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Curative strategies for human immunodeficiency virus (HIV-1) infection are hindered by incomplete characterization of the latent reservoir and limited enhancement of anti-HIV immune responses. In this study, we identified a novel dual role for peripheral and tissue-resident Vδ1 T cells within the gastrointestinal mucosa of virally suppressed people with HIV. Phenotypic analyses identified an increased frequency of highly differentiated, cytotoxic effector Vδ1 T cells that exerted potent inhibition of HIV-1 replication in vitro coinciding with direct increases in cytolytic function. Conversely, we detected an enrichment of HIV-1 DNA in tissue-resident CD4+Vδ1 T cells in situ . Despite low CD4 expression, we found circulating Vδ1 T cells also contained HIV-1 DNA which was replication-competent. We show that TCR-mediated activation of peripheral Vδ1 T cells induced de novo upregulation of CD4 providing a plausible mechanism for increased permissibility to infection. These findings highlight juxtaposing roles for Vδ1 T cells in HIV-1 persistence including significant contribution to tissue reservoirs.
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Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8+ T cell functions, which requires a deeper understanding of CD8+ T cells promoting HIV control. Here we identifiy an antigen-responsive TOXhiTCF1+CD39+CD8+ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8+ T cells and proteomic analysis of purified CD8+ T cell subsets identified TOXhiTCF1+CD39+CD8+ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOXhiTCF1+CD39+CD8+ T cells were found at higher frequency than TCF1-CD39+CD8+ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA+ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOXhiTCF1+CD39+CD8+ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8+ T cells contributes to limiting SIV and HIV persistence.
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Linfócitos T CD8-Positivos , Linfonodos , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T CD8-Positivos/imunologia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Linfonodos/imunologia , Humanos , Macaca mulatta , Infecções por HIV/imunologia , Infecções por HIV/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
We report 3 complicated and prolonged cases of mpox in people with advanced human immunodeficiency virus (HIV) not on antiretroviral therapy (ART) at mpox diagnosis. Multiple medical countermeasures were used, including prolonged tecovirimat treatment and immune optimization with ART initiation. Immunofluorescence of skin biopsies demonstrated a dense immune infiltrate of predominantly myeloid and CD8+ T cells, with a strong type I interferon local response. RNAscope detected abundant replication of monkeypox virus (MPXV) in epithelial cells and dendritic cells. These data suggest that prolonged mpox in people with advanced HIV may be due to ongoing MPXV replication, warranting aggressive medical countermeasures and immune optimization.
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Infecções por HIV , Mpox , Dermatopatias , Humanos , HIV , BenzamidasRESUMO
The main barrier to HIV cure is a persistent reservoir of latently infected CD4+ T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4+ T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.
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Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Vírus da Imunodeficiência Símia/fisiologia , Macaca mulatta , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Latência Viral , Replicação Viral , Anticorpos/uso terapêutico , Linfonodos , Linfócitos T CD4-Positivos , Carga ViralRESUMO
Here, we provide the first regional analysis of intact and defective HIV reservoirs within the brain. Brain tissue from both viremic and virally suppressed people with HIV (PWH) harbored HIV pol DNA in all regions tested, with lower levels present in basal ganglia and cerebellum relative to frontal white matter. Intact proviruses were primarily found in the frontal white matter but also detected in other brain regions of PWH, demonstrating frontal white matter as a major brain reservoir of intact, potentially replication competent HIV DNA that persists despite antiretroviral therapy. ANN NEUROL 2023;94:798-802.
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Infecções por HIV , HIV-1 , Humanos , Provírus/genética , Linfócitos T CD4-Positivos , HIV-1/genética , Carga Viral , Infecções por HIV/tratamento farmacológico , EncéfaloRESUMO
Since the first HIV-cured person was reported in 2009, a strong interest in developing highly sensitive HIV and SIV reservoir assays has emerged. In particular, the question arose about the comparative value of state-of-the-art assays to measure and characterize the HIV reservoir, and how these assays can be applied to accurately detect changes in the reservoir during efforts to develop a cure for HIV infection. Second, it is important to consider the impact on the outcome of clinical trials if these relatively new HIV reservoir assays are incorporated into clinical trial endpoints and/or used for clinical decision-making. To understand the advantages and limitations and the regulatory implications of HIV reservoir assays, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored and convened a meeting on September 16, 2022, to discuss the state of knowledge concerning these questions and best practices for selecting HIV reservoir assays for a particular research question or clinical trial protocol.
