RESUMO
The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.
Assuntos
Microbioma Gastrointestinal , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Terapia Antirretroviral de Alta Atividade , Biodiversidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocinas/sangue , Estudos de Coortes , Glicólise , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Inflamação/genética , Inflamação/patologia , Mitocôndrias/metabolismo , Monócitos/metabolismo , Ácidos Nucleicos/sangue , Análise de Componente Principal , Serratia/fisiologia , Células Th1/imunologia , Células Th2/imunologia , Transcrição Gênica , Uganda , Carga Viral/imunologiaRESUMO
CD8 T cells are emerging as important mediators in atherosclerosis and cardiovascular disease (CVD). Immune activation may play a particular role in people with HIV (PWH) who are at an increased risk of CVD, even after controlling for known CVD risk factors. Latent CMV infection is associated with increased CVD risk for both PWH and people without HIV, and human CMV-specific CD4 and CD8 T cells are enriched for an immunosenescent phenotype. We previously showed that CMV coinfection in PWH promotes vascular homing and activation of inflammatory CD4 T cells through the CD2-LFA-3 axis. However, the role of CD2/LFA3 costimulation of CD8 T cells in PWH with CMV has yet to be described. In the present study, we demonstrate that CD2 expression on CX3CR1+CD57+CD28- inflammescent CD8 T cells is increased on cells from CMV-seropositive PWH. In vitro CD2/LFA-3 costimulation enhances TCR-mediated activation of these inflammatory CD8 memory T cells. Finally, we show that LFA-3 is highly expressed in aortas of SIV-infected rhesus macaques and in atherosclerotic plaques of people without HIV. Our findings are consistent with a model in which CMV infection enhances CD2 expression on highly proinflammatory CD8 T cells that can then be stimulated by LFA-3 expressed in the vasculature, even in the absence of CD28 costimulation. This model, in which CMV infection exacerbates toxic cytokine and granzyme production by CD8 T cells within the vasculature, highlights a potential therapeutic target in atherosclerosis development and progression, especially for PWH.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Infecções por Citomegalovirus , Infecções por HIV , Animais , Humanos , Antígenos CD28/metabolismo , Infecções por HIV/tratamento farmacológico , Citomegalovirus , Antígenos CD58/metabolismo , Macaca mulatta , Linfócitos T CD8-Positivos , Linfócitos T CD4-Positivos , Aterosclerose/metabolismoRESUMO
HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.
Assuntos
Linfócitos T CD8-Positivos , Infecções por HIV , Humanos , Células Matadoras Naturais , Ativação Linfocitária , RNA , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , ViremiaRESUMO
Plasma extracellular vesicle (EV)-associated cytokines were quantified in people with HIV (PWH) with different virological control status, including elite controllers (EC) who maintain persistent control (PC) or not (TC). Cytokine signatures and pathways were determined for each group. Median EV-associated cytokine levels were higher among PWH than HIV-uninfected. EC showed the highest levels of EV-associated cytokines among PWH with PC levels higher than TC levels. IL-18 levels best distinguished PWH from uninfected controls, and EC from ART-treated, and IL-3 distinguished PC from TC. The role of EV-cytokines in intercellular communication and endogenous control of HIV expression should be investigated further.
Assuntos
Vesículas Extracelulares , Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , HIV-1/metabolismo , Interleucina-18/metabolismo , Interleucina-3 , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Biomarcadores , Vesículas Extracelulares/metabolismoRESUMO
Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates.
Assuntos
Infecções por Citomegalovirus , Infecções por HIV , Masculino , Humanos , Feminino , Citomegalovirus/genética , DNA Viral/genética , Infecções por HIV/complicações , HIV/genética , Inflamação/complicações , Eliminação de Partículas ViraisRESUMO
BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.
Assuntos
Infecções por HIV , Interleucina-6 , Humanos , Infecções por HIV/tratamento farmacológico , Inflamação/tratamento farmacológico , Interleucina-6/metabolismo , Lipídeos , Estudos Cross-OverRESUMO
Latent HIV-1 persists indefinitely during antiretroviral therapy (ART) as an integrated silent genome in long-lived memory CD4+ T cells. In untreated infections, immune activation increases the turnover of intrinsically long-lived provirus-containing CD4+ T cells. Those are 'washed out' as a result of their activation, which when coupled to viral protein expression can facilitate local inflammation and recruitment of uninfected cells to activation sites, causing latently infected cells to compete for survival. De novo infection can counter this washout. During ART, inflammation and CD4+ T cell activation wane, resulting in reduced cell turnover and a persistent reservoir. We propose accelerating reservoir washout during ART by triggering sequential waves of polyclonal CD4+ T cell activation while simultaneously enhancing virus protein expression. Reservoir reduction as an adjunct to other therapies might achieve lifelong viral control.
