quintero-Fabián
- Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Pediatría, Av. del Iman No. 1, Cuarto Piso, 04530 Mexico City, Mexico
| | - Lenin Pavón
- Department of Psychoimmunology, National Institute of Psychiatry “Ramón de la Fuente”, Calzada México-Xochimilco 101, Colonia San Lorenzo Huipulco, Tlalpan, 14370 Mexico City, Mexico
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15
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Kallas E, Huik K, Türk S, Pauskar M, Jõgeda EL, Šunina M, Karki T, Des Jarlais D, Uusküla A, Avi R, Lutsar I. T Cell Distribution in Relation to HIV/HBV/HCV Coinfections and Intravenous Drug Use. Viral Immunol 2016; 29:464-470. [PMID: 27564643 DOI: 10.1089/vim.2016.0057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Intravenous drug use (IDU) is one of the most important transmission routes for blood borne viruses, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). These infections alter the subset distributions of T cells; however, knowledge of such effects during HIV, HBV, and or HCV coinfection is limited. Therefore, we aimed to evaluate any associations between T cell distribution and the presence of HIV, HBV, and HCV coinfections among persons who inject drugs (PWID). Blood samples from 88 Caucasian PWID (mean age 30; 82% male) and 47 age-matched subjects negative for all three infections (mean age of 29; 83% male) were analyzed. The T cell markers CD3, CD4, CD8, CD45RA, CCR7, HLA-DR, and CCR5 were assessed using flow cytometry. Of the PWID, 40% were HIV+HBV+HCV+, 20% HBV+HCV+, 19% HCV+, and 13% negative for all three infections. The HIV+HBV+HCV+ PWID had lower percentages of CD4+ and higher percentages of CD8+ cells compared to triple negative PWID (p < 0.001 in all cases). The only difference between HBV+HCV+ with triple negative PWID was the lower CD4+ cell percentages among the former (52.1% and 58.6%, p = 0.021). Triple negative PWID had higher immune activation and number of CCR5+ cells compared to the controls. We suggest that the altered T cell subset distribution among PWID is mainly triggered by HIV infection and or IDU, while HBV and or HCV seropositivity has minimal additional effects on CD4+ cell distribution.
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Affiliation(s)
- Eveli Kallas
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Kristi Huik
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Silver Türk
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Merit Pauskar
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Ene-Ly Jõgeda
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Marina Šunina
- 2 Department of Immunology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Tõnis Karki
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Don Des Jarlais
- 3 Icahn School of Medicine at Mount Sinai , New York, New York
| | - Anneli Uusküla
- 4 Institute of Family Medicine and Public Health, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Radko Avi
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
| | - Irja Lutsar
- 1 Department of Microbiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu , Tartu, Estonia
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16
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Joseph SB, Arrildt KT, Sturdevant CB, Swanstrom R. HIV-1 target cells in the CNS. J Neurovirol 2015; 21:276-89. [PMID: 25236812 PMCID: PMC4366351 DOI: 10.1007/s13365-014-0287-x] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 08/23/2014] [Accepted: 08/27/2014] [Indexed: 10/24/2022]
Abstract
HIV-1 replication in the central nervous system (CNS) is typically limited by the availability of target cells. HIV-1 variants that are transmitted and dominate the early stages of infection almost exclusively use the CCR5 coreceptor and are well adapted to entering, and thus infecting, cells expressing high CD4 densities similar to those found on CD4+ T cells. While the "immune privileged" CNS is largely devoid of CD4+ T cells, macrophage and microglia are abundant throughout the CNS. These cells likely express CD4 densities that are too low to facilitate efficient entry or allow sustained replication by most HIV-1 isolates. Examination of CNS viral populations reveals that late in disease the CNS of some individuals contains HIV-1 lineages that have evolved the ability to enter cells expressing low levels of CD4 and are well-adapted to entering macrophages. These macrophage-tropic (M-tropic) viruses are able to maintain sustained replication in the CNS for many generations, and their presence is associated with severe neurocognitive impairment. Whether conditions such as pleocytosis are necessary for macrophage-tropic viruses to emerge in the CNS is unknown, and extensive examinations of macrophage-tropic variants have not revealed a genetic signature of this phenotype. It is clear, however, that macrophage tropism is rare among HIV-1 isolates and is not transmitted, but is important due to its pathogenic effects on hosts. Prior to the evolution of macrophage-tropic variants, the viruses that are predominately infecting T cells (R5 T cell-tropic) may infect macrophages at a low level and inefficiently, but this could contribute to the reservoir.
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Affiliation(s)
- Sarah B Joseph
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA,
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17
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Mefford ME, Kunstman K, Wolinsky SM, Gabuzda D. Bioinformatic analysis of neurotropic HIV envelope sequences identifies polymorphisms in the gp120 bridging sheet that increase macrophage-tropism through enhanced interactions with CCR5. Virology 2015; 481:210-22. [PMID: 25797607 DOI: 10.1016/j.virol.2015.01.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 12/17/2013] [Accepted: 01/28/2015] [Indexed: 10/23/2022]
Abstract
Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.
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Affiliation(s)
- Megan E Mefford
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Kevin Kunstman
- Northwestern University Medical School, Chicago, IL, USA.
| | | | - Dana Gabuzda
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Neurology (Microbiology and Immunobiology), Harvard Medical School, Boston, MA, USA.
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18
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Gaskill PJ, Yano HH, Kalpana GV, Javitch JA, Berman JW. Dopamine receptor activation increases HIV entry into primary human macrophages. PLoS One 2014; 9:e108232. [PMID: 25268786 PMCID: PMC4182469 DOI: 10.1371/journal.pone.0108232] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 08/25/2014] [Indexed: 01/11/2023] Open
Abstract
Macrophages are the primary cell type infected with HIV in the central nervous system, and infection of these cells is a major component in the development of neuropathogenesis and HIV-associated neurocognitive disorders. Within the brains of drug abusers, macrophages are exposed to increased levels of dopamine, a neurotransmitter that mediates the addictive and reinforcing effects of drugs of abuse such as cocaine and methamphetamine. In this study we examined the effects of dopamine on HIV entry into primary human macrophages. Exposure to dopamine during infection increased the entry of R5 tropic HIV into macrophages, irrespective of the concentration of the viral inoculum. The entry pathway affected was CCR5 dependent, as antagonizing CCR5 with the small molecule inhibitor TAK779 completely blocked entry. The effect was dose-dependent and had a steep threshold, only occurring above 108 M dopamine. The dopamine-mediated increase in entry required dopamine receptor activation, as it was abrogated by the pan-dopamine receptor antagonist flupenthixol, and could be mediated through both subtypes of dopamine receptors. These findings indicate that the effects of dopamine on macrophages may have a significant impact on HIV pathogenesis. They also suggest that drug-induced increases in CNS dopamine may be a common mechanism by which drugs of abuse with distinct modes of action exacerbate neuroinflammation and contribute to HIV-associated neurocognitive disorders in infected drug abusers.
