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Cong Z, Xiong Y, Lyu L, Fu B, Guo D, Sha Z, Yang B, Wu H. The relationship between Listeria infections and host immune responses: Listeriolysin O as a potential target. Biomed Pharmacother 2024; 171:116129. [PMID: 38194738 DOI: 10.1016/j.biopha.2024.116129] [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: 10/28/2023] [Revised: 12/31/2023] [Accepted: 01/02/2024] [Indexed: 01/11/2024] Open
Abstract
Listeria monocytogenes (Lm), a foodborne bacterium, can infect people and has a high fatality rate in immunocompromised individuals. Listeriolysin O (LLO), the primary virulence factor of Lm, is critical in regulating the pathogenicity of Lm. This review concludes that LLO may either directly or indirectly activate a number of host cell viral pathophysiology processes, such as apoptosis, pyroptosis, autophagy, necrosis and necroptosis. We describe the invasion of host cells by Lm and the subsequent removal of Lm by CD8 T cells and CD4 T cells upon receipt of the LLO epitopes from major histocompatibility complex class I (MHC-I) and major histocompatibility complex class II (MHC-II). The development of several LLO-based vaccines that make use of the pore-forming capabilities of LLO and the immune response of the host cells is then described. Finally, we conclude by outlining the several natural substances that have been shown to alter the three-dimensional conformation of LLO by binding to particular amino acid residues of LLO, which reduces LLO pathogenicity and may be a possible pharmacological treatment for Lm.
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Affiliation(s)
- Zixuan Cong
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Yan Xiong
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Lyu Lyu
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China
| | - Beibei Fu
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Dong Guo
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Zhou Sha
- School of Life Sciences, Chongqing University, Chongqing 401331, China
| | - Bo Yang
- State Key Laboratory of Veterinary Etiological Biology, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu 730046, China.
| | - Haibo Wu
- School of Life Sciences, Chongqing University, Chongqing 401331, China.
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Arduini A, Laprise F, Liang C. SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19. Viruses 2023; 15:871. [PMID: 37112851 PMCID: PMC10141009 DOI: 10.3390/v15040871] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/26/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023] Open
Abstract
The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and the frequent emergence of variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely to remain endemic, making it critical to understand its viral mechanisms contributing to pathogenesis and discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set of strategies to evade host immunity, accounting for its high pathogenicity and rapid spread throughout the COVID-19 pandemic. Behind some of these critical host evasion strategies is the accessory protein Open Reading Frame 8 (ORF8), which has gained recognition in SARS-CoV-2 pathogenesis due to its hypervariability, secretory property, and unique structure. This review discusses the current knowledge on SARS-CoV-2 ORF8 and proposes actualized functional models describing its pivotal roles in both viral replication and immune evasion. A better understanding of ORF8's interactions with host and viral factors is expected to reveal essential pathogenic strategies utilized by SARS-CoV-2 and inspire the development of novel therapeutics to improve COVID-19 disease outcomes.
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Affiliation(s)
- Ariana Arduini
- Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; (A.A.); (F.L.)
- Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
| | - Frederique Laprise
- Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; (A.A.); (F.L.)
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
| | - Chen Liang
- Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada; (A.A.); (F.L.)
- Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada
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Munusamy Ponnan S, Hayes P, Fernandez N, Thiruvengadam K, Pattabiram S, Nesakumar M, Srinivasan A, Kathirvel S, Shankar J, Goyal R, Singla N, Mukherjee J, Chatrath S, Gilmour J, Subramanyam S, Prasad Tripathy S, Swaminathan S, Hanna LE. Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India. PLoS One 2020; 15:e0229461. [PMID: 32097435 PMCID: PMC7041807 DOI: 10.1371/journal.pone.0229461] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/06/2020] [Indexed: 02/07/2023] Open
Abstract
T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.
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Affiliation(s)
| | - Peter Hayes
- IAVI Human Immunology Laboratory, Imperial College, London, England, United Kingdom
| | - Natalia Fernandez
- IAVI Human Immunology Laboratory, Imperial College, London, England, United Kingdom
| | - Kannan Thiruvengadam
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Sathyamurthi Pattabiram
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Manohar Nesakumar
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Ashokkumar Srinivasan
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Sujitha Kathirvel
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Janani Shankar
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Rajat Goyal
- International AIDS Vaccine Initiative, New Delhi, India
| | - Nikhil Singla
- International AIDS Vaccine Initiative, New Delhi, India
| | | | | | - Jill Gilmour
- IAVI Human Immunology Laboratory, Imperial College, London, England, United Kingdom
| | - Sudha Subramanyam
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Srikanth Prasad Tripathy
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Soumya Swaminathan
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
| | - Luke Elizabeth Hanna
- National Institute for Research in Tuberculosis (Indian Council of Medical Research), Chennai, India
- * E-mail:
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Dias ASO, Santos ICL, Delphim L, Fernandes G, Endlich LR, Cafasso MOSD, Maranhão AL, da Silva SR, Andrade RM, Agrawal A, Linhares UC, Bento CAM. Serum leptin levels correlate negatively with the capacity of vitamin D to modulate the in vitro cytokines production by CD4 + T cells in asthmatic patients. Clin Immunol 2019; 205:93-105. [PMID: 31173888 DOI: 10.1016/j.clim.2019.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/25/2019] [Accepted: 06/03/2019] [Indexed: 12/14/2022]
Abstract
Both obesity and low vitamin D levels have been associated with allergic asthma (AA) severity. In the present study, severity of AA was associated with obesity but to the in vitro IgE production. In those patients, higher levels of IL-5, IL-6 and IL-17 were quantified in CD4+ T-cell cultures as compared with patients with mild and moderate AA. In addition, the lowest IL-10 levels were detected in the cell cultures from patients with a worse prognosis. Interestingly, the occurrence of AA elevates the plasma levels of leptin, and this adipokine was positively correlated with the release of IL-5, IL-6 and IL-17, but inversely correlated with IL-10 production, by CD4+ T-cells from patients. In AA-derived CD4+ T-cell cultures, 1,25(OH)2D3 was less efficient at inhibiting IL-5, IL-6 and IL-17 production, and up regulating IL-10 release, as those from healthy subjects. Interestingly, the in vitro immunomodulatory effects of vitamin D were inversely correlated with serum leptin levels. In summary, our findings suggested that obesity, probably due to the overproduction of leptin, negatively impacts AA as it favors imbalance between Th2/Th17 and regulatory phenotypes. The deleterious effects of leptin may also be due to its ability to counter-regulate the immunosuppressive effects of vitamin D.
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Affiliation(s)
- Aleida S O Dias
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil; Post-graduate Program in Microbiology, University of the State of Rio de Janeiro, Brazil
| | - Isabelle C L Santos
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil
| | - Letícia Delphim
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil
| | - Gabriel Fernandes
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil
| | - Larissa R Endlich
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil
| | | | - Ana Lúcia Maranhão
- Pulmonology Service, Federal University of the State of Rio de Janeiro, Brazil
| | | | - Regis M Andrade
- Department of General Medicine Department, Federal University of the State of Rio de Janeiro, Brazil
| | - Anshu Agrawal
- Department of Medicine, University of California, Irvine, CA, USA
| | - Ulisses C Linhares
- Department of Morphological Sciences, Federal University of the State of Rio de Janeiro, Brazil
| | - Cleonice A M Bento
- Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Brazil; Post-graduate Program in Microbiology, University of the State of Rio de Janeiro, Brazil.