Assuntos
Infecções por HIV , HIV-1 , Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , Humanos , Ativação Linfocitária , Latência Viral/efeitos dos fármacos , Latência Viral/imunologiaRESUMO
BACKGROUND: The role of extracellular vesicles (EVs) in human immunodeficiency virus (HIV) pathogenesis is unknown. We examine the cellular origin of plasma microvesicles (MVs), a type of ectocytosis-derived EV, the presence of mitochondria in MVs, and their relationship to circulating cell-free mitochondrial deoxyribonucleic acid (ccf-mtDNA) in HIV-infected patients and controls. METHODS: Five participant groups were defined: 30 antiretroviral therapy (ART)-naive; 30 ART-treated with nondetectable viremia; 30 elite controllers; 30 viremic controllers; and 30 HIV-uninfected controls. Microvesicles were quantified and characterized from plasma samples by flow cytometry. MitoTrackerDeepRed identified MVs containing mitochondria and ccf-mtDNA was quantified by real-time polymerase chain reaction. RESULTS: Microvesicle numbers were expanded at least 10-fold in all HIV-infected groups compared with controls. More than 79% were platelet-derived MVs. Proportions of MVs containing mitochondria (22.3% vs 41.6%) and MV mitochondrial density (706 vs 1346) were significantly lower among HIV-infected subjects than controls, lowest levels for those on ART. Microvesicle numbers correlated with ccf-mtDNA levels that were higher among HIV-infected patients. CONCLUSIONS: A massive release of platelet-derived MVs occurs during HIV infection. Some MVs contain mitochondria, but their proportion and mitochondrial densities were lower in HIV infection than in controls. Platelet-derived MVs may be biomarkers of platelet activation, possibly reflecting pathogenesis even in absence of HIV replication.
Assuntos
Micropartículas Derivadas de Células , Vesículas Extracelulares , Infecções por HIV , DNA Mitocondrial , Humanos , Tetraspanina 29 , ViremiaRESUMO
BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (Pâ =â .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; Pâ =â .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.
Assuntos
Infecções por HIV , Pirimidinas , Adulto , HIV , Humanos , Nitrilas/uso terapêutico , Pirazóis , Pirimidinas/uso terapêuticoRESUMO
T-cell accumulation in atherosclerotic plaques contributes to plaque destabilization. We found that several chemokine receptors are differentially expressed on peripheral blood compared to plaque-resident T cells and corresponding ligands are upregulated in plaques. These data indicate that T-cell migration into human atherosclerotic plaques may predominantly occur via CCR5-CCL3 and CX3CR1-CX3CL1 interactions.
Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Movimento Celular/fisiologia , Quimiocina CCL3/metabolismo , Quimiocina CX3CL1/metabolismo , Placa Aterosclerótica/metabolismo , Receptores CCR5/metabolismo , Linfócitos T/metabolismo , Aterosclerose/metabolismo , Células Cultivadas , HumanosRESUMO
Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.
Assuntos
Aterosclerose/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CX3CL1/metabolismo , Infecções por HIV/metabolismo , Interleucina-15/metabolismo , Idoso , Animais , Células Endoteliais/metabolismo , Humanos , Macaca mulatta/metabolismo , Receptores de Quimiocinas/metabolismoRESUMO
People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1ß, TLR expression, PPAR ßδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.
Assuntos
Aterosclerose/etiologia , Infecções por HIV/virologia , HIV/imunologia , Lipídeos/sangue , Macrófagos/patologia , Modelos Cardiovasculares , Monócitos/virologia , Aterosclerose/patologia , Estudos de Casos e Controles , HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/virologia , Monócitos/metabolismo , TranscriptomaRESUMO
Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57+ CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57+ CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57+ CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57+ CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection.