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Affiliation(s)
- Peter J. Gaskill
- Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America
- * E-mail:
| | - Hideaki H. Yano
- Department of Psychiatry and Pharmacology, Columbia University, New York, New York, United States of America
| | - Ganjam V. Kalpana
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
| | - Jonathan A. Javitch
- Department of Psychiatry and Pharmacology, Columbia University, New York, New York, United States of America
| | - Joan W. Berman
- Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America
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Emergence of CD4 independence envelopes and astrocyte infection in R5 simian-human immunodeficiency virus model of encephalitis. J Virol 2014; 88:8407-20. [PMID: 24829360 DOI: 10.1128/jvi.01237-14] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
UNLABELLED Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4(low) cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE). Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.
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Gorry PR, Francella N, Lewin SR, Collman RG. HIV-1 envelope-receptor interactions required for macrophage infection and implications for current HIV-1 cure strategies. J Leukoc Biol 2014; 95:71-81. [PMID: 24158961 PMCID: PMC3868190 DOI: 10.1189/jlb.0713368] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Revised: 10/07/2013] [Accepted: 10/09/2013] [Indexed: 01/25/2023] Open
Abstract
Myeloid cells residing in the CNS and lymphoid tissues are targets for productive HIV-1 replication, and their infection contributes to the pathological manifestations of HIV-1 infection. The Envs can adopt altered configurations to overcome entry restrictions in macrophages via a more efficient and/or altered mechanism of engagement with cellular receptors. This review highlights evidence supporting an important role for macrophages in HIV-1 pathogenesis and persistence, which need to be considered for strategies aimed at achieving a functional or sterilizing cure. We also highlight that the molecular mechanisms underlying HIV-1 tropism for macrophages are complex, involving enhanced and/or altered interactions with CD4, CCR5, and/or CXCR4, and that the nature of these interactions may depend on the anatomical location of the virus.
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Affiliation(s)
- Paul R. Gorry
- Center for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia
- Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia; and
| | - Nicholas Francella
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Sharon R. Lewin
- Center for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia
- Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Ronald G. Collman
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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21
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Dahiya S, Irish BP, Nonnemacher MR, Wigdahl B. Genetic variation and HIV-associated neurologic disease. Adv Virus Res 2013; 87:183-240. [PMID: 23809924 DOI: 10.1016/b978-0-12-407698-3.00006-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte-macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease.
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Affiliation(s)
- Satinder Dahiya
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Bryan P Irish
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Michael R Nonnemacher
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
| | - Brian Wigdahl
- Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
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Gaskill PJ, Calderon TM, Coley JS, Berman JW. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. J Neuroimmune Pharmacol 2013; 8:621-42. [PMID: 23456305 PMCID: PMC4303241 DOI: 10.1007/s11481-013-9443-y] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 02/13/2013] [Indexed: 02/08/2023]
Abstract
Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers.
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Affiliation(s)
- Peter J Gaskill
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
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Liu W, Tang Y, Feng J. Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 2011; 89:141-6. [PMID: 21684291 DOI: 10.1016/j.lfs.2011.05.011] [Citation(s) in RCA: 224] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2011] [Revised: 04/14/2011] [Accepted: 05/26/2011] [Indexed: 10/18/2022]
Abstract
Microglia and astrocytes in the central nervous system are now recognized as active participants in various pathological conditions such as trauma, stroke, or chronic neurodegenerative disorders. Their activation is closely related with the development and severity of diseases. Interestingly, activation of microglia and astrocytes occurs with a spatially and temporarily distinct pattern. The present review explores the cross talk in the process of their activation. Microglia, activated earlier than astrocytes, promote astrocytic activation. On the other hand, activated astrocytes not only facilitate activation of distant microglia, but also inhibit microglial activities. Molecules contributing to their intercommunication include interleukin-1 (IL-1), adenosine triphosphate (ATP), and transforming growth factor beta (TGF-β). A better understanding about the cross talk between activation of microglia and astrocytes would be helpful to elucidate the role of glial cells in pathological conditions, which could accelerate the development of treatment for various diseases.
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Affiliation(s)
- W Liu
- Department of Physiology, College of fundamental Medical Science, Guangzhou University of Chinese Medicine, PR China.
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24
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Freisinger E, Cramer C, Xia X, Murthy SN, Slakey DP, Chiu E, Newsome ER, Alt EU, Izadpanah R. Characterization of hematopoietic potential of mesenchymal stem cells. J Cell Physiol 2010; 225:888-97. [DOI: 10.1002/jcp.22299] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Abstract
HIV entry into CD4(+) cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5Δ32/Δ32 stem cells. However, it was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4(+) T cells at the systemic level as well as in the gut mucosal immune system after CCR5Δ32/Δ32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4(+) T cells contain a high proportion of activated memory CD4(+) T cells, ie, the preferential targets of HIV, and are susceptible to productive infection with CXCR4-tropic HIV. Furthermore, during the process of immune reconstitution, we found evidence for the replacement of long-lived host tissue cells with donor-derived cells, indicating that the size of the viral reservoir has been reduced over time. In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient.
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Richards KH, Aasa-Chapman MM, McKnight A, Clapham PR. Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies. Retrovirology 2010; 7:48. [PMID: 20507591 PMCID: PMC2890664 DOI: 10.1186/1742-4690-7-48] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2010] [Accepted: 05/27/2010] [Indexed: 11/10/2022] Open
Abstract
HIV-1 R5 viruses vary widely in their capacity to infect primary macrophages. R5 macrophage-tropism is associated with an increased envelope:CD4 affinity that partly results from an increased exposure of CD4 contact residues on gp120 and allows the use of low levels of CD4 for infection. The selective pressures in vivo that modulate R5 macrophage-tropism are not understood. It is possible that different R5 variants adapt for replication in either T-cells (high CD4) or in macrophages (low CD4). However, other selective pressures in vivo (e.g. neutralizing antibodies) may also impact R5 tropism. Here, we measured macrophage infectivity conferred by gp120 sequences amplified sequentially from subjects in London followed from the acute stage of infection. We report wide variation in the capacity of these envelopes to confer macrophage infection in the complete absence of both autologous and heterologous neutralizing antibodies. Our data show that the variation in macrophage tropism observed at early times cannot have been influenced by neutralizing antibodies.
