• AIDS
• HIV
• NLR
• PFS
• meta-analysis
• mortality
• prognosis

• Air pollutant
• Ground-based observations
• Outliers detection
• Particulate matter
• Residual analysis
• Time-series data

• Air Pollution
• Air Pollutants/analysis
• Environmental Monitoring/methods
• Particulate Matter/analysis
• Probability
• Cities

• human immunodeficiency virus
• interleukin-10
• preeclampsia

• Humans
• Interleukin-10/metabolism
• Interleukin-10/genetics
• Pregnancy
• HIV Infections/complications
• HIV Infections/immunology
• Pre-Eclampsia/immunology
• Pre-Eclampsia/virology
• Female
• Pregnancy Complications, Infectious/immunology
• Comorbidity

• Humans
• Particulate Matter/adverse effects
• Particulate Matter/analysis
• Air Pollutants/adverse effects
• Air Pollutants/analysis
• Air Pollution/adverse effects
• Air Pollution/analysis
• Acquired Immunodeficiency Syndrome
• HIV Infections/complications
• Renal Insufficiency, Chronic/epidemiology
• Renal Insufficiency/chemically induced
• Kidney

• HIV neuropathogenesis
• Vpr
• inflammation
• polymorphisms
• sequence variations

• NRF Thuthuka
• Poliomyelitis Research Foundation
• NRF
• PRF

• HIV-1
• drug delivery
• exosomes
• immune system
• vaccine

• Humans
• Exosomes/metabolism
• HIV-1
• Drug Delivery Systems
• Vaccine Development

• SARS-CoV-2
• human endogenous retrovirus K
• human immunodeficiency virus
• inflammation
• pulmonary arterial hypertension

• Humans
• Endogenous Retroviruses
• HIV
• Pulmonary Arterial Hypertension
• SARS-CoV-2
• COVID-19
• Familial Primary Pulmonary Hypertension
• Inflammation
• HIV Infections

• R01 HL111656 NHLBI NIH HHS
• R01 HL127342 NHLBI NIH HHS

• AIDS
• HIV
• SMAD2/3
• TGF-β
• inflammation

• AIDS
• HIV
• high-sensitivity C-reactive protein
• hypertension
• inflammation markers

• National Health Commission of the People's Republic of China

• CD4+T cells
• GALT
• IL-1R1/IL-1R3
• caspase-1
• inflammation
• monocytes/macrophages
• pyroptosis

• HIV
• aging
• immunosenescence
• inflammation

• Exosomes
• Extracellular vesicles
• HIV-1
• HTLV-1
• Retroviruses

• Antiretroviral therapy
• Cardiovascular disease
• HIV
• Heart ischemic disease

• CD4
• HIV
• diabetes
• mellitus

Several cellular functions such as apoptosis, cellular proliferation, inflammation, and immune regulation involve the tumor necrosis factor-α (TNF)/TNF receptor (TNFR) pathway. Human immunodeficiency virus 1 (HIV-1) interacts with the TNF/TNFR pathway. The activation of the TNF/TNFR pathway impacts HIV-1 replication, and the TNF/TNFR pathway is the target of HIV-1 proteins. A hallmark of HIV-1 infection is immune activation and inflammation with increased levels of TNF in the plasma and the tissues. Therefore, the control of the TNF/TNFR pathway by new therapeutic approaches could participate in the control of immune activation and impact both viral replication and viral persistence. In this review, we will describe the intricate interplay between HIV-1 proteins and TNF/TNFR signaling and how TNF/TNFR activation modulates HIV-1 replication and discuss new therapeutic approaches, especially anti-TNF therapy, that could control this pathway and ultimately favor the clearance of infected cells to cure HIV-infected patients.