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HIV-associated neurocognitive disorders (HAND) affect ~40% of virally suppressed people with HIV (PWH), however, the precise viral dependent and independent changes to the brain are unclear. Here we characterized the CNS reservoir and immune environment of SIV-infected (SIV+) rhesus macaques during acute (n = 4), chronic (n = 12) or ART-suppressed SIV infection (n = 11). Multiplex immunofluorescence for markers of SIV infection (vRNA/vDNA) and immune activation was performed on frontal cortex and matched colon tissue. SIV+ animals contained detectable viral DNA+ cells that were not reduced in the frontal cortex or the gut by ART, supporting the presence of a stable viral reservoir in these compartments. SIV+ animals had impaired blood brain barrier (BBB) integrity and heightened levels of astrocytes or myeloid cells expressing antiviral, anti-inflammatory or oxidative stress markers which were not abrogated by ART. Neuroinflammation and BBB dysfunction correlated with measures of viremia and immune activation in the gut. Furthermore, SIV-uninfected animals with experimentally induced gut damage and colitis showed a similar immune activation profile in the frontal cortex to those of SIV-infected animals, supporting the role of chronic gut damage as an independent source of neuroinflammation. Together, these findings implicate gut-associated immune activation/damage as a significant contributor to neuroinflammation in ART-suppressed HIV/SIV infection which may drive HAND pathogenesis.
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Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Macaca mulatta , Doenças NeuroinflamatóriasRESUMO
We employed a dose-escalation regimen in rhesus macaques to deliver glycosylated IL-7, a cytokine critical for development and maintenance of T lymphocytes. IL-7 increased proliferation and survival of T cells and triggered several chemokines and cytokines. Induction of CXCL13 in lymph nodes (LNs) led to a remarkable increase of B cells in the LNs, proliferation of germinal center follicular T helper cells and elevated IL-21 levels suggesting an increase in follicle activity. Transcriptomics analysis showed induction of IRF-7 and Flt3L, which was linked to increased frequency of circulating plasmacytoid dendritic cells (pDCs) on IL-7 treatment. These pDCs expressed higher levels of CCR7, homed to LNs, and were associated with upregulation of type-1 interferon gene signature and increased production of IFN-α2a on TLR stimulation. Superior effects and dose-sparing advantage was observed by the step-dose regimen. Thus, IL-7 treatment leads to systemic effects involving both lymphoid and myeloid compartments.
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BACKGROUND: HIV can infect multiple cells in the liver including hepatocytes, Kupffer cells and infiltrating T cells, but whether HIV can persist in the liver in people with HIV (PWH) on suppressive antiretroviral therapy (ART) remains unknown. METHODS: In a prospective longitudinal cohort of PWH and hepatitis B virus (HBV) co-infection living in Bangkok, Thailand, we collected blood and liver biopsies from 18 participants prior to and following ART and quantified HIV and HBV persistence using quantitative (q)PCR and RNA/DNAscope. Antiretroviral (ARV) drug levels were quantified using mass spectroscopy. FINDINGS: In liver biopsies taken prior to ART, HIV DNA and HIV RNA were detected by qPCR in 53% (9/17) and 47% (8/17) of participants respectively. Following a median ART duration of 3.4 years, HIV DNA was detected in liver in 61% (11/18) of participants by either qPCR, DNAscope or both, but only at very low and non-quantifiable levels. Using immunohistochemistry, HIV DNA was observed in both hepatocytes and liver infiltrating CD4+ T cells on ART. HIV RNA was not detected in liver biopsies collected on ART, by either qPCR or RNAscope. All ARVs were clearly detected in liver tissue. INTERPRETATION: Persistence of HIV DNA in liver in PWH on ART represents an additional reservoir that warrants further investigation. FUNDING: National Health and Medical Research Council of Australia (Project Grant APP1101836, 1149990, and 1135851); This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024.