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Affiliation(s)
- Kathryn H Richards
- Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Biotech 2, 373 Plantation Street, Worcester, MA 01605, USA
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Jakobsen MR, Ellett A, Churchill MJ, Gorry PR. Viral tropism, fitness and pathogenicity of HIV-1 subtype C. Future Virol 2010. [DOI: 10.2217/fvl.09.77] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The majority of studies on HIV-1 pathogenesis have been conducted on subtype B HIV-1 (B-HIV) strains. However, B-HIV strains constitute the minority of HIV-1 cases worldwide, and are not common in regions that stand to benefit the most from advances in HIV-1 research such as southern Africa and Asia, where the HIV-1 pandemic is at its worst. The majority of individuals with HIV-1 are infected with subtype C HIV-1 (C-HIV) and reside in Southern Africa and Central Asia. Relatively little is known about C-HIV, but current evidence suggests the pathogenesis of C-HIV is distinct from B-HIV and other HIV-1 subtypes. This article summarizes what is currently known about the viral tropism, fitness and pathogenicity of C-HIV, and compares and contrasts these features to B-HIV. A thorough understanding of the molecular pathogenesis of C-HIV is important for a targeted approach to developing vaccines and novel drugs optimized for effectiveness in populations that are most in need.
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Affiliation(s)
- Martin R Jakobsen
- Centre for Virology, Burnet Institute, Melbourne, Victoria, Australia and Department of Infectious Diseases, Aarhus University Hospital, Skejby, Brendstrupgaardvej 100, 8200 Aarhus N, Denmark
| | - Anne Ellett
- Centre for Virology, Burnet Institute, Melbourne, Victoria, Australia
| | - Melissa J Churchill
- Centre for Virology, Burnet Institute, Melbourne, Victoria, Australia and Department of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Paul R Gorry
- Centre for Virology, Burnet Institute, Melbourne, Victoria, Australia and Department of Medicine, Monash University, Melbourne, Victoria, Australia and Department of Microbiology & Immunology, University of Melbourne, Melbourne, Victoria, Australia
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Almolda B, Costa M, Montoya M, González B, Castellano B. CD4 microglial expression correlates with spontaneous clinical improvement in the acute Lewis rat EAE model. J Neuroimmunol 2009; 209:65-80. [DOI: 10.1016/j.jneuroim.2009.01.026] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2008] [Revised: 01/27/2009] [Accepted: 01/27/2009] [Indexed: 02/04/2023]
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Dash PK, Siddappa NB, Mangaiarkarasi A, Mahendarkar AV, Roshan P, Anand KK, Mahadevan A, Satishchandra P, Shankar SK, Prasad VR, Ranga U. Exceptional molecular and coreceptor-requirement properties of molecular clones isolated from an Human Immunodeficiency Virus Type-1 subtype C infection. Retrovirology 2008; 5:25. [PMID: 18328091 PMCID: PMC2292743 DOI: 10.1186/1742-4690-5-25] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2007] [Accepted: 03/07/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The pathogenic significance of coreceptor switch in the viral infection of HIV-1 is not completely understood. This situation is more complex in subtype C infection where coreceptor switch is either absent or extremely rare. To gain insights into the mechanisms that underlie coreceptor requirement of subtype C, we screened several primary viral isolates and identified a clinical sample that demonstrated a potential to grow on standard T-cell lines with no detectable CCR5 expression. The subject was diagnosed with HIV-1 associated dementia in the absence of opportunistic infections of the brain. To isolate molecular clones from this virus, we devised a novel strategy based on anchor primers that target a sequence in the reverse transcriptase, highly conserved among diverse subtypes of HIV-1. RESULTS Using this strategy, we isolated 8 full-length molecular clones from the donor. Two of the eight molecular clones, 03In94_D17 and 03In94_D24, (D17 and D24) generated replication-competent viruses. Phylogenetic analysis of the full-length viral sequences revealed that both clones were non-recombinant subtype C viruses. They contain intact open reading frames in all the viral proteins. Both the viral clones are endowed with several unique molecular and biological properties. The viral promoter of the clones is characterized by the presence of four NF-kB binding elements, a feature rarely seen in the subtype C HIV-1 LTR. Interestingly, we identified the coexistence of two different forms of Rev, a truncated form common to subtype C and a full-length form less common for this subtype, in both proviral and plasma virus compartments. An exceptional property of the viruses, atypical of subtype C, is their ability to use a wide range of coreceptors including CCR5, CXCR4, and several others tested. Sequence analysis of Env of D17 and D24 clones identified differences within the variable loops providing important clues for the expanded coreceptor use. The V1, V2 and V4 loops in both of the molecular clones are longer due to the insertion of several amino acid residues that generated potential N-linked glycosylation sites. CONCLUSION The exceptional biological and molecular properties of these clones make them invaluable tools to understand the unique pathogenic characteristics of subtype C.
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Affiliation(s)
- Prasanta K Dash
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Nagadenahalli B Siddappa
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
- Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, JFB-809, Boston, MA 02115-6084, USA
| | - Asokan Mangaiarkarasi
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Aruna V Mahendarkar
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Padmanabhan Roshan
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Krishnamurthy Kumar Anand
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
| | - Anita Mahadevan
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | | | - Susarla K Shankar
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Vinayaka R Prasad
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Udaykumar Ranga
- Molecular Virology Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
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Differentiation of monocytes into CD1a- dendritic cells correlates with disease progression in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 46:519-28. [PMID: 18043312 DOI: 10.1097/qai.0b013e31815b1278] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Monocyte differentiation into dendritic cells (DCs) depends on microenvironmental conditions. In this study, the capacity of human monocytes to differentiate into mature DCs and their ability to induce an antiviral immune response was investigated in HIV-infected patients. In healthy subjects, monocytes differentiate into CD1a+ DCs in the presence of granulocyte macrophage colony-stimulating factor and interleukin (IL)-4 and matured in the presence of lipopolysaccharide. Here, we found that in 30% and 45% of HIV-infected white and African subjects, respectively, monocytes gave rise to a homogeneous CD1a* DC population. In the patients who gave rise only to the CD1a* DCs, this population spontaneously produced IL-10 but not IL-12, and induced a T helper 2-like immune response when cultured with human T cells isolated from cord blood mononuclear cells. In patients with monocytes differentiated into CD1a* DCs, a high percentage of HIV-specific CD4 T cells producing IL-4 were seen in the peripheral blood. Furthermore, differentiation of monocytes into DCs with CD1a* phenotype correlated with low CD4 T-cell counts and high viral loads in HIV-infected subjects. These results suggest that the differentiation of monocytes into CD1a* DCs may be a phenotypic marker associated with progression of the disease.