Assuntos
Vasos Sanguíneos/fisiologia , Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Placa Aterosclerótica/imunologia , Antígenos CD28/metabolismo , Antígenos CD57/metabolismo , Antígenos CD58/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Movimento Celular , Quimiocina CX3CL1/metabolismo , Coinfecção , Citotoxicidade Imunológica , Humanos , Receptores CXCR3/metabolismo , RiscoRESUMO
Lymph nodes (LN) and their resident T follicular helper CD4+ T cells (Tfh) are a critical site for HIV replication and persistence. Therefore, optimizing antiviral activity in lymphoid tissues will be needed to reduce or eliminate the HIV reservoir. In this study, we retained effector immune cells in LN of cART-suppressed, SIV-infected rhesus macaques by treatment with the lysophospholipid sphingosine-1 phosphate receptor modulator FTY720 (fingolimod). FTY720 was remarkably effective in reducing circulating CD4+ and CD8+ T cells, including those with cytolytic potential, and in increasing the number of these T cells retained in LN, as determined directly in situ by histocytometry and immunohistochemistry. The FTY720-induced inhibition of T cell egress from LN resulted in a measurable decrease of SIV-DNA content in blood as well as in LN Tfh cells in most treated animals. In conclusion, FTY720 administration has the potential to limit viral persistence, including in the critical Tfh cellular reservoir. These findings provide rationale for strategies designed to retain antiviral T cells in lymphoid tissues to target HIV remission.
Assuntos
Cloridrato de Fingolimode/uso terapêutico , Imunossupressores/uso terapêutico , Linfopenia/induzido quimicamente , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Feminino , Centro Germinativo/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologiaRESUMO
Oxidized low-density lipoprotein (LDL) contributes to cardiovascular disease in part by mediating activation and maturation of monocytes and macrophages. Furthermore, co-localization studies using histochemical approaches have implicated a potential role for oxidized LDL as a mediator of interleukin-15 (IL-15) expression in myeloid cells of atherosclerotic plaque. The latter activity could be an important pro-inflammatory mechanism that mediates myeloid cell/T-cell crosstalk. Here, we examined the responses of primary human monocytes to highly oxidized LDL molecules. Oxidized LDL readily induced secretion of chemokines MCP-1 (CCL2) and GRO-α (CXCL1) but unlike lipopolysaccharide (LPS), has limited capacity to induce a variety of other cytokines including tumor necrosis factor-α, IL-6, IL-1ß and interferon-γ-induced protein-10 and also displayed a poor capacity to induce p-Akt or P-S6 signaling. Failure of oxidized LDL to induce IL-1ß secretion was associated with limited induction of caspase-1 activation. Furthermore, despite finding evidence that oxidized LDL could enhance the expression of IL-15 and IL-15 receptor expression in monocytes, we found no evidence that it could confer IL-15 transpresentation capability to these cells. This observation contrasted with induction of IL-15 transpresentation in lipopolysaccharide-stimulated monocytes. Overall, our data suggest that highly oxidized LDL is a selective inducer of monocyte activation. Sterile inflammatory mediators, particularly those implicated in Toll-like receptor 4 signaling, may play a role in vascular pathology but the activities of these agents are not uniform.
Assuntos
Interleucina-15/metabolismo , Interleucina-1beta/metabolismo , Lipoproteínas LDL/farmacologia , Monócitos/efeitos dos fármacos , Caspase 1/metabolismo , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Via Secretória , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Leucócitos Mononucleares , Mitocôndrias , TranscriptomaRESUMO
IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice. Previous results showed that IL-7 can restore TRAF1 expression in virus-specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. In this article, we show that IL-7 therapy in humans increases the number of circulating HIV-specific CD8 T cells. For a subset of patients, we also observed an increased frequency of TRAF1+ HIV-specific CD8 T cells 10 wk after completion of IL-7 treatment. IL-7 treatment increased levels of phospho-ribosomal protein S6 in HIV-specific CD8 T cells, suggesting increased activation of the metabolic checkpoint kinase mTORC1. Thus, IL-7 therapy in antiretroviral therapy-treated patients induces sustained changes in the number and phenotype of HIV-specific T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , HIV-1/imunologia , Proteína S6 Ribossômica/metabolismo , Fator 1 Associado a Receptor de TNF/metabolismo , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Citocinas/biossíntese , Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Interleucina-7/farmacologia , Interleucina-7/uso terapêutico , Contagem de Linfócitos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Proteína S6 Ribossômica/genética , Fator 1 Associado a Receptor de TNF/genética , Carga ViralRESUMO
Circulating CD8+ T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8+ T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8+ T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Monócitos/imunologia , Tromboplastina/imunologia , Fator de Necrose Tumoral alfa/imunologia , Coagulação Sanguínea/imunologia , Células Cultivadas , Células Endoteliais/imunologia , Infecções por HIV/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
BACKGROUND: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events. METHODS: Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference. RESULTS: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. CONCLUSIONS: Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.