• HIV-1
• TNF
• TNF receptor
• anti-TNF therapy
• immune activation
• reservoirs

• HIV Infections/immunology
• HIV Infections/pathology
• HIV-1/immunology
• HIV-1/pathogenicity
• Host-Pathogen Interactions
• Human Immunodeficiency Virus Proteins/metabolism
• Humans
• Receptors, Tumor Necrosis Factor/metabolism
• Signal Transduction
• Tumor Necrosis Factor-alpha/metabolism

• HIV-1
• Inflammasome
• Inflammation
• Innate immunity
• Metabolism

• HIV-1
• Immuno-metabolism
• Inflammation
• Innate/adaptive immunity

• Adaptive Immunity
• Adult
• Cytokines/immunology
• Cytokines/metabolism
• Glucose/metabolism
• HIV Infections/immunology
• HIV Infections/metabolism
• HIV Infections/virology
• HIV-1/pathogenicity
• Humans
• Immunity, Innate
• Inflammation/etiology
• Inflammation/virology
• Lipid Metabolism
• Oxidative Stress
• T-Lymphocytes/immunology
• T-Lymphocytes/physiology
• Tryptophan/metabolism
• Viral Proteins/immunology

Tumor necrosis factor (TNF) and TNF receptors (TNFR) superfamily members are engaged in diverse cellular phenomena such as cellular proliferation, morphogenesis, apoptosis, inflammation, and immune regulation. Their role in regulating viral infections has been well documented. Viruses have evolved with numerous strategies to interfere with TNF-mediated signaling indicating the importance of TNF and TNFR superfamily in viral pathogenesis. Recent research reports suggest that TNF and TNFRs play an important role in the pathogenesis of HIV. TNFR signaling modulates HIV replication and HIV proteins interfere with TNF/TNFR pathways. Since immune activation and inflammation are the hallmark of HIV infection, the use of TNF inhibitors can have significant impact on HIV disease progression. In this review, we will describe how HIV infection is modulated by signaling mediated through members of TNF and TNFR superfamily and in turn how these latter could be targeted by HIV proteins. Finally, we will discuss the emerging therapeutics options based on modulation of TNF activity that could ultimately lead to the cure of HIV-infected patients.

The pathophysiological mechanisms that underlie the progression of human immunodeficiency virus-1 (HIV-1) disease to full-blown AIDS are not well understood. Findings suggest that, during HIV-1 infection, plasma lipopolysaccharide (LPS) levels, which are used as an indicator of microbial translocation (MT), are elevated throughout the acute and chronic phases of HIV-1 disease. The translocation of bacterial products through the damaged gastrointestinal barrier into the systemic circulation has been described as a driver of immune activation. In contrast, comorbidities that are associated with HIV-1 infection have been attributed to chronic inflammation and immune system dysfunction secondary to MT or low-level HIV-1 replication in plasma and cell reservoirs. Moreover, accelerated aging is significantly associated with chronic inflammation, immune activation, and immune senescence. In this review, we aimed to investigate the role of inflammation as a pivotal marker in the pathogenesis of HIV-1 disease. We will discuss the key features of chronic inflammation and immune activation that are observed during the natural course of the disease and those features that are detected in cART-modified infection. The review will focus on the following aspects of HIV-1 infection: (1) MT; (2) the role of residual viremia; and (3) “immune senescence” or “inflammaging.” Many questions remain unanswered about the potential mechanisms that are involved in HIV-1 pathogenesis. Further studies are needed to better investigate the mechanisms that underlie immune activation and their correlation with HIV-1 disease progression.

• Human immunodeficiency virus-1
• Combined antiretroviral therapy
• Immune activation
• Microbial translocation
• Residual viremia
• Immune senescence

• HIV
• T cells
• activation
• cytokines
• inflammation
• semen

Platelets, anucleate cell fragments abundant in human blood, can capture HIV-1 and platelet counts have been associated with viral load and disease progression. However, the impact of platelets on HIV-1 infection of T cells is unclear.

We found that platelets suppress HIV-1 spread in co-cultured T cells in a concentration-dependent manner. Platelets containing granules inhibited HIV-1 spread in T cells more efficiently than degranulated platelets, indicating that the granule content might exert antiviral activity. Indeed, supernatants from activated and thus degranulated platelets suppressed HIV-1 infection. Infection was inhibited at the stage of host cell entry and inhibition was independent of the viral strain or coreceptor tropism. In contrast, blockade of HIV-2 and SIV entry was less efficient. The chemokine CXCL4, a major component of platelet granules, blocked HIV-1 entry and neutralization of CXCL4 in platelet supernatants largely abrogated their anti-HIV-1 activity.

Release of CXCL4 by activated platelets inhibits HIV-1 infection of adjacent T cells at the stage of virus entry. The inhibitory activity of platelet-derived CXCL4 suggests a role of platelets in the defense against infection by HIV-1 and potentially other pathogens.

HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42–45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38–40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity.

Fever is a complex reaction triggered in response to pathogen infection. It induces diverse effects on the human body and especially on the immune system. The functions of immune cells are positively affected by fever, helping them to fight infection. Fever consists in a physiological elevation of temperature and in inflammation. While the role of inflammatory molecules on HIV-1 replication has been widely studied, little is known about the direct effect of temperature on viral replication. Here, we report that hyperthermia (39.5°C) boosts HIV-1 replication in CD4+ T cells. In single-cycle infection experiments, hyperthermia increased HIV-1 infection up to 7-fold. This effect was mediated in part by an increased activation of the HIV-1 promoter by the viral protein Tat. Our results also indicate that hyperthermia may help HIV-1 to reactivate from latency. We also show that the Heat Shock Protein Hsp90, which levels are increased at 39.5°C, mediates in a large part the positive effect of hyperthermia on HIV-1 infection. Our work suggests that in HIV-1-infected patients, fever episodes may facilitate viral replication.

• Benzoquinones/pharmacology
• CD4-Positive T-Lymphocytes/virology
• Fever/physiopathology
• Gene Expression Regulation, Viral
• HIV Infections/metabolism
• HIV Infections/virology
• HIV Long Terminal Repeat/genetics
• HIV-1/physiology
• HSP90 Heat-Shock Proteins/antagonists & inhibitors
• HSP90 Heat-Shock Proteins/metabolism
• HeLa Cells
• Hot Temperature
• Humans
• Jurkat Cells
• Lactams, Macrocyclic/pharmacology
• Promoter Regions, Genetic
• Transcriptional Activation
• Virus Activation
• Virus Latency
• Virus Replication/drug effects
• tat Gene Products, Human Immunodeficiency Virus/metabolism

• G0900950 Medical Research Council

Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.

To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.

The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006). These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy). As plasma HIV levels fell with interferon therapy, this was correlated with a “paradoxical” increase in CD8+ T cell activation (p<0.001).

Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection.

A massive and selective loss of CD4+ memory T cells occurs during the acute phase of immunodeficiency virus infections. The mechanism of this depletion is poorly understood but constitutes a key event with implications for progression. We assessed gene expression of purified T cells in Rhesus Macaques during acute SIVmac239 infection in order to define mechanisms of pathogenesis. We observe a general transcriptional program of over 1,600 interferon-stimulated genes induced in all T cells by the infection. Furthermore, we identify 113 transcriptional changes that are specific to virally infected cells. A striking downregulation of several key cell cycle regulator genes was observed and shared promotor-region E2F binding sites in downregulated genes suggested a targeted transcriptional control of an E2F regulated cell cycle program. In addition, the upregulation of the gene for the fundamental regulator of RNA polymerase II, TAF7, demonstrates that viral interference with the cell cycle and transcriptional regulation programs may be critical components during the establishment of a pathogenic infection in vivo.

• Animals
• CD4-Positive T-Lymphocytes/virology
• Cell Cycle/genetics
• Down-Regulation
• Gene Expression Profiling
• Host-Pathogen Interactions/genetics
• Macaca mulatta
• Repressor Proteins
• Simian Acquired Immunodeficiency Syndrome/virology
• Simian Immunodeficiency Virus/physiology
• Transcription, Genetic

• Intramural NIH HHS

Human cytomegalovirus (CMV) is a ubiquitous DNA virus that causes severe disease in patients with immature or impaired immune systems. During active infection, CMV modulates host immunity, and CMV-infected patients often develop signs of immune dysfunction, such as immunosuppression and autoimmune phenomena. Furthermore, active viral infection has been observed in several autoimmune diseases, and case reports have linked primary CMV infection and the onset of autoimmune disorders. In addition, CMV infection promotes allograft rejection and graft-versus-host disease in solid organ and bone marrow transplant recipients, respectively, further implicating CMV in the genesis and maintenance of immunopathological phenomena. The mechanisms by which CMV could induce inhibition of host defense, inflammation, and autoimmunity are discussed, as is the treatment of virus-induced immunopathology with antivirals.