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Coinfecção , Infecções por HIV , Hepatite B , Humanos , Estudos Prospectivos , Tailândia , Hepatite B/complicações , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Vírus da Hepatite B/genética , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , DNA Viral/genética , HepatócitosRESUMO
OBJECTIVE: The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo , which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential 'double-edged sword' effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo . DESIGN: We used the BLT (bone marrow, liver, thymus) humanized mouse model to evaluate the impact of Gal-9 on HIV persistence in vivo during antiretroviral therapy (ART). METHODS: Two independent cohorts of ART-suppressed HIV-infected BLT mice were treated with either recombinant Gal-9 or phosphate-buffered saline control. Plasma viral loads and levels of tissue-associated HIV DNA and RNA were measured by qPCR. Immunohistochemistry and HIV RNAscope were used to quantify CD4 + T, myeloid, and HIV RNA+ cells in tissues. T cell activation and exhaustion were measured by flow cytometry, and plasma markers of inflammation were measured by multiplex cytokine arrays. RESULTS: Gal-9 did not induce plasma markers of inflammation or T cell markers of activation/exhaustion in vivo . However, the treatment significantly increased levels of tissue-associated HIV DNA and RNA compared to controls ( P â=â0.0007 and P â=â0.011, respectively, for cohort I and P â=â0.002 and P â=â0.005, respectively, for cohort II). RNAscope validated the Gal-9 mediated induction of HIV RNA in tissue-associated myeloid cells, but not T cells. CONCLUSIONS: Our study highlights the overall adverse effects of Gal-9 on HIV persistence and the potential need to block Gal-9 interactions during ART-suppressed HIV infection.
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Infecções por HIV , HIV-1 , Humanos , Camundongos , Animais , HIV-1/genética , RNA , Galectinas , Inflamação , Linfócitos T CD4-PositivosRESUMO
Antiretroviral therapy (ART) is not curative due to the persistence of a reservoir of HIV-infected cells, particularly in tissues such as lymph nodes, with the potential to cause viral rebound after treatment cessation. In this study, fingolimod (FTY720), a lysophospholipid sphingosine-1-phosphate receptor modulator is administered to SIV-infected rhesus macaques at initiation of ART to block the egress from lymphoid tissues of natural killer and T-cells, thereby promoting proximity between cytolytic cells and infected CD4+ T-cells. When compared with the ART-only controls, FTY720 treatment during the initial weeks of ART induces a profound lymphopenia and increases frequencies of CD8+ T-cells expressing perforin in lymph nodes, but not their killing capacity; FTY720 also increases frequencies of cytolytic NK cells in lymph nodes. This increase of cytolytic cells, however, does not limit measures of viral persistence during ART, including intact proviral genomes. After ART interruption, a subset of animals that initially receives FTY720 displays a modest delay in viral rebound, with reduced plasma viremia and frequencies of infected T follicular helper cells. Further research is needed to optimize the potential utility of FTY720 when coupled with strategies that boost the antiviral function of T-cells in lymphoid tissues.
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Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais , Linfócitos T CD4-Positivos , Cloridrato de Fingolimode , Macaca mulatta , Carga ViralRESUMO
INTRODUCTION: HIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4+ T cells and cell-associated RT-SHIV viral RNA. METHODS: Between December 2014 and April 2017, RT-SHIV infected (SHIV+; N = 6) and healthy (SHIV-; N = 6) male rhesus macaques received two selected four-drug combinations of six ARVs over 10 days to attain steady-state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4+ T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co-registered images using MATLAB. RESULTS: Through MSI, ARV-dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5-6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2-1.4] mm; SHIV-: 1.3 [0.5-1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen-wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94-2.69] -fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co-localization of drug with CD4+ target cells and vRNA varied widely by ARV (5.1-100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell-associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value. CONCLUSIONS: Our investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low-level viral replication during suppressive ART.