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Showa SP, Nyabadza F, Hove-Musekwa SD, Magombedze G. A comparison of elasticities of viral levels to specific immune response mechanisms in human immunodeficiency virus infection. BMC Res Notes 2014; 7:737. [PMID: 25331717 PMCID: PMC4221687 DOI: 10.1186/1756-0500-7-737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 10/02/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The presence of an asymptomatic phase in an HIV infection indicates that the immune system can partially control the infection. Determining the immune mechanisms that contribute significantly to the partial control of the infection enhance the HIV infection intervention strategies and is important in vaccine development. Towards this goal, a discrete time HIV model, which incorporates the life cycle aspects of the virus, the antibody (humoral) response and the cell-mediated immune response is formulated to determine immune system components that are most efficient in controlling viral levels. Ecological relationships are used to model the interplay between the immune system components and the HIV pathogen. Model simulations and transient elasticity analysis of the viral levels to immune response parameters are used to compare the different immune mechanisms. RESULTS It is shown that cell-mediated immune response is more effective in controlling the viral levels than the antibody response. Killing of infected cells is shown to be crucial in controlling the viral levels. Our results show a negative correlation between the antibody response and the viral levels in the early stages of the infection, but we predicted this immune mechanism to be positively correlated with the viral levels in the late stage of the infection. A result that suggests lack of relevance of antibody response with infection progression. On the contrary, we predicted the cell-mediated immune response to be always negatively correlated with viral levels. CONCLUSION Neutralizing antibodies can only control the viral levels in the early days of the HIV infection whereas cell-mediated immune response is beneficial during all the stages of the infection. This study predicts that vaccine design efforts should also focus on stimulating killer T cells that target infected cells.
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Affiliation(s)
- Sarudzai P Showa
- Department of Applied Mathematics, National University of Science and Technology, P,O, Box AC 939 Ascot, Bulawayo, Zimbabwe.
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6
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Wodarz D. Modeling T cell responses to antigenic challenge. J Pharmacokinet Pharmacodyn 2014; 41:415-29. [PMID: 25269610 DOI: 10.1007/s10928-014-9387-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 09/17/2014] [Indexed: 01/12/2023]
Abstract
T cell responses are a crucial part of the adaptive immune system in the fight against infections. This article discusses the use of mathematical models for understanding the dynamics of cytotoxic T lymphocyte (CTL) responses against viral infections. Complementing experimental research, mathematical models have been very useful for exploring new hypotheses, interpreting experimental data, and for defining what needs to be measured to improve understanding. This review will start with minimally parameterized models of CTL responses, which have generated some valuable insights into basic dynamics and correlates of control. Subsequently, more biological complexity is incorporated into this modeling framework, examining different mechanisms of CTL expansion, different effector activities, and the influence of T cell help. Models and results are discussed in the context of data from specific infections.
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Affiliation(s)
- Dominik Wodarz
- Department of Ecology and Evolutionary Biology and Department of Mathematics, University of California, 321 Steinhaus Hall, Irvine, CA, 92617, USA,
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7
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Fan R, Dong Y, Huang G, Takeuchi Y. Apoptosis in virus infection dynamics models. JOURNAL OF BIOLOGICAL DYNAMICS 2014; 8:20-41. [PMID: 24963975 PMCID: PMC4220821 DOI: 10.1080/17513758.2014.895433] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 02/04/2014] [Indexed: 06/03/2023]
Abstract
In this paper, on the basis of the simplified two-dimensional virus infection dynamics model, we propose two extended models that aim at incorporating the influence of activation-induced apoptosis which directly affects the population of uninfected cells. The theoretical analysis shows that increasing apoptosis plays a positive role in control of virus infection. However, after being included the third population of cytotoxic T lymphocytes immune response in HIV-infected patients, it shows that depending on intensity of the apoptosis of healthy cells, the apoptosis can either promote or comfort the long-term evolution of HIV infection. Further, the discrete-time delay of apoptosis is incorporated into the pervious model. Stability switching occurs as the time delay in apoptosis increases. Numerical simulations are performed to illustrate the theoretical results and display the different impacts of a delay in apoptosis.
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Affiliation(s)
- Ruili Fan
- School of Mathematics and Physics, China University of Geosciences, Wuhan430074, China
| | - Yueping Dong
- Graduate School of Science and Technology, Shizuoka University, Hamamatsu432-8561, Japan
| | - Gang Huang
- School of Mathematics and Physics, China University of Geosciences, Wuhan430074, China
| | - Yasuhiro Takeuchi
- Department of Physics and Mathematics, Aoyama Gakuin University, Sagamihara252-5258, Japan
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Kaneyasu K, Kita M, Ohkura S, Yamamoto T, Ibuki K, Enose Y, Sato A, Kodama M, Miura T, Hayami M. Protective Efficacy of Nonpathogenic Nef-Deleted SHIV Vaccination Combined with Recombinant IFN-γ Administration against a Pathogenic SHIV Challenge in Rhesus Monkeys. Microbiol Immunol 2013; 49:1083-94. [PMID: 16365534 DOI: 10.1111/j.1348-0421.2005.tb03706.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We previously reported that a nef-deleted SHIV (SHIV-NI) is nonpathogenic and gave macaques protection from challenge infection with pathogenic SHIV-C2/1. To investigate whether IFN-gamma augments the immune response induced by this vaccination, we examined the antiviral and adjuvant effect of recombinant human IFN-gamma (rIFN-gamma) in vaccinated and unvaccinated monkeys. Nine monkeys were vaccinated with nef-deleted nonpathogenic SHIV-NI. Four of them were administered with rIFN-gamma and the other five monkeys were administered with placebo. After the challenge with pathogenic SHIV-C2/1, CD4(+) T-cell counts were maintained similarly in monkeys of both groups, while those of the unvaccinated monkeys decreased dramatically at 2 weeks after challenge. However, the peaks of plasma viral load were reduced to 100-fold in SHIV-NI vaccinated monkeys combined with rIFN-gamma compared with those in SHIV-NI vaccinated monkeys without rIFN-gamma. The peaks of plasma viral load were inversely correlated with the number of SIV Gag-specific IFN-gamma-producing cells. In SHIV-NI-vaccinated monkeys with rIFN-gamma, the number of SIV Gag-specific IFN-gamma-producing cells of PBMCs increased 2-fold compared with those in SHIV-NI-vaccinated monkeys without rIFN-gamma, and the NK activity and MIP-1alpha production of PBMCs were also enhanced. Thus, vaccination of SHIV-NI in combination with rIFN-gamma was more effective in modulating the antiviral immune system into a Th1 type response than SHIV-NI vaccination alone. These results suggest that IFN-gamma augmented the anti-viral effect by enhancing innate immunity and shifting the immune response to Th1.
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Affiliation(s)
- Kentaro Kaneyasu
- Institute for Virus Research, Kyoto University, Kyoto, Kyoto 606-8507, Japan
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9
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Tossige-Gomes R, Avelar NCP, Simão AP, Neves CDC, Brito-Melo GEA, Coimbra CC, Rocha-Vieira E, Lacerda ACR. Whole-body vibration decreases the proliferativeb response of TCD4(+) cells in elderly individuals with knee osteoarthritis. Braz J Med Biol Res 2012; 45:1262-8. [PMID: 22948377 PMCID: PMC3854226 DOI: 10.1590/s0100-879x2012007500139] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 08/09/2012] [Indexed: 12/02/2022] Open
Abstract
The aim of this study was to investigate the effect of adding whole-body vibration (WBV; frequency = 35 to 40 Hz; amplitude = 4 mm) to squat training on the T-cell proliferative response of elderly patients with osteoarthritis (OA) of the knee. This study was a randomized controlled trial in which the selected variables were assessed before and after 12 weeks of training. Twenty-six subjects (72 ± 5 years of age) were divided into three groups: 1) squat training with WBV (WBV, N = 8); 2) squat training without WBV (N = 10), and 3) a control group (N = 8). Women who were ≥60 years of age and had been diagnosed with OA in at least one knee were eligible. The intervention consisted of 12 uninterrupted weeks of squatting exercise training performed 3 times/week. Peripheral blood mononuclear cells were obtained from peripheral blood collected before and after training. The proliferation of TCD4+ and TCD8+ cells was evaluated by flow cytometry measuring the carboxyfluorescein succinimidyl ester fluorescence decay before and after the intervention (Δ). The proliferative response of TCD4+ cells (P = 0.02, effect size = 1.0) showed a significant decrease (23%) in the WBV group compared to the control group, while there was no difference between groups regarding the proliferative response of TCD8+ cells (P = 0.12, effect size = 2.23). The data suggest that the addition of WBV to squat exercise training might modulate T-cell-mediated immunity, minimizing or slowing disease progression in elderly patients with OA of the knee.