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Abstract
BACKGROUND During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. RESULTS We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics. CONCLUSION The results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.
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Affiliation(s)
- Luca Sguanci
- CSDC, Center for the Study of Complex Systems, Firenze, Italy
- Computer Laboratory, University of Cambridge, CB3 0FD Cambridge, UK
| | - Franco Bagnoli
- CSDC, Center for the Study of Complex Systems, Firenze, Italy
- Dipartimento di Energetica, Università di Firenze, Via S. Marta 3, 50139 Firenze, Italy
- INFN, sezione di Firenze, Italy
| | - Pietro Liò
- Computer Laboratory, University of Cambridge, CB3 0FD Cambridge, UK
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Dunfee RL, Thomas ER, Wang J, Kunstman K, Wolinsky SM, Gabuzda D. Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia. Virology 2007; 367:222-34. [PMID: 17599380 PMCID: PMC2201988 DOI: 10.1016/j.virol.2007.05.029] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2007] [Revised: 05/14/2007] [Accepted: 05/23/2007] [Indexed: 11/17/2022]
Abstract
HIV infects macrophages and microglia in the central nervous system (CNS). Mechanisms that enhance HIV macrophage/microglial tropism are not well understood. Here, we identify an HIV Env variant in the V4 region of gp120, Asp 386 (D386), that eliminates an N-linked glycosylation site at position 386, enhances viral replication in macrophages, and is present at a higher frequency in AIDS patients with HIV-associated dementia (HAD) compared with non-HAD patients. D386 enhances HIV entry and replication in macrophages but not in microglia or peripheral blood mononuclear cells, possibly due to differential glycosylation in these cell types. A D386N mutation in the UK1br Env, which restores the N-linked glycan site, reduced neutralization sensitivity to the IgG1b12 (b12) monoclonal antibody, which recognizes a conserved neutralization epitope that overlaps the CD4 binding site. Molecular modeling suggested that loss of the glycan at position 386 increases exposure of the CD4 and b12 binding sites on gp120. Loss of a glycan at 386 was more frequent in Envs from HAD patients (26%; n=185) compared with non-HAD patients (7%; n=99; p<0.001). The most significant association of these Env variants with HAD was in blood or lymphoid tissue rather than brain. These findings suggest that increased exposure of the b12 epitope overlapping the CD4 binding site via elimination of a glycan at position 386 is associated with enhanced HIV macrophage tropism, and provide evidence that determinants of macrophage and microglia tropism are overlapping but distinct.
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Affiliation(s)
- Rebecca L. Dunfee
- Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Elaine R. Thomas
- Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Jianbin Wang
- Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Kevin Kunstman
- Department of Medicine, Northwestern University Medical School, Chicago, IL, USA
| | - Steven M. Wolinsky
- Department of Medicine, Northwestern University Medical School, Chicago, IL, USA
| | - Dana Gabuzda
- Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Boston, MA, USA
- Corresponding Author. Mailing Address: Dana-Farber Cancer Institute, JFB 816, 44 Binney St., Boston, MA 02115, Phone: (617) 632-2154, Fax: (617) 632 3113, E-mail:
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Price P, Keane N, Gray L, Lee S, Gorry PR, French MA. CXCR4 or CCR5 tropism of human immunodeficiency virus type 1 isolates does not determine the immunological milieu in patients responding to antiretroviral therapy. Viral Immunol 2007; 19:734-40. [PMID: 17201668 DOI: 10.1089/vim.2006.19.734] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Here we address whether CCR5 or CXCR4 tropism of the predominant viral strain detected before or on combination antiretroviral therapy (ART) explains why some human immunodeficiency virus (HIV)-infected patients who begin ART with advanced HIV disease retain low interferon (IFN)-gamma responses, despite recovery of CD4(+) T cell counts. Tropism was determined by culture and confirmed by gp120 V3 loop sequence of multiple plasma samples in eight adult male patients who began treatment with <50 CD4(+) T cells/microL. Four patients had mixed infections, one had only R5 HIV, and three had only X4 HIV. Of these, two carried CCR5Delta32. Viral tropism was not related to CD4(+) T cell counts or HIV RNA levels. When immunological responses were monitored over several years, IFN-gamma responses to cytomegalovirus were below the median value of uninfected controls and similar in patients with R5, X4, or mixed infection. Interleukin-5 responses were low and plasma soluble CD30 levels were high at treatment onset, but resolved with control of HIV replication irrespective of HIV tropism. Levels of LAG-3 (lymphocyte activation gene-3 protein) were elevated in patients with uncontrolled HIV replication. Hence the immunological milieu did not reflect HIV tropism.
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Affiliation(s)
- Patricia Price
- School of Surgery and Pathology, University of Western Australia, Perth, WA, Australia.
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Kremlev SG, Roberts RL, Palmer C. Minocycline modulates chemokine receptors but not interleukin-10 mRNA expression in hypoxic-ischemic neonatal rat brain. J Neurosci Res 2007; 85:2450-9. [PMID: 17549754 DOI: 10.1002/jnr.21380] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hypoxic-ischemic (HI) brain injury in the perinatal period causes significant morbidity. Minocycline (MN) is a tetracycline derivative that has reduced brain injury in various animal models of neurodegeneration, including perinatal ischemia. To determine whether MN can modulate the expression of chemokine receptors and interleukin-10 (IL10) in a model of neonatal brain injury, we produced an HI insult to the right cerebral hemisphere (ipsilateral) of the 7-day-old rat (PD7) by right common carotid artery ligation and 2.25 hr of hypoxia in 8% oxygen. MN (45 mg/kg, i.p.) or vehicle (PBS) was injected twice: 2 days and immediately before the HI insult. At 0, 1, 3, and 24 hr and 14 days after HI, total RNA from the ipsilateral and contralateral (exposed to hypoxia only) hemispheres was extracted, reverse transcribed, and amplified with gene-specific primers using a semiquantitative RT-PCR for macrophage inflammatory protein-1alpha), interferon-inducible protein (IP-10), C-C chemokine receptor 5 (CCR5; MIP-1alpha receptor), C-X-C chemokine receptor 3 (CXCR3; IP-10 receptor), and IL10. We found that, in the ipsilateral hemisphere, a significant (P < 0.05) increase in MIP-1alpha, IP-10, CCR5, and CXCR3 mRNA levels was observed. MN treatment decreased mRNA levels for CCR5 and CXCR3. In contrast, the levels of antiinflammatory cytokine IL10 were markedly decreased as a result of HI insult. Treatment with MN, however, had no effect on IL10. We conclude that MN decreased proinflammatory chemokine receptor expression but had little or no influence on the expression of antiinflammatory cytokine IL10. These effects confirm the antiinflammatory effect of MN in neonatal HI brain injury.