• collapsing glomerulopathy
• gene expression
• glomerulonephritis
• hiv-1
• inflammation
• podocytes
• proliferation
• tumor necrosis factor

• Biomarkers/metabolism
• Cardiovascular Diseases/metabolism
• Cardiovascular Diseases/virology
• HIV Infections/complications
• HIV Infections/metabolism
• Humans

• R01 HL090934 NHLBI NIH HHS
• 1R01HL 090934-01 NHLBI NIH HHS
• 1R01HL095417-01 NHLBI NIH HHS
• K12 RR023247 NCRR NIH HHS
• KL2 RR033182 NCRR NIH HHS
• 5 K12 RR023247 NCRR NIH HHS

• Dendritic Cells/metabolism
• Gene Products, vpr/metabolism
• HIV Infections/metabolism
• Humans
• Immunosuppressive Agents/pharmacology
• Interleukin-12/metabolism
• Mucous Membrane/metabolism
• Mucous Membrane/virology
• Mutation
• Plasmids/metabolism
• Protein Structure, Tertiary
• RNA, Viral/metabolism
• Transcription, Genetic
• Ubiquitin/metabolism
• Virulence Factors
• vpr Gene Products, Human Immunodeficiency Virus/chemistry
• vpr Gene Products, Human Immunodeficiency Virus/metabolism

Visceral leishmaniasis has emerged as an important opportunistic disease among patients infected with HIV-1. Both HIV-1 and the protozoan parasite Leishmania can productively infect cells of the macrophage-dendritic cell lineage.

Here we demonstrate that Leishmania infantum amastigotes increase HIV-1 production when human primary dendritic cells (DCs) are cocultured together with autologous CD4⁺ T cells. Interestingly, the promastigote form of the parasite does not modulate virus replication. Moreover, we report that amastigotes promote virus replication in both cell types. Our results indicate that this process is due to secretion of parasite-induced soluble factors by DCs. Luminex micro-beads array system analyses indicate that Leishmania infantum amastigotes induce a higher secretion of several cytokines (i.e. IL-1α, IL-2, IL-6, IL-10 and TNF-α) and chemokines (i.e. MIP-1α, MIP-1β and RANTES) in these cells. Studies conducted with pentoxifylline and neutralizing antibodies revealed that the Leishmania-dependent augmentation in HIV-1 replication is due to a higher secretion of IL-6 and TNF-α.

Altogether these findings suggest that the presence of Leishmania within DC/T-cell conjugates leads to an enhancement of virus production and demonstrate that HIV-1 and Leishmania can establish complex interactions in such a cellular microenvironment.

Visceral leishmaniasis (VL) is a potentially deadly parasitic disease afflicting millions worldwide. Although itself an important infectious illness, VL has also emerged as an opportunistic disease among patients infected with HIV-1. This is partly due to the increasing overlap between urban regions of high HIV-1 transmission and areas where Leishmania is endemic. Furthermore, VL increases the development and clinical progression of AIDS-related diseases. Conversely, HIV-1-infected individuals are at greater risk of developing VL or suffering relapse. Finally, HIV-1 and Leishmania can both productively infect cells of the macrophage-dendritic cell lineage, resulting in a cumulative deficiency of the immune response. We therefore studied the effect of Leishmania infantum on HIV-1 production when dendritic cells (DCs) are cocultured with autologous CD4⁺ T cells. We show that amastigotes promote virus replication in both DCs and lymphocytes, due to a parasite-mediated production of soluble factors by DCs. Micro-beads array analyses indicate that Leishmania infantum amastigotes infection induces a higher secretion of several cytokines in these cells, and use of specific neutralizing antibodies revealed that the Leishmania-induced increase in HIV-1 replication is due to IL-6 and TNF-α. These findings suggest that Leishmania's presence within DC/T-cell conjugates leads to an enhanced HIV-1 production.

• CD4-Positive T-Lymphocytes/metabolism
• Cells, Cultured
• Dendritic Cells/metabolism
• Dendritic Cells/parasitology
• Dendritic Cells/virology
• HIV-1/growth & development
• Humans
• Interleukin-6/metabolism
• Leishmania infantum/growth & development
• Leishmania infantum/immunology
• Tumor Necrosis Factor-alpha/metabolism

• MGC-14500 Canadian Institutes of Health Research
• MOP-84555 Canadian Institutes of Health Research

Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner.

To study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells) were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Δenv-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs) or MOLT4 cells (CD4+ CCR5+) by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner.

Oral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h.