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Affiliation(s)
- R Tossige-Gomes
- Departamento de Fisioterapia, Faculdade de Ciências Biológicas e da Saúde, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, MG, Brasil
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10
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Huang G, Takeuchi Y, Korobeinikov A. HIV evolution and progression of the infection to AIDS. J Theor Biol 2012; 307:149-59. [PMID: 22634206 DOI: 10.1016/j.jtbi.2012.05.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 05/11/2012] [Accepted: 05/14/2012] [Indexed: 12/12/2022]
Abstract
In this paper, we propose and discuss a possible mechanism, which, via continuous mutations and evolution, eventually enables HIV to break from immune control. In order to investigate this mechanism, we employ a simple mathematical model, which describes the relationship between evolving HIV and the specific CTL response and explicitly takes into consideration the role of CD4(+)T cells (helper T cells) in the activation of the CTL response. Based on the assumption that HIV evolves towards higher replication rates, we quantitatively analyze the dynamical properties of this model. The model exhibits the existence of two thresholds, defined as the immune activation threshold and the immunodeficiency threshold, which are critical for the activation and persistence of the specific cell-mediated immune response: the specific CTL response can be established and is able to effectively control an infection when the virus replication rate is between these two thresholds. If the replication rate is below the immune activation threshold, then the specific immune response cannot be reliably established due to the shortage of antigen-presenting cells. Besides, the specific immune response cannot be established when the virus replication rate is above the immunodeficiency threshold due to low levels of CD4(+)T cells. The latter case implies the collapse of the immune system and beginning of AIDS. The interval between these two thresholds roughly corresponds to the asymptomatic stage of HIV infection. The model shows that the duration of the asymptomatic stage and progression of the disease are very sensitive to variations in the model parameters. In particularly, the rate of production of the naive lymphocytes appears to be crucial.
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Affiliation(s)
- Gang Huang
- School of Mathematics and Physics, China University of Geosciences, Wuhan 430074, PR China
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11
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Roy SM, Wodarz D. Infection of HIV-specific CD4 T helper cells and the clonal composition of the response. J Theor Biol 2012; 304:143-51. [PMID: 22480435 DOI: 10.1016/j.jtbi.2012.03.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 03/13/2012] [Accepted: 03/14/2012] [Indexed: 11/24/2022]
Abstract
A hallmark of human immunodeficiency virus is its ability to infect CD4+ T helper cells, thus impairing helper cell responses and consequently effector responses whose maintenance depends on help (such as killer T cells and B cells). In particular, the virus has been shown to infect HIV-specific helper cells preferentially. Using mathematical models, we investigate the consequence of this assumption for the basic dynamics between HIV and its target cells, assuming the existence of two independently regulated helper cell clones, directed against different epitopes of the virus. In contrast to previous studies, we examine a relatively simple scenario, only concentrating on the interactions between the virus and its target cells, not taking into account any helper-dependent effector responses. Further, there is no direct competition for space or antigenic stimulation in the model. Yet, a set of interesting outcomes is observed that provide further insights into factors that shape helper cell responses. Despite the absence of competition, a stronger helper cell clone can still exclude a weaker one because the two clones are infected by the same pathogen, an ecological concept called "apparent competition". Moreover, we also observe "facilitation": if one of the helper cell clones is too weak to become established in isolation, the presence of a stronger clone can provide enhanced antigenic stimulation, thus allowing the weaker clone to persist. The dependencies of these outcomes on parameters is explored. Factors that reduce viral infectivity and increase the death rate of infected cells promote coexistence, which is in agreement with the observation that stronger immunity correlates with broader helper cell responses. The basic model is extended to explicitly take into account helper-dependent CTL responses and direct competition. This study sheds further light onto the factors that can influence the clonal composition of HIV-specific helper cell responses, which has implications for the overall pattern of disease progression.
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Affiliation(s)
- Sarah M Roy
- Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA
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12
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García-Ramos G, Castillo D, Crowley PH. Effectiveness of a 'hunter' virus in controlling human immunodeficiency virus type 1 infection. J Gen Virol 2010; 91:2513-23. [PMID: 20573853 PMCID: PMC3052598 DOI: 10.1099/vir.0.023028-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Engineered therapeutic viruses provide an alternative method for treating infectious diseases, and mathematical models can clarify the system's dynamics underlying this type of therapy. In particular, this study developed models to evaluate the potential to contain human immunodeficiency virus type 1 (HIV-1) infection using a genetically engineered 'hunter' virus that kills HIV-1-infected cells. First, we constructed a novel model for understanding the progression of HIV infection that predicted the loss of the immune system's CD4(+) T cells across time. Subsequently, it determined the effects of introducing hunter viruses in restoring cell population. The model implemented direct and indirect mechanisms by which HIV-1 may cause cell depletion and an immune response. Results suggest that the slow progression of HIV infection may result from a slowly decaying CTL immune response, leading to a limited but constant removal of uninfected CD4 resting cells through apoptosis - and from resting cell proliferation that reduces the rate of cell depletion over time. Importantly, results show that the hunter virus does restrain HIV infection and has the potential to allow major cell recovery to 'functional' levels. Further, the hunter virus persisted at a reduced HIV load and was effective either early or late in the infection. This study indicates that hunter viruses may halt the progression of the HIV infection by restoring and sustaining high CD4(+) T-cell levels.
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13
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CD4+ T cell epitope discovery and rational vaccine design. Arch Immunol Ther Exp (Warsz) 2010; 58:121-30. [PMID: 20155490 DOI: 10.1007/s00005-010-0067-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Accepted: 08/08/2009] [Indexed: 12/15/2022]
Abstract
T cell epitope-driven vaccine design employs bioinformatic algorithms to identify potential targets of vaccines against infectious diseases or cancer. Potential epitopes can be identified with major histocompatibility complex (MHC)-binding algorithms, and the ability to bind to MHC class I or class II indicates a predominantly CD4(+) or CD8(+) T cell response. Furthermore, an epitope-based vaccine can circumvent evolutionary events favoring immune escape present in native proteins from pathogens. It can also focus on only the most relevant epitopes (i.e. conserved and promiscuous) recognized by the majority of the target population. Mounting evidence points to the critical role of CD4(+) T cells in natural antigen encounter and active immunization. In this paper the need for CD4(+) T cell help in vaccine development, the selection of CD4(+) T cell epitopes for an epitope-based vaccine, and how the approach can be used to induce a protective effect are reviewed.