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Affiliation(s)
- Sergey G Kremlev
- The Milton S. Hershey Medical Center, The College of Medicine, Hershey, Pennsylvania 19122, USA.
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Thomas ER, Dunfee RL, Stanton J, Bogdan D, Taylor J, Kunstman K, Bell JE, Wolinsky SM, Gabuzda D. Macrophage entry mediated by HIV Envs from brain and lymphoid tissues is determined by the capacity to use low CD4 levels and overall efficiency of fusion. Virology 2006; 360:105-19. [PMID: 17084877 PMCID: PMC1890014 DOI: 10.1016/j.virol.2006.09.036] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2006] [Revised: 08/28/2006] [Accepted: 09/22/2006] [Indexed: 01/09/2023]
Abstract
HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.
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Affiliation(s)
- Elaine R. Thomas
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rebecca L. Dunfee
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Derek Bogdan
- Northwestern University Medical School, Chicago, IL, USA
| | - Joann Taylor
- Northwestern University Medical School, Chicago, IL, USA
| | - Kevin Kunstman
- Northwestern University Medical School, Chicago, IL, USA
| | - Jeanne E. Bell
- Department of Pathology, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | | | - Dana Gabuzda
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Boston, MA, USA
- *Corresponding Author. Mailing Address: Dana-Farber Cancer Institute, JFB 816 44 Binney St. Boston, MA 02115 Phone: (617) 632-2154 Fax: (617) 632 3113 E-mail:
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Peters PJ, Dueñas-Decamp MJ, Sullivan WM, Clapham PR. Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues. J Neuroimmune Pharmacol 2006; 2:32-41. [PMID: 18040824 DOI: 10.1007/s11481-006-9042-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2006] [Accepted: 08/15/2006] [Indexed: 11/30/2022]
Abstract
Human immunodeficiency virus (HIV)-positive individuals frequently suffer from progressive encephelopathy, which is characterized by sensory neuropathy, sensory myelopathy, and dementia. Our group and others have reported the presence of highly macrophage-tropic R5 variants of HIV-1 in brain tissue of patients with neurological complications. These variants are able to exploit low amounts of CD4 and/or CCR5 for infection and potentially confer an expanded tropism for any cell types that express low CD4 and/or CCR5. In contrast to the brain-derived envelopes, we found that envelopes from lymph node tissue, blood, or semen were predominantly non-macrophage-tropic and required high amounts of CD4 for infection. Nevertheless, where tested, the non-macrophage-tropic envelopes conferred efficient replication in primary CD4(+) T-cell cultures. Determinants of R5 macrophage tropism appear to involve changes in the CD4 binding site, although further unknown determinants are also involved. The variation of R5 envelopes also affects their sensitivity to inhibition by ligands and entry inhibitors that target CD4 and CCR5. In summary, HIV-1 R5 viruses vary extensively in macrophage tropism. In the brain, highly macrophage-tropic variants may represent neurotropic or neurovirulent viruses. In addition, variation in R5 macrophage tropism may also have implications (1) for transmission, depending on what role macrophages or cells that express low CD4 and/or CCR5 play in the establishment of infection in a new host, and (2) for pathogenesis and depletion of CD4(+) T cells (i.e., do highly macrophage-tropic variants confer a broader tropism among CD4(+) T-cell populations late in disease and contribute to their depletion?).
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Affiliation(s)
- Paul J Peters
- Center for AIDS Research, Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 373 Plantation Street Biotech II Suite 315, Worcester, MA 01605, USA
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Dunfee RL, Thomas ER, Gorry PR, Wang J, Taylor J, Kunstman K, Wolinsky SM, Gabuzda D. The HIV Env variant N283 enhances macrophage tropism and is associated with brain infection and dementia. Proc Natl Acad Sci U S A 2006; 103:15160-5. [PMID: 17015824 PMCID: PMC1586182 DOI: 10.1073/pnas.0605513103] [Citation(s) in RCA: 138] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Indexed: 11/18/2022] Open
Abstract
HIV infects tissue macrophages and brain microglia, which express lower levels of CD4 and CCR5 than CD4+ T cells in peripheral blood. Mechanisms that enhance HIV tropism for macrophages in the CNS and other tissues are not well understood. Here, we identify an HIV envelope glycoprotein (Env) variant in the CD4-binding site of gp120, Asn 283 (N283), that is present at a high frequency in brain tissues from AIDS patients with HIV-associated dementia (HAD). N283 increases gp120 affinity for CD4 by decreasing the gp120-CD4 dissociation rate, enhancing the capacity of HIV Envs to use low levels of CD4 for virus entry and increasing viral replication in macrophages and microglia. Structural modeling suggests that the enhanced ability of Envs with N283 to use low levels of CD4 is due to a hydrogen bond formed with Gln 40 of CD4. N283 is significantly more frequent in brain-derived Envs from HAD patients (41%; n=330) compared with non-HAD patients (8%; n=151; P<0.001). These findings suggest that the macrophage-tropic HIV Env variant N283 is associated with brain infection and dementia in vivo, representing an example of a HIV variant associated with a specific AIDS-related complication.