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Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais/uso terapêutico , Colágeno/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Linfonodos/metabolismo , Macaca mulatta/genética , Macaca mulatta/metabolismo , Masculino , RNA Viral/genética , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/metabolismoRESUMO
Interleukin-10 (IL-10) is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper (Tfh) cell differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph nodes (LNs) were induced by infection and not normalized with antiretroviral therapy (ART). During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4+ memory subsets, including Tfh cells, and predicted the frequency of CD4+ Tfh cells and their cell-associated SIV-DNA content during ART, respectively. In ART-treated rhesus macaques, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and, by extension, LN memory CD4+ T cells, including Tfh cells and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4+ T cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.
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Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Linfócitos T CD4-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Interleucina-10/genética , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológicoRESUMO
The relationship between spatiotemporal distribution of HIV-1 proviruses and their transcriptional activity is not well understood. To elucidate the intranuclear positions of transcriptionally active HIV-1 proviruses, we utilized an RNA fluorescence in situ hybridization assay and RNA stem loops that bind to fluorescently labeled bacterial protein (Bgl-mCherry) to specifically detect HIV-1 transcription sites. Initially, transcriptionally active wild-type proviruses were located closer to the nuclear envelope (NE) than expected by random chance in HeLa (â¼1.4 µm) and CEM-SS T cells (â¼0.9 µm). Disrupting interactions between HIV-1 capsid and host cleavage and polyadenylation specificity factor (CPSF6) resulted in localization of proviruses to lamina-associated domains (LADs) adjacent to the NE in HeLa cells (â¼0.9 - 1.0 µm); however, in CEM-SS T cells, there was little or no shift toward the NE (â¼0.9 µm), indicating cell-type differences in the locations of transcriptionally active proviruses. The distance from the NE was not correlated with transcriptional activity, and transcriptionally active proviruses were randomly distributed throughout the HeLa cell after several cell divisions, indicating that the intranuclear locations of the chromosomal sites of integration are dynamic. After nuclear import HIV-1 cores colocalized with nuclear speckles, nuclear domains enriched in pre-mRNA splicing factors, but transcriptionally active proviruses detected 20 h after infection were mostly located outside but near nuclear speckles, suggesting a dynamic relationship between the speckles and integration sites. Overall, these studies establish that the nuclear distribution of HIV-1 proviruses is dynamic and the distance between HIV-1 proviruses and the NE does not correlate with transcriptional activity. IMPORTANCE HIV-1 integrates its genomic DNA into the chromosomes of the infected cell, but how it selects the site of integration and the impact of their location in the 3-dimensional nuclear space is not well understood. Here, we examined the nuclear locations of proviruses 1 and 5 days after infection and found that integration sites are first located near the nuclear envelope but become randomly distributed throughout the nucleus after a few cell divisions, indicating that the locations of the chromosomal sites of integration that harbor transcriptionally active proviruses are dynamic. We also found that the distance from the nuclear envelope to the integration site is cell-type dependent and does not correlate with proviral transcription activity. Finally, we observed that HIV-1 cores were localized to nuclear speckles shortly after nuclear import, but transcriptionally active proviruses were located adjacent to nuclear speckles. Overall, these studies provide insights into HIV-1 integration site selection and their effect on transcription activities.
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Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Provírus/genética , HIV-1/genética , Células HeLa , Integração Viral , Hibridização in Situ Fluorescente , RNA/metabolismoRESUMO
The main barrier to a cure for HIV is the persistence of long-lived and proliferating latently infected CD4+ T-cells despite antiretroviral therapy (ART). Latency is well characterized in multiple CD4+ T-cell subsets, however, the contribution of regulatory T-cells (Tregs) expressing FoxP3 as well as immune checkpoints (ICs) PD-1 and CTLA-4 as targets for productive and latent HIV infection in people living with HIV on suppressive ART is less well defined. We used multiplex detection of HIV DNA and RNA with immunohistochemistry (mIHC) on formalin-fixed paraffin embedded (FFPE) cells to simultaneously detect HIV RNA and DNA and cellular markers. HIV DNA and RNA were detected by in situ hybridization (ISH) (RNA/DNAscope) and IHC was used to detect cellular markers (CD4, PD-1, FoxP3, and CTLA-4) by incorporating the tyramide system amplification (TSA) system. We evaluated latently infected cell lines, a primary cell model of HIV latency and excisional lymph node (LN) biopsies collected from people living with HIV (PLWH) on and off ART. We clearly detected infected cells that coexpressed HIV RNA and DNA (active replication) and DNA only (latently infected cells) in combination with IHC markers in the in vitro infection model as well as LN tissue from PLWH both on and off ART. Combining ISH targeting HIV RNA and DNA with IHC provides a platform to detect and quantify HIV persistence within cells identified by multiple markers in tissue samples from PLWH on ART or to study HIV latency.