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Abstract
Vaccinations typically rely on immunization with live virus for eliciting protective CD8 T cell immunity. There is increasing interest to use subunit vaccination strategies to achieve such responses. Complete Freund's adjuvant (CFA) and unmethylated cytosine-guanine dinucleotide containing DNA are considered some of the most potent adjuvants for eliciting immunity. Whereas a wealth of information is available on how these adjuvants affect CD4 T cell responses, their effects on engaging CD8 T cell immunity are not completely understood. We immunized C57BL/6J mice with the class I restricted peptides Uty or SIINFEKL using these 2 adjuvants and tested for cytokine secretion, proliferation, in vivo cytotoxicity, and delayed-type hypersensitivity (DTH). Our data show that CFA-induced CD8 T cells to proliferate, mediate DTH, and to secrete interferon-gamma, interleukin (IL)-2 and IL-17. Despite these markers of CD8 T cell activation, CFA failed to induce an early cytotoxic CD8 T cell response. In contrast, unmethylated cytosine-guanine dinucleotide containing DNA promoted a vigorous cytolytic response without activating substantial cytokine production, proliferation or DTH. These data have implications for CD8 T cell subunit vaccine design in which cytotoxicity versus DTH plays a key role in host defense.
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15
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CD4+ T cells are required for the priming of CD8+ T cells following infection with herpes simplex virus type 1. J Virol 2009; 83:5256-68. [PMID: 19279095 DOI: 10.1128/jvi.01997-08] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The role of CD4(+) helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4(+) T cells are needed for the generation of the protective HSV-1-specific CD8(+)-T-cell response. This study examined the contribution of CD4(+) T cells in the generation of the primary CD8(+)-T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8(+)-T-cell response generated in the draining lymph nodes of CD4(+)-T-cell-depleted C57BL/6 mice and B6-MHC-II(-/-) mice is quantitatively and qualitatively distinct from the CD8(+) T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8(+) T cells express comparable levels of the activation marker CD44 in mice lacking CD4(+) T cells and normal mice. In contrast, CD8(+) T cells generated in the absence of CD4(+) T cells express the interleukin 2 receptor alpha-chain (CD25) at lower levels. Importantly, the CD8(+) T cells in the CD4(+)-T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8(+) T cells is diminished in the absence of CD4(+)-T-cell help. These results suggest that CD4(+)-T-cell help is essential for the generation of fully functional CD8(+) T cells during the primary response to HSV-1 infection.
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16
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Iwami S, Takeuchi Y, Iwamoto K, Naruo Y, Yasukawa M. A mathematical design of vector vaccine against autoimmune disease. J Theor Biol 2009; 256:382-92. [PMID: 18996399 PMCID: PMC7185877 DOI: 10.1016/j.jtbi.2008.09.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2008] [Revised: 09/30/2008] [Accepted: 09/30/2008] [Indexed: 12/11/2022]
Abstract
Viruses have been implicated in the initiation, progression, and exacerbation of several human autoimmune diseases. Evidence also exists that viruses can protect against autoimmune disease. Several proposed mechanisms explain the viral effects. One mechanism is "molecular mimicry" which represents a shared immunologic epitope with a microbe and the host. We consider, using a simple mathematical model, whether and how a viral infection with molecular mimicry can be beneficial or detrimental for autoimmune disease. Furthermore, we consider the possibility of development of a vector therapeutic vaccine that can relieve autoimmune disease symptoms. Our findings demonstrate that vaccine therapy success necessitates (i) appropriate immune response function, (ii) appropriate affinities with self and non-self antigen, and (iii) a replicative vector vaccine. Moreover, the model shows that the viral infection can cause autoimmune relapses.
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Affiliation(s)
- Shingo Iwami
- Graduate School of Science and Technology, Shizuoka University, Japan.
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17
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Salha MD, Cheynier R, Halwani R, McGrath H, Langaee TY, Yassine Diab B, Fournier J, Parenteau M, Edgar J, Ko D, Sherring A, Bogdanovic D, Sekaly RP, Rud EW. Persistence of restricted CD4 T cell expansions in SIV-infected macaques resistant to SHIV89.6P superinfection. Virology 2008; 377:239-47. [PMID: 18570962 DOI: 10.1016/j.virol.2008.04.031] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 02/29/2008] [Accepted: 04/24/2008] [Indexed: 12/11/2022]
Abstract
Attempts to evaluate the protective effect of live attenuated SIV vaccine strains have yielded variable results depending on the route of immunization, the level of attenuation, the level of divergence between the vaccine candidate and the challenge. The protective mechanisms induced by these vaccines are still not well understood. In an effort to address whether the diversity of the CD4+ T cell repertoire in cynomolgus macaques plays a role in the immunological protection following SIVmacC8 infection, we have performed a longitudinal follow-up of the CD4 repertoire by heteroduplex tracking assay in macaques mock-infected or infected with either the attenuated SIVmacC8 or its homologous SIVmacJ5 and challenged with simian-human immunodeficiency virus (SHIV89.6P). Viral load and CD4 absolute counts were determined in these animals and the presence of SHIV89.6P virus in challenged animals was evaluated by PCR and serology. In all macaques that were protected against the challenging virus, we demonstrated a reduced diversity in the CD4+ TRBV repertoire and a few dominant CD4+ T cell clones during early primary infection. In contrast, CD4 TRBV repertoire in unprotected macaques remained highly diverse. Moreover, some of the CD4 T cell clones that were expanded during primary SIV infection re-emerged after challenge suggesting their role in protection against the challenging virus. These results underline the importance of maintaining the CD4 T cell repertoire developed during acute infection and point to the restriction of the CD4 response to the vaccine as a correlate of protection.
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Affiliation(s)
- M-D Salha
- Department of Microbiology and Immunology, McGill University, Montreal, Canada PQ H3A 2B4
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18
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Gupta S, Boppana R, Mishra GC, Saha B, Mitra D. Interleukin-12 is necessary for the priming of CD4+ T cells required during the elicitation of HIV-1 gp120-specific cytotoxic T-lymphocyte function. Immunology 2008; 124:553-61. [PMID: 18298551 DOI: 10.1111/j.1365-2567.2008.02809.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The mechanism of the T-cell response and cytokine induction to restrict human immunodeficiency virus 1 (HIV-1) infection is not clear. During early infection, HIV-infected individuals have a high frequency of virus-specific cytotoxic T lymphocytes (CTLs) that effectively reduces the viral load. However, the CTLs are unable to clear the virus at later stages of infection, leading to disease progression. Dysregulation of cytokines like interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) as a result of the interaction of HIV-1-specific T cells with antigen-presenting cells is one of the possible causes of CTL dysfunction. Secretion of IL-12 is reduced with the progression of HIV infection, correlating with impaired CTL function; however, the role of IL-12 in CTL regulation awaits elucidation. Here, we have studied the role of IL-12 in CTL dysfunction by using DNA immunization of wild-type (WT) and IL-12-deficient mice with HIV-1 gp120 complementary DNA. It was observed that the CTL response in IL-12-deficient mice was significantly less than that in WT mice. Our results further demonstrated that coimmunization with IL-12 vector restored the impaired CTL response in IL-12-deficient mice. However, immunization with IL-12 vector failed to rescue the CTL response in IFN-gamma deficient mice, suggesting that the CTL-promoting function of IL-12 is IFN-gamma-mediated. Our data suggest a phase-specific role of IL-12 in the CTL response, specifically in the priming of CD4+ T cells that provide help to CD8+ T cells. Our results also suggest that IL-12 is vital for the priming of antigen-specific T cells and plays an essential role in IFN-gamma induction in T cells.