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Affiliation(s)
- Rebecca L. Dunfee
- *Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
- Departments of Pathology and
| | - Elaine R. Thomas
- *Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
- Departments of Pathology and
| | - Paul R. Gorry
- *Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
- Departments of Pathology and
| | - Jianbin Wang
- *Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
- Departments of Pathology and
| | - Joann Taylor
- Department of Medicine, Northwestern University Medical School, Chicago, IL 60611
| | - Kevin Kunstman
- Department of Medicine, Northwestern University Medical School, Chicago, IL 60611
| | - Steven M. Wolinsky
- Department of Medicine, Northwestern University Medical School, Chicago, IL 60611
| | - Dana Gabuzda
- *Department of Cancer Immunology and AIDS, Dana–Farber Cancer Institute, Boston, MA 02115
- Neurology, Harvard Medical School, Boston, MA 02115; and
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Chen MF, Westmoreland S, Ryzhova EV, Martín-García J, Soldan SS, Lackner A, González-Scarano F. Simian immunodeficiency virus envelope compartmentalizes in brain regions independent of neuropathology. J Neurovirol 2006; 12:73-89. [PMID: 16798669 DOI: 10.1080/13550280600654565] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) gp160s obtained from the brain are often genetically distinct from those isolated from other organs, suggesting the presence of brain-specific selective pressures or founder effects that result in the compartmentalization of viral quasi-species. Whereas HIV has also been found to compartmentalize within different regions of the brain, the extent of brain-regional compartmentalization of SIV in rhesus macaques has not been characterized. Furthermore, much is still unknown about whether phenotypic differences exist in envelopes from different brain regions. To address these questions, env DNA sequences were amplified from four SIVmac239-infected macaques and subjected to phylogenetic and phenetic analysis. The authors demonstrated that sequences from different areas of the brain form distinct clades, and that the long-term progressing macaques demonstrated a greater degree of regional compartmentalization compared to the rapidly progressing macaques. In addition, regional compartmentalization occurred regardless of the presence of giant-cell encephalitis. Nucleotide substitution rates at synonymous and nonsynonymous sites (ds:dn rates) indicated that positive selection varied among envelopes from different brain regions. In one macaque, envelopes from some but not all brain regions acquired changes in a conserved CD4-binding motif GGGDPE at amino acids 382 to 387. Furthermore, gp160s with the mutation G383E were able to mediate cell-to-cell fusion in a CD4-independent manner and were more susceptible to fusion inhibition by pooled plasma from infected macaques. Reversion of this mutation by site-directed mutagenesis resulted in reduction of CD4-independence and resistance to fusion inhibition in cell fusion assays. These studies demonstrate that SIV evolution within the brain results in a heterogeneous viral population with different phenotypes among different regions.
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Affiliation(s)
- Maria F Chen
- Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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Lambotte O, Deiva K, Tardieu M. HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era. Brain Pathol 2006; 13:95-103. [PMID: 12580549 PMCID: PMC8095761 DOI: 10.1111/j.1750-3639.2003.tb00010.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
HAART therapy has led to a significant reduction of general and neurological morbidity, and mortality among HIV-1 infected patients. It can also decrease HIV-1 RNA titres in plasma and CSF towards undetectable level. However, the initial hope of achieving total eradication of the virus from the body has vanished. Even in patients who do not develop viral resistance or treatment intolerance, two kinds of viral persistence have been demonstrated both in lymphoid and central nervous system. The first one is a smoldering infection that persists, despite prolonged and apparently efficient HAART, in monocytes, tissue macrophages and most probably microglia. The second one is an integration of proviral DNA in the genome of subpopulations of CD4 lymphocytes of patients receiving efficient HAART. A similar viral integration in astrocytes and less likely in resting microglia is suggested by several studies, although it has yet to be demonstrated conclusively.
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Affiliation(s)
- Olivier Lambotte
- Laboratoire—Immunité antivirale systémique et cérébrale—Equipe Mixte INSERM et Université Paris Sud N° 0109 et Hôpital Bicêtre Assistance Publique‐Hôpitaux de Paris, France
| | - Kumaran Deiva
- Laboratoire—Immunité antivirale systémique et cérébrale—Equipe Mixte INSERM et Université Paris Sud N° 0109 et Hôpital Bicêtre Assistance Publique‐Hôpitaux de Paris, France
| | - Marc Tardieu
- Laboratoire—Immunité antivirale systémique et cérébrale—Equipe Mixte INSERM et Université Paris Sud N° 0109 et Hôpital Bicêtre Assistance Publique‐Hôpitaux de Paris, France
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40
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Cowell RM, Xu H, Parent JM, Silverstein FS. Microglial expression of chemokine receptor CCR5 during rat forebrain development and after perinatal hypoxia–ischemia. J Neuroimmunol 2006; 173:155-65. [PMID: 16516309 DOI: 10.1016/j.jneuroim.2006.01.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2005] [Revised: 01/07/2006] [Accepted: 01/09/2006] [Indexed: 11/16/2022]
Abstract
The chemokine macrophage inflammatory protein 1alpha (CCL3) is expressed by immune cells in the normal and injured perinatal brain. To determine whether the chemokine receptor CCR5 is a relevant target for CCL3 in the brain, we used RT-PCR and immunocytochemistry to assess changes in CCR5 expression and localization in developing normal and injured rat forebrain. CCR5 protein was expressed predominately by resting and activated microglia until 2 weeks of age. Neonatal hypoxia-ischemia increased CCR5 mRNA expression while causing CCR5 internalization, indicating receptor activation. These data implicate CCR5 in microglial recruitment and activation during brain development and after neonatal brain injury.
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Affiliation(s)
- Rita M Cowell
- Department of Neurology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
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41
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Priami C. Modeling Evolutionary Dynamics of HIV Infection. COMPUTATIONAL METHODS IN SYSTEMS BIOLOGY 2006. [PMCID: PMC7119952 DOI: 10.1007/11885191_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
We have modelled the within-patient evolutionary process during HIV infection. We have studied viral evolution at population level (competition on the same receptor) and at species level (competitions on different receptors). During the HIV infection, several mutants of the virus arise, which are able to use different chemokine receptors, in particular the CCR5 and CXCR4 coreceptors (termed R5 and X4 phenotypes, respectively). Phylogenetic inference of chemokine receptors suggests that virus mutational pathways may generate R5 variants able to interact with a wide range of chemokine receptors different from CXCR4. Using the chemokine tree topology as conceptual framework for HIV viral speciation, we present a model of viral phenotypic mutations from R5 to X4 strains which reflect HIV late infection dynamics. Our model investigates the action of Tumor Necrosis Factor in AIDS progression and makes suggestions on better design of HAART therapy.