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DNA Viral/análise , Infecções por HIV/diagnóstico , HIV/genética , Inibidores de Checkpoint Imunológico/análise , Imuno-Histoquímica , Hibridização In Situ , Infecção Latente/diagnóstico , Linfonodos/imunologia , Linfonodos/virologia , RNA Viral/análise , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Células Jurkat , Infecção Latente/imunologia , Infecção Latente/virologia , Valor Preditivo dos Testes , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/virologiaRESUMO
Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.
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Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Linfócitos B/imunologia , Centro Germinativo/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Viremia/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/imunologia , Adulto , Fármacos Anti-HIV/farmacologia , Anticorpos Antivirais/sangue , Técnicas de Cocultura , Feminino , Centro Germinativo/patologia , Hemoglobinas/análise , Humanos , Hiperplasia , Linfonodos/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos B/genética , Transcrição Gênica , Carga Viral , Viremia/imunologia , Adulto JovemRESUMO
BACKGROUND: Possible human immunodeficiency virus (HIV)-1 clearance has rarely been reported. In this study, we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART. METHODS: Leukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls. RESULTS: No HIV-specific antibodies were detected in serum. Plasma HIV ribonucleic acid (RNA) levels were <0.2 copies/mL, and, except for low-frequency HIV deoxyribonucleic acid (DNA)+ cells in lymph node tissue (1 copy/3 × 106 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/106 CD4+ T cells) or by most measurements of HIV RNA or DNA in blood, lymph node, or gut-associated mononuclear cells. Human immunodeficiency virus-specific T-cell responses were detectable but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. Human immunodeficiency virus DNA+ cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis. CONCLUSIONS: This represents the first report of complete seroreversion, prolonged posttreatment virus suppression, a profoundly small HIV reservoir, and persistent HIV-specific T cells in an adult with prior AIDS.
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The effectiveness of virus-specific strategies, including administered HIV-specific mAbs, to target cells that persistently harbor latent, rebound-competent HIV genomes during combination antiretroviral therapy (cART) has been limited by inefficient induction of viral protein expression. To examine antibody-mediated viral reservoir targeting without a need for viral induction, we used an anti-CD4 mAb to deplete both infected and uninfected CD4+ T cells. Ten rhesus macaques infected with barcoded SIVmac239M received cART for 93 weeks starting 4 days after infection. During cART, 5 animals received 5 to 6 anti-CD4 antibody administrations and CD4+ T cell populations were then allowed 1 year on cART to recover. Despite profound CD4+ T cell depletion in blood and lymph nodes, time to viral rebound following cART cessation was not significantly delayed in anti-CD4-treated animals compared with controls. Viral reactivation rates, determined based on rebounding SIVmac239M clonotype proportions, also were not significantly different in CD4-depleted animals. Notably, antibody-mediated depletion was limited in rectal tissue and negligible in lymphoid follicles. These results suggest that, even if robust viral reactivation can be achieved, antibody-mediated viral reservoir depletion may be limited in key tissue sites.
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Antirretrovirais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/imunologia , Animais , Fármacos Anti-HIV/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD4/antagonistas & inibidores , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Depleção Linfocítica , Tecido Linfoide/imunologia , Tecido Linfoide/virologia , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Ativação Viral/efeitos dos fármacos , Ativação Viral/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologiaRESUMO