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Affiliation(s)
- Shalini Gupta
- National Centre for Cell Science, Ganeshkhind, Pune, India
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19
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Durando P, Fenoglio D, Boschini A, Ansaldi F, Icardi G, Sticchi L, Renzoni A, Fabbri P, Ferrera A, Parodi A, Bruzzone B, Gabutti G, Podda A, Del Giudice G, Fragapane E, Indiveri F, Crovari P, Gasparini R. Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2008; 15:253-9. [PMID: 18003811 PMCID: PMC2238067 DOI: 10.1128/cvi.00316-07] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Revised: 08/31/2007] [Accepted: 11/01/2007] [Indexed: 11/20/2022]
Abstract
The objective of this study was to evaluate and compare both the safety and tolerability and the humoral and cell-mediated immune responses for two influenza virus subunit vaccines, one with MF59 adjuvant (Fluad) and one without an adjuvant (Agrippal), in healthy and in human immunodeficiency virus type 1 (HIV-1)-infected adult individuals. To achieve this aim, an open, randomized, comparative clinical trial was performed during the 2005-2006 season. A total of 256 subjects were enrolled to receive one dose of vaccine intramuscularly. Blood samples were taken at the time of vaccination and at 1 and 3 months postvaccination. A good humoral antibody response was detected for both vaccines, meeting all the criteria of the Committee for Medical Products for Human Use. After Beyer's correction for prevaccination status, Fluad exhibited better immunogenicity than Agrippal, as shown from the analysis of the geometric mean titers, with significant differences for some virus strains; however, no definitive conclusions on the clinical significance of such results can be drawn, because the method used to estimate antibody response is currently nonstandard for influenza virus vaccines. Significant induction of an antigen-specific CD4+ T-lymphocyte proliferative response was detected at all time points after immunization, for both the vaccines, among HIV-1-seronegative subjects. This was different from what was observed for HIV-1-infected individuals. In this group, significance was not reached at 30 days postvaccination (T30) for those immunized with Agrippal. Also when data were compared between treatment groups, a clear difference in the response at T30 was observed in favor of Fluad (P = 0.0002). The safety profiles of both vaccines were excellent. For HIV-1-infected individuals, no significant changes either in viremia or in the CD4+ cell count were observed at any time point. The results showed good safety and immunogenicity for both vaccines under study for both uninfected and HIV-1-infected adults, confirming current recommendations for immunization of this high-risk category.
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Affiliation(s)
- P Durando
- Department of Health Sciences, University of Genoa, 16132 Genoa, Italy.
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20
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Gupta S, Boppana R, Mishra GC, Saha B, Mitra D. HIV-1 Tat Suppresses gp120-Specific T Cell Response in IL-10-Dependent Manner. THE JOURNAL OF IMMUNOLOGY 2007; 180:79-88. [DOI: 10.4049/jimmunol.180.1.79] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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21
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Wodarz D, Hamer DH. Infection dynamics in HIV-specific CD4 T cells: does a CD4 T cell boost benefit the host or the virus? Math Biosci 2007; 209:14-29. [PMID: 17379260 PMCID: PMC4058052 DOI: 10.1016/j.mbs.2007.01.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2006] [Revised: 01/22/2007] [Accepted: 01/26/2007] [Indexed: 12/30/2022]
Abstract
Recent experimental data have shown that HIV-specific CD4 T cells provide a very important target for HIV replication. We use mathematical models to explore the effect of specific CD4 T cell infection on the dynamics of virus spread and immune responses. Infected CD4 T cells can provide antigen for their own stimulation. We show that such autocatalytic cell division can significantly enhance virus spread, and can also provide an additional reservoir for virus persistence during anti-viral drug therapy. In addition, the initial number of HIV-specific CD4 T cells is an important determinant of acute infection dynamics. A high initial number of HIV-specific CD4 T cells can lead to a sudden and fast drop of the population of HIV-specific CD4 T cells which results quickly in their extinction. On the other hand, a low initial number of HIV-specific CD4 T cells can lead to a prolonged persistence of HIV-specific CD4 T cell help at higher levels. The model suggests that boosting the population of HIV-specific CD4 T cells can increase the amount of virus-induced immune impairment, lead to less efficient anti-viral effector responses, and thus speed up disease progression, especially if effector responses such as CTL have not been sufficiently boosted at the same time.
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Affiliation(s)
- Dominik Wodarz
- Department of Ecology and Evolutionary Biology, 321 Steinhaus Hall, University of California, Irvine, CA 92697, USA.
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22
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Scharnagl NC, Klade CS. Experimental discovery of T-cell epitopes: combining the best of classical and contemporary approaches. Expert Rev Vaccines 2007; 6:605-15. [PMID: 17669013 DOI: 10.1586/14760584.6.4.605] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
T cells specifically recognize antigens as peptide epitope-MHC complexes on the surface of target cells. The inherent complexities of antigen processing and presentation, the polygenic and polymorphic nature of MHC and the technical hurdles in working with T cells have made epitope discovery challenging. Here, we review significant experimental advances in recent years. These include new and sensitive assays and the availability of human cells and high numbers of synthetic peptides for screening, which have allowed for the first time comprehensive analysis of antigens and whole virus genomes. Such studies have provided important insights into the immunobiology of a number of diseases. The newly gathered detailed information on T-cell epitopes will aid vaccine design and immunological monitoring in clinical trials.
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23
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Elamanchili P, Lutsiak CME, Hamdy S, Diwan M, Samuel J. “Pathogen-Mimicking” Nanoparticles for Vaccine Delivery to Dendritic Cells. J Immunother 2007; 30:378-95. [PMID: 17457213 DOI: 10.1097/cji.0b013e31802cf3e3] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A clinically relevant delivery system that can efficiently target and deliver antigens and adjuvant to dendritic cells (DCs) is under active investigation. Immunization with antigens and immunomodulators encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles elicits potent cellular immune responses; but understanding how this mode of delivery affects DCs and priming of naive T cells needs further investigation. In the current study, we assessed the extent of maturation of DCs after treatment with monophosphoryl lipid A (MPLA) encapsulated in PLGA nanoparticles and the generation of primary T-cell immune responses elicited by DCs loaded with antigens using this approach. Results indicated that DCs up-regulated the expression of surface maturation markers and demonstrated an enhanced allostimulatory capacity after treatment with MPLA containing PLGA nanoparticles. Treatment of DCs with MPLA containing nanoparticles released high amounts of proinflammatory and TH1 (T helper 1) polarizing cytokines and chemokines greater than that achieved by MPLA in solution. The delivery of ovalbumin in PLGA nanoparticles to DCs induced potent in vitro and in vivo antigen-specific primary TH1 immune responses that were furthermore enhanced with codelivery of MPLA along with the antigen in the nanoparticle formulation. Delivery of MUC1 lipopeptide (BLP25, a cancer vaccine candidate) and MPLA in PLGA nanoparticles to human DCs induced proliferation of MUC1 reactive T cells in vitro demonstrating the break in tolerance to self-antigen MUC1. These results demonstrated that targeting antigens along with toll-like receptor ligands in PLGA nanoparticles to DCs is a promising approach for generating potent TH1 polarizing immune responses that can potentially override self-tolerance mechanisms and become beneficial in the immunotherapy of cancer and infectious diseases.