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Affiliation(s)
- Corrado Priami
- Centre for Computational and Systems Biology, The Microsoft Research - University of Trento, Piazza Manci, 17, 38050 Povo, (TN) Italy
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42
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Gallagher M, Malhotra I, Mungai PL, Wamachi AN, Kioko JM, Ouma JH, Muchiri E, King CL. The effects of maternal helminth and malaria infections on mother-to-child HIV transmission. AIDS 2005; 19:1849-55. [PMID: 16227793 DOI: 10.1097/01.aids.0000189846.90946.5d] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE To investigate the effect of helminth and/or malaria infection on the risk of HIV infection in pregnant women and its transmission to their offspring. DESIGN A retrospective cohort study of pregnant Kenyan women and their offspring from term, uncomplicated vaginal deliveries (n = 936) with a nested case-control study. METHODS We determined the presence of HIV, malaria, schistosomiasis, lymphatic filariasis, and intestinal helminthes in mothers and tested for HIV antibodies in 12-24 month-old offspring of HIV-positive women. We related these findings to the presence of cord blood lymphocyte activation and cytokine production in response to helminth antigens. RESULTS HIV-positive women (n = 83, 8.9% of all women tested) were 2-fold more likely to have peripheral blood and/or placental malaria (P < 0.025) and a 2.1-fold greater likelihood of lymphatic filariasis infection (P < 0.001) compared to location-and-parity matched HIV-negative women. Women with HIV and malaria tended to show an increased risk for mother-to-child-transmission (MTCT) of HIV, although this difference was not significant. MTCT of HIV, however, was significantly higher in women co-infected with one or more helminthes (48%) verses women without helminth infections (10%, P < 0.01; adjusted odds ratio, 7.3; 95% confidence interval, 2.4-33.7). This increased risk for MTCT of HIV correlated with cord blood lymphocytes production of interleukin-5/interleukin-13 in response to helminth antigens (P < 0.001). CONCLUSION Helminth co-infection is associated with increased risk for MTCT of HIV, possibly by a mechanism in which parasite antigens activates lymphocytes in utero. Treatment of helminthic infections during pregnancy may reduce the risk of MTCT of HIV.
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Affiliation(s)
- Maureen Gallagher
- Center for Global Health and Diseases and Center for AIDS Research, Case Western Reserve University, Cleveland, OH 44106-7286, USA
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Musso T, Cappello P, Stornello S, Ravarino D, Caorsi C, Otero K, Novelli F, Badolato R, Giovarelli M. IL-10 enhances CCL2 release and chemotaxis induced by CCL16 in human monocytes. Int J Immunopathol Pharmacol 2005; 18:339-49. [PMID: 15888256 DOI: 10.1177/039463200501800216] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.
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Affiliation(s)
- T Musso
- Department of Public Health and Microbiology, University of Turin, Italy
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Gray L, Sterjovski J, Churchill M, Ellery P, Nasr N, Lewin SR, Crowe SM, Wesselingh SL, Cunningham AL, Gorry PR. Uncoupling coreceptor usage of human immunodeficiency virus type 1 (HIV-1) from macrophage tropism reveals biological properties of CCR5-restricted HIV-1 isolates from patients with acquired immunodeficiency syndrome. Virology 2005; 337:384-98. [PMID: 15916792 DOI: 10.1016/j.virol.2005.04.034] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2005] [Revised: 04/18/2005] [Accepted: 04/27/2005] [Indexed: 11/23/2022]
Abstract
The mechanisms underlying the pathogenicity of CCR5-restricted (R5) human immunodeficiency virus type-1 (HIV-1) strains are incompletely understood. Acquisition or enhancement of macrophage (M)-tropism by R5 viruses contributes to R5 HIV-1 pathogenesis. In this study, we show that M-tropic R5 viruses isolated from individuals with acquired immunodeficiency syndrome (late R5 viruses) require lower levels of CD4/CCR5 expression for entry, have decreased sensitivity to inhibition by the entry inhibitors TAK-779 and T-20, and have increased sensitivity to neutralization by the Env MAb IgG1b12 compared with non-M-tropic R5 viruses isolated from asymptomatic, immunocompetent individuals (early R5 viruses). Augmenting CCR5 expression levels on monocyte-derived macrophages via retroviral transduction led to a complete or marginal restoration of M-tropism by early R5 viruses, depending on the viral strain. Thus, reduced CD4/CCR5 dependence is a phenotype of R5 HIV-1 associated with M-tropism and late stage infection, which may affect the efficacy of HIV-1 entry inhibitors.
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Affiliation(s)
- Lachlan Gray
- Macfarlane Burnet Institute for Medical Research and Public Health, GPO Box 2284, Melbourne, 3001 Victoria, Australia; Department of Microbiology and Immunology, University of Melbourne, Victoria, Australia
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Smith MS, Niu Y, Buch S, Li Z, Adany I, Pinson DM, Potula R, Novembre FJ, Narayan O. Active simian immunodeficiency virus (strain smmPGm) infection in macaque central nervous system correlates with neurologic disease. J Acquir Immune Defic Syndr 2005; 38:518-30. [PMID: 15793361 DOI: 10.1097/01.qai.0000156395.65562.99] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Simian immunodeficiency virus strain smmPGm can induce neuropathology in macaques and is a model for the development of human HIV-related brain injury. For quantitative studies of proviral presence and expression in the central nervous system (CNS), we inoculated 8 macaques intravenously with the virus. Three animals were necropsied 2 to 4 weeks after development of infection, and we obtained lymphoid tissue biopsies from 5 animals before 5 weeks after infection. Peak plasma viral loads averaged 10 viral RNA Eq/mL at week 2, whereas cerebrospinal fluid viral loads peaked at 10 viral RNA Eq/mL. The proviral DNA loads and viral gag mRNA expression in tissues were quantified by real-time polymerase chain reaction. Two animals developed neurologic disease characterized by meningoencephalitis and meningitis. Proviral DNA levels in CNS tissues of these animals at necropsy revealed 10 and 10 copies/microg of DNA, respectively, whereas viral RNA expression in the CNS reached 100 to 1000 times higher levels than those seen in early necropsies. In sharp contrast, in 2 animals necropsied at later times without CNS disease, virus mRNA expression was not detected in any CNS tissue. Our results are consistent with the hypothesis that active virus expression in the CNS is strongly correlated with neurologic disease and that the event occurs at variable periods after infection.
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Affiliation(s)
- Marilyn S Smith
- Marion Merrell Dow Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA.