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Affiliation(s)
- Praveen Elamanchili
- Faculty of Pharmacy and Pharmaceutical Sciences, 3118, Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2N8
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24
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Chen J, Hsu HC, Zajac AJ, Wu Q, Yang P, Xu X, McPherson SA, Li J, Curiel DT, Mountz JD. In vivo analysis of adenovirus-specific cytotoxic T lymphocyte response in mice deficient in CD28, fas ligand, and perforin. Hum Gene Ther 2006; 17:669-82. [PMID: 16776575 DOI: 10.1089/hum.2006.17.669] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Adenoviruses (Ad) have been extensively studied as gene delivery vectors in gene therapy and as vaccine carriers. The cell-mediated cytotoxicity induced by Ad is of great interest in both applications. However, the mechanism underlying Ad-specific cytotoxic T lymphocyte (CTL) generation and effector function remains unclear. In this study, we used a novel MHC class I tetramer and an in vivo CTL assay to examine the role of CD28, perforin, Fas ligand (FasL), and TNF-alpha in the generation and function of Ad-specific CTLs in vivo. During the primary response, there was a significant defect in both the generation and in vivo effector function of Ad-specific CTLs in CD28-/- mice, but not in CD4+ T cell-depleted mice or CD4-/- mice. The relative role of CTL effector molecules was assayed by in vivo CTL assay in perforin- or FasL-mutant mice, using donor cells from Fas-deficient or TNFR1/TNFR2-deficient mice. The results indicated that the in vivo CTL activity is mediated mainly by perforin. In the absence of perforin, production of FasL, but not TNF-alpha, by the CTLs results in lower level Ad-specific killing of target cells. These results provide important implications concerning the development of safe and effective Ad vectors for gene therapy and vaccines.
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Affiliation(s)
- Jian Chen
- Department of Medicine, University of Alabama at Birmingham, and Veterans Administration Medical Center, Birmingham, AL 35294, USA
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25
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Korthals Altes H, de Boer R, Boerlijst M. Role of avidity and breadth of the CD4 T cell response in progression to AIDS. Proc Biol Sci 2006; 273:1697-704. [PMID: 16769643 PMCID: PMC1634931 DOI: 10.1098/rspb.2006.3511] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The great variability in the time between infection with HIV and the onset of AIDS has been the object of intense study. In the current work, we examine a mathematical model that focuses on the role of immune response variability between patients. We study the effect of variation in both the avidity and the breadth of the immune response on within-patient disease dynamics, viral setpoint and time to AIDS. We conclude that immune response variability can explain the observed variability in disease progression to a large extent. It turns out that the avidity, more than the breadth of the immune response, determines disease progression, and that the average avidity of the five best clones is a much better correlate for disease progression than the total number of clones responding. For the design of vaccines, this would suggest that, if given the choice between stimulating a broader, but average avidity response or a narrower high-avidity response, the latter option would yield better control of virus load and consequently slow down disease progression.
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Affiliation(s)
- Hester Korthals Altes
- Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, PO Box 94084, 1090 GB Amsterdam, The Netherlands.
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26
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Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, Kobayashi T, Shimosegawa T. Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B. World J Gastroenterol 2006; 12:4310-4317. [PMID: 16865771 PMCID: PMC4087740 DOI: 10.3748/wjg.v12.i27.4310] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2006] [Revised: 01/28/2006] [Accepted: 02/18/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the mechanisms of hyporesponsiveness of HBV-specific CD4+ T cells by testing TH1 and TH2 commitment and regulatory T cells. METHODS Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation. HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4+CD25+ cells. RESULTS Level of mRNAs for T-bet, IL-12R beta2 and IL-4 was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4+CD25highCTLA-4+ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4+ cells and CD4+CD25+ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAg-specific TH1 antibody compared with control antibody (P < 0.01, 0.34% +/- 0.12% vs 0.15% +/- 0.04%). Deletion of CD4+CD25+ T cells increased the amount of HBcAg-specific TH1 antibody when compared with lymphocytes reconstituted using regulatory T cells (P < 0.01, 0.03% +/- 0.02% vs 0.18% +/- 0.05%). CONCLUSION The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.
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MESH Headings
- Adult
- CD24 Antigen/analysis
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/pathology
- Cells, Cultured
- Female
- GATA3 Transcription Factor/genetics
- GATA3 Transcription Factor/metabolism
- Gene Expression Regulation
- Hepatitis B Core Antigens/physiology
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/metabolism
- Humans
- Interferon-gamma/genetics
- Interferon-gamma/metabolism
- Interleukin-10/genetics
- Interleukin-10/metabolism
- Interleukin-4/genetics
- Interleukin-4/metabolism
- Lymphocyte Depletion
- Male
- Middle Aged
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptors, Interleukin-2/analysis
- T-Box Domain Proteins
- T-Lymphocytes, Helper-Inducer/drug effects
- T-Lymphocytes, Helper-Inducer/immunology
- T-Lymphocytes, Helper-Inducer/metabolism
- T-Lymphocytes, Helper-Inducer/pathology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
- Transcription Factors/genetics
- Transcription Factors/metabolism
- T-bet Transcription Factor
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Affiliation(s)
- Yasuteru Kondo
- Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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27
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Chen J, Hsu HC, Zajac AJ, Wu Q, Yang P, Xu X, McPherson SA, Li J, Curiel DT, Mountz JD. In Vivo Analysis of Adenovirus-Specific Cytotoxic T Lymphocyte Response in Mice Deficient in CD28, Fas Ligand, and Perforin. Hum Gene Ther 2006. [DOI: 10.1089/hum.2006.17.ft-217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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28
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Banks HT, Bortz DM. A parameter sensitivity methodology in the context of HIV delay equation models. J Math Biol 2004; 50:607-25. [PMID: 15614552 DOI: 10.1007/s00285-004-0299-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2002] [Revised: 01/24/2004] [Indexed: 10/26/2022]
Abstract
A sensitivity methodology for nonlinear delay systems arising in one class of cellular HIV infection models is presented. Theoretical foundations for a typical sensitivity investigation and illustrative computations are given.
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Affiliation(s)
- H T Banks
- Center for Research in Scientific Computation, North Carolina State University, Raleigh, NC 27695-8205, USA.
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29
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Jansen VAA, Altes HK, Funk GA, Wodarz D. Contrasting B cell- and T cell-based protective vaccines. J Theor Biol 2004; 234:39-48. [PMID: 15721034 DOI: 10.1016/j.jtbi.2004.11.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2004] [Revised: 11/02/2004] [Accepted: 11/03/2004] [Indexed: 11/19/2022]
Abstract
A substantial research effort is devoted to the development of vaccines based on T cells. Such a vaccine would provide a means to protect against infection with HIV and stop the current pandemic. Here we investigate the possibility to develop a protective T cell-based vaccine. We do this by means of a mathematical model which describes the dynamics of a pathogen and the immune system in the early stages of infection. We compare an immune response that is near immediate--as is the case for a humoral response--with that of a response in which the effector cells have to be formed from precursor cells--as occurs in T cell responses. The latter applies to a T cell-based vaccine. A near immediate response is associated with a threshold number of effector cells above which an infection cannot take hold. For a T cell-based vaccine this threshold increases with the amount of antigen the immune system is exposed to. For small initial doses, as one would naturally expect to occur, this gives rise to impractically large thresholds. Thus, although a T cell vaccine might work against a high dose exposure, it might fail when exposed against to a low-dose exposure. This limits, we argue, the efficacy of T cell-based vaccines.
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Affiliation(s)
- Vincent A A Jansen
- School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey TW20 0EX, UK.