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Speth C, Dierich MP, Sopper S. HIV-infection of the central nervous system: the tightrope walk of innate immunity. Mol Immunol 2005; 42:213-28. [PMID: 15488609 DOI: 10.1016/j.molimm.2004.06.018] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Infection of the central nervous system (CNS) by HIV is a frequent and sometimes very early event in the course of HIV pathogenesis. Possible consequences are diverse symptoms of neurological dysfunction, but also the establishment of a lifelong latent viral reservoir in the brain. Whereas in the periphery innate and adaptive immunity are equal partners, the blood-brain barrier (BBB) with its restricted access of peripheral immune effectors shifts this balance in favour of the local innate immunity. Four main elements of cerebral innate immunity are discussed in the present article, including two cell types with immunological functions and two soluble immune systems: (1) the stimulation of microglial cells as the predominant brain-resident immune cell and the main local reservoir for the virus; (2) the reaction of astrocytes in response to viral infection; (3) the activation of the local complement system as important soluble immune cascade; and (4) the role of chemokines and cytokines which help to conduct and cross-link the interplay between the different immune elements. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. A dual role of these components with both harmful and protective effects further enhances the complexity of the mutual interactions.
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Affiliation(s)
- Cornelia Speth
- Institute of Hygiene and Social Medicine, Medical University Innsbruck and Ludwig-Boltzmann-Institute for AIDS Research, Fritz-Pregl-Str. 3, A-6020 Innsbruck, Austria.
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Choudhary SK, Choudhary NR, Kimbrell KC, Colasanti J, Ziogas A, Kwa D, Schuitemaker H, Camerini D. R5 human immunodeficiency virus type 1 infection of fetal thymic organ culture induces cytokine and CCR5 expression. J Virol 2005; 79:458-71. [PMID: 15596839 PMCID: PMC538709 DOI: 10.1128/jvi.79.1.458-471.2005] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Late-stage CCR5 tropic human immunodeficiency virus type 1 (HIV-1) isolates (R5 HIV-1) can deplete nearly all CD4+ thymocytes from human thymus/liver grafts, despite the fact that fewer than 5% of these cells express CCR5. To resolve this paradox, we studied the replication and cytopathic effects (CPE) of late-stage R5 HIV-1 biological clones from two progressors and two long-term nonprogressors (LTNP) in fetal thymic organ culture (FTOC) with and without added cytokines. We found that R5 HIV-1 clones from progressors but not LTNP were cytopathic in untreated FTOC. Moreover, R5 HIV-1 clones from progressors replicated to higher levels than LTNP-derived R5 HIV-1 clones in this system. In contrast, when FTOC was maintained in the presence of interleukin 2 (IL-2), IL-4, and IL-7, both progressor and LTNP clones exhibited similar replication and CPE, which were equal to or greater than the levels achieved by progressor-derived R5 HIV-1 clones in untreated FTOC. This finding was likely due to IL-2-induced CCR5 expression on CD4+ thymocytes in FTOC. R5 HIV-1 clones showed greater pathogenesis for CCR5+ cells but also showed evidence of CPE on CCR5- cells. Furthermore, infection of FTOC by R5 HIV-1 induced IL-10 and transforming growth factor beta (TGF-beta) expression. Both IL-10 and TGF-beta in turn induced CCR5 expression in FTOC. Induction of CCR5 expression via cytokine induction by R5 HIV-1 infection of CCR5+ thymocytes likely permitted further viral replication in newly CCR5+ thymocytes. CCR5 expression, therefore, is a key determinant of pathogenesis of R5 HIV-1 in FTOC.
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Affiliation(s)
- Shailesh K Choudhary
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California 92697-3900, USA
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Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK. Role of microglia in central nervous system infections. Clin Microbiol Rev 2004; 17:942-64, table of contents. [PMID: 15489356 PMCID: PMC523558 DOI: 10.1128/cmr.17.4.942-964.2004] [Citation(s) in RCA: 512] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed.
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Affiliation(s)
- R Bryan Rock
- Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, and University of Minnesota Medical School, USA
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Peters PJ, Bhattacharya J, Hibbitts S, Dittmar MT, Simmons G, Bell J, Simmonds P, Clapham PR. Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol 2004; 78:6915-26. [PMID: 15194768 PMCID: PMC421670 DOI: 10.1128/jvi.78.13.6915-6926.2004] [Citation(s) in RCA: 156] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Complete envelope genes were amplified from autopsy brain tissue of five individuals who had died of AIDS and had neurological complications. Lymph node samples were included for two of the patients. Nineteen different envelope clones from the five patients had distinct V1V2 sequences. Thirteen of the envelopes were functional and conferred fusigenicity and infectivity for CD4(+) CCR5(+) cells. Infectivity and cell-cell fusion assays showed that most envelopes used both CCR5 and CCR3. One brain-derived envelope used a broad range of coreceptors, while three other brain envelopes from one individual were restricted to CCR5. However, there was no correlation between tissue of origin and coreceptor use. Envelopes showed two very distinct phenotypes depending on their capacity to infect macrophages and to exploit low levels of CD4 and/or CCR5 for infection. Envelopes that were highly fusigenic and tropic for macrophages were identified in brain tissue from four of the five patients. The enhanced macrophage tropism correlated with reduced sensitivity to inhibition by Q4120, a CD4-specific antibody, but not with sensitivity to the CCR5 inhibitor, TAK779. The highly macrophage-tropic envelopes were able to infect cells expressing low levels of CD4 and/or CCR5. Comparison with several well-characterized macrophage-tropic envelopes showed that the four identified patient envelopes were at the top limit of macrophage tropism. In contrast, all four lymph node-derived envelopes exhibited a non-macrophage-tropic phenotype and required high levels of CD4 for infection. Our data support the presence of envelopes that are highly fusigenic and tropic for macrophages in the brains of patients with neurological complications. These envelopes are able to infect cells that express low levels of CD4 and/or CCR5 and may have adapted for replication in brain macrophages and microglia, which are known to express limited amounts of CD4.
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Affiliation(s)
- Paul J Peters
- Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester MA 01605, USA
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Abstract
The development of T helper 1 versus T helper 2 cells is a major branch point in the immune response and is an important determinant of the body’s response to an infectious pathogen, leading to protection of the host or dissemination of the disease. Resent studies have shown that there exist macrophage activation states in parallel to the T helper cell type 1/2 paradigm, and the T helper 1 development process is governed to a great degree by cytokine IL-12 provided mainly by antigen presenting cells such as macrophages and dendritic cells. A model in patients with hepatitis is proposed that links the pathogen, macrophage activation and T helper cell polarization.
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Affiliation(s)
- Qiao-Ling Sun
- Department of Biotechnological Pharmaceutics, Taishan Medical University, Tai'an 271000, Shangdong Province, China.
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