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30
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Someya K, Xin KQ, Matsuo K, Okuda K, Yamamoto N, Honda M. A consecutive priming-boosting vaccination of mice with simian immunodeficiency virus (SIV) gag/pol DNA and recombinant vaccinia virus strain DIs elicits effective anti-SIV immunity. J Virol 2004; 78:9842-53. [PMID: 15331719 PMCID: PMC515009 DOI: 10.1128/jvi.78.18.9842-9853.2004] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
To evaluate immunity induced by a novel DNA prime-boost regimen, we constructed a DNA plasmid encoding the gag and pol genes from simian immunodeficiency virus (SIV) (SIVgag/pol DNA), in addition to a replication-deficient vaccinia virus strain DIs recombinant expressing SIV gag and pol genes (rDIsSIVgag/pol). In mice, priming with SIVgag/pol DNA, followed by rDIsSIVgag/pol induced an SIV-specific lymphoproliferative response that was mediated by a CD4+-T-lymphocyte subset. Immunization with either vaccine alone was insufficient to induce high levels of proliferation or Th1 responses in the animals. The prime-boost regimen also induced SIV Gag-specific cellular responses based on gamma interferon secretion, as well as cytotoxic-T-lymphocyte responses. Thus, the regimen of DNA priming and recombinant DIs boosting induced Th1-type cell-mediated immunity, which was associated with resistance to viral challenge with wild-type vaccinia virus expressing SIVgag/pol, suggesting that this new regimen may hold promise as a safe and effective vaccine against human immunodeficiency virus type 1.
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Affiliation(s)
- Kenji Someya
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
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31
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Chaui-Berlinck JG, Barbuto JAM, Monteiro LHA. Conditions for pathogen elimination by immune systems. Theory Biosci 2004; 123:195-208. [PMID: 18236099 DOI: 10.1016/j.thbio.2004.01.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
A continuous harvest effort can lead a population to extinction. How an "unconscious" immune system would perpetrate such an effort in order to eliminate a self-replicating antigen (a pathogen) becomes an intriguing problem if the system responses are functions of the pathogen population: the responses cannot be a continuous effort as the pathogen vanishes. On theoretical grounds, we show some qualities an immune response must have to support pathogen elimination. Then, three specific mechanisms are addressed: a pathogen-independent positive feedback loop among the responding cells of the system (e.g., B-lymphocyte and T-helper); the persistence of antigen bound to presenting cells; and the programmed expansion/contraction of a pool of responding cells. The maintenance of responding cells due to these mechanisms is the essential feature to the effective clearance of self-replicating agents. Thus, evolutionarily, the primary function of a helper lymphocyte would be to amplify a response and the primary function of memory would be the very elimination of pathogens.
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Affiliation(s)
- José Guilherme Chaui-Berlinck
- Departamento de Fisiologia, Instituto de Biociências, da Universidade de São Paulo, Rua do Matao tr. 14, 321, 05508-900, São Paulo, SP, Brazil,
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32
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Draenert R, Verrill CL, Tang Y, Allen TM, Wurcel AG, Boczanowski M, Lechner A, Kim AY, Suscovich T, Brown NV, Addo MM, Walker BD. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. J Virol 2004; 78:630-41. [PMID: 14694094 PMCID: PMC368768 DOI: 10.1128/jvi.78.2.630-641.2004] [Citation(s) in RCA: 119] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
CD8 T-cell responses are thought to be crucial for control of viremia in human immunodeficiency virus (HIV) infection but ultimately fail to control viremia in most infected persons. Studies in acute infection have demonstrated strong CD8-mediated selection pressure and evolution of mutations conferring escape from recognition, but the ability of CD8 T-cell responses that persist in late-stage infection to recognize viruses present in vivo has not been determined. Therefore, we studied 24 subjects with advanced HIV disease (median viral load = 142,000 copies/ml; median CD4 count = 71/ micro l) and determined HIV-1-specific CD8 T-cell responses to all expressed viral proteins using overlapping peptides by gamma interferon Elispot assay. Chronic-stage virus was sequenced to evaluate autologous sequences within Gag epitopes, and functional avidity of detected responses was determined. In these subjects, the median number of epitopic regions targeted was 13 (range, 2 to 39) and the median cumulative magnitude of CD8 T-cell responses was 5,760 spot-forming cells/10(6) peripheral blood mononuclear cells (range, 185 to 24,700). On average six (range, one to 8) proteins were targeted. For 89% of evaluated CD8 T-cell responses, the autologous viral sequence was predicted to be well recognized by these responses and the majority of analyzed optimal epitopes were recognized with medium to high functional avidity by the contemporary CD8 T cells. Withdrawal of antigen by highly active antiretroviral therapy led to a significant decline both in breadth (P = 0.032) and magnitude (P = 0.0098) of these CD8 T-cell responses, providing further evidence that these responses had been driven by recognition of autologous virus. These results indicate that strong, broadly directed, and high-avidity gamma-interferon-positive CD8 T-cells directed at autologous virus persist in late disease stages, and the absence of mutations within viral epitopes indicates a lack of strong selection pressure mediated by these responses. These data imply functional impairment of CD8 T-cell responses in late-stage infection that may not be reflected by gamma interferon-based screening techniques.
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Affiliation(s)
- R Draenert
- Howard Hughes Medical Institute, Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School Division of AIDS, Boston, Massachusetts 02129, USA
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33
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Pires A, Pido-Lopez J, Moyle G, Gazzard B, Gotch F, Imami N. Enhanced T-Cell Maturation, Differentiation and Function in HIV-1-Infected Individuals after Growth Hormone and Highly Active Antiretroviral Therapy. Antivir Ther 2004. [DOI: 10.1177/135965350400900110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Strong virus-specific helper and cytotoxic T-cell responses correlate with non-progression during HIV-1 infection. Administration of antiretroviral therapy (ART) during the chronic phases of HIV-1 infection fails to restore these responses in most patients. Design and methods We assessed the changes in immune function of 12 HIV-1-positive individuals treated with ART for over 4 years, who received 4 mg/day of recombinant human growth hormone (rhGH) for 12 weeks and were then randomized into groups receiving either placebo, twice weekly or alternate day dosing of rhGH. Peripheral blood was drawn for phenotypic analysis and functional assays at time points 0, 12 and 24 weeks. Results At week 12, we observed significant increases in naive CD4 T cells ( P<0.01) and effector CD8 T cells based on CD45RA and CCR7 expression ( P<0.02). In addition, we observed a rise in HIV-1 antigen-specific CD4 ( P<0.005) and CD8 ( P<0.05) T-cell responses. Twelve weeks post-randomization into placebo, alternate day or twice weekly dosing (24 weeks post-baseline), the phenotype and function of the virus-specific effector CD8 T cells seen at week 12 was maintained in most patients regardless of randomization arm and despite the disappearance of HIV-1-specific CD4 T-cell responses. Conclusions Concomitant administration of rhGH at 4 mg/day with highly active ART appears to partially reverse some of the defects exerted on the immune system by HIV-1. This combination may represent a valuable immunotherapeutic intervention aiding in the treatment of chronic HIV-1 infection.
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Affiliation(s)
- Antonio Pires
- Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, UK
| | - Jeffrey Pido-Lopez
- Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, UK
| | - Graeme Moyle
- Department of HIV/GU Medicine, Imperial College, Chelsea & Westminster Hospital, London, UK
| | - Brian Gazzard
- Department of HIV/GU Medicine, Imperial College, Chelsea & Westminster Hospital, London, UK
| | - Frances Gotch
- Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, UK
| | - Nesrina Imami
- Department of Immunology, Imperial College, Chelsea & Westminster Hospital, London, UK
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Banks HT, Bortz DM, Holte SE. Incorporation of variability into the modeling of viral delays in HIV infection dynamics. Math Biosci 2003; 183:63-91. [PMID: 12604136 DOI: 10.1016/s0025-5564(02)00218-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We consider classes of functional differential equation models which arise in attempts to describe temporal delays in HIV pathogenesis. In particular, we develop methods for incorporating arbitrary variability (i.e., general probability distributions) for these delays into systems that cannot readily be reduced to a finite number of coupled ordinary differential equations (as is done in the method of stages). We discuss modeling from first principles, introduce several classes of non-linear models (including discrete and distributed delays) and present a discussion of theoretical and computational approaches. We then use the resulting methodology to carry out simulations and perform parameter estimation calculations, fitting the models to a set of experimental data. Results obtained confirm the statistical significance of the presence of delays and the importance of including delays in validating mathematical models with experimental data. We also show that the models are quite sensitive to the mean of the distribution which describes the delay in viral production, whereas the variance of this distribution has relatively little impact.
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Affiliation(s)
- H T Banks
- Center for Research in Scientific Computation, Box 8205, North Carolina State University, Raleigh, NC 27695-8205, USA.
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35
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Shedlock DJ, Whitmire JK, Tan J, MacDonald AS, Ahmed R, Shen H. Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 170:2053-63. [PMID: 12574376 DOI: 10.4049/jimmunol.170.4.2053] [Citation(s) in RCA: 123] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
CD4 T cells are known to assist the CD8 T cell response by activating APC via CD40-CD40 ligand (L) interactions. However, recent data have shown that bacterial products can directly activate APC through Toll-like receptors, resulting in up-regulation of costimulatory molecules necessary for the efficient priming of naive T cells. It remains unclear what role CD4 T cell help and various costimulation pathways play in the development of CD8 T cell responses during bacterial infection. In this study, we examined these questions using an intracellular bacterium, Listeria monocytogenes, as a model of infection. In CD4 T cell-depleted, CD4(-/-), and MHC class II(-/-) mice, L. monocytogenes infection induced CD8 T cell activation and primed epitope-specific CD8 T cells to levels commensurate with those in normal C57BL/6 mice. Furthermore, these epitope-specific CD8 T cells established long-term memory in CD4(-/-) mice that was capable of mounting a protective recall response. In vitro analysis showed that L. monocytogenes directly stimulated the activation and maturation of murine dendritic cells. The CD8 T cell response to L. monocytogenes was normal in CD40L(-/-) mice but defective in CD28(-/-) and CD137L(-/-) mice. These data show that in situations where infectious agents or immunogens can directly activate APC, CD8 T cell responses are less dependent on CD4 T cell help via the CD40-CD40L pathway but involve costimulation through CD137-CD137L and B7-CD28 interactions.
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MESH Headings
- 4-1BB Ligand
- Animals
- Antigens, CD
- CD4 Antigens/genetics
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/microbiology
- CD40 Antigens/metabolism
- CD40 Antigens/physiology
- CD40 Ligand/metabolism
- CD40 Ligand/physiology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/microbiology
- Cells, Cultured
- Cytotoxicity, Immunologic/genetics
- Dendritic Cells/immunology
- Dendritic Cells/metabolism
- Dendritic Cells/microbiology
- Female
- Histocompatibility Antigens Class II/genetics
- Immunologic Memory/genetics
- Ligands
- Listeria monocytogenes/immunology
- Listeriosis/genetics
- Listeriosis/immunology
- Lymphocyte Activation/genetics
- Lymphocyte Cooperation/genetics
- Lymphocyte Cooperation/immunology
- Lymphocyte Depletion
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Receptors, Nerve Growth Factor/metabolism
- Receptors, Nerve Growth Factor/physiology
- Receptors, Tumor Necrosis Factor/metabolism
- Receptors, Tumor Necrosis Factor/physiology
- Tumor Necrosis Factor Receptor Superfamily, Member 9
- Tumor Necrosis Factor-alpha/metabolism
- Tumor Necrosis Factor-alpha/physiology
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Affiliation(s)
- Devon J Shedlock
- Department of Microbiology, School of Medicine, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104-6076, USA
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Altes HK, Wodarz D, Jansen VAA. The dual role of CD4 T helper cells in the infection dynamics of HIV and their importance for vaccination. J Theor Biol 2002; 214:633-46. [PMID: 11851372 DOI: 10.1006/jtbi.2001.2483] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Given the role of the CD4 T helper cells in the development of memory CTL precursors, it seems beneficial to boost the CD4 T helper response in the context of vaccination against the human immunodeficiency virus (HIV). However, CD4 T cells are also the preferred targets of infection by HIV. Here, we address the question as to whether it is advantageous to stimulate the CD4 T helper cell response, as this will increase the pool of potential target cells of infection. To do so we formulated a mathematical model describing the interactions between virus-infected cells, susceptible cells, HIV-specific CD4 helper T cells, and CTL precursor (CTLp) and effector cells (CTLe). The effect of increased initial CD4 helper and CTLp numbers on the outcome of infection, as well as the effect on viral set point of increased CD4 T helper growth rate, CTL responsiveness and the rate at which CTLp and CTLe are produced were studied. We found that only when the virus has a low basic reproductive number does the number of CTLp and CD4 T helper cells at the moment of infection influence the outcome of infection. In this situation, high initial T helper and CTL numbers can switch the outcome from full-blown infection to virus control. However, this holds for virus with infectivity in a limited range, and current estimates of virus infectivity suggest that it is higher. In that case, only a vaccination protocol that increases CTL responsiveness, ideally in combination with the rate of production of CD4 T helper cells, may offer a solution as it can reduce the viral set point considerably. If brought under a certain level, the viral population might be unable to replicate any further. However, changing these parameters of the immune response is only beneficial when infection is controlled by CTL in the long term. When a CD4 lymphoproliferative response is mounted but the CTL response is not maintained, increasing the CD4 T helper growth rate is deleterious.
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Affiliation(s)
- H Korthals Altes
- Laboratoire d'Immunologie Cellulaire et Tissulaire, CH Pitié-Salpétrière, 91, Bd de l'hôpital, Paris, 75013, France.
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Abstract
During the past 6 years, there have been substantial advances in our understanding of human immunodeficiency virus 1 and other viruses, such as hepatitis B virus and hepatitis C virus, that cause chronic infection. The use of mathematical modelling to interpret experimental results has made a significant contribution to this field. Mathematical modelling is also improving our understanding of T-cell dynamics and the quantitative events that underlie the immune response to pathogens.
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Affiliation(s)
- Alan S Perelson
- Theoretical Division, Los Alamos National Laboratory, New Mexico 87545, USA.
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38
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Wodarz D. Helper-dependent vs. helper-independent CTL responses in HIV infection: implications for drug therapy and resistance. J Theor Biol 2001; 213:447-59. [PMID: 11735291 DOI: 10.1006/jtbi.2001.2426] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Clinical data from HIV-infected patients, as well as theoretical studies, suggest that CTL responses in the presence and absence of CD4 cell help are qualitatively different. In the presence of help, CTL responses are maintained despite very low antigenic loads and control the infection in the long term. In the absence of specific helper cell responses, CTL require high antigenic loads to be maintained, are short lived at low levels of antigen, and do not control the infection in the long term. This paper describes mathematical models analysing the dynamics of helper-dependent and helper-independent CTL in HIV infection with special focus on the dynamics during drug therapy in chronic infection. Theory suggests that a fast rate of virus spread results in high degrees of helper cell impairment which promotes the development of helper-independent CTL responses and compromised immunological control. In agreement with clinical findings, the model suggests that upon start of therapy, there is a transient increase in the level of CTL, followed by a decline to low levels once virus load has been significantly suppressed. According to the model, the presence of helper-independent CTL can promote the establishment of a helper-dependent memory response. Interestingly, this gives rise to the prediction that a relatively early stop of therapy, before the level of CTL has fallen below a threshold, can promote improved immunological control. Issues concerning the timing and duration of treatment are discussed. The CTL kinetics during drug therapy also provide new insights into the principles underlying the emergence of drug-resistant strains during the course of treatment.
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Affiliation(s)
- D Wodarz
- Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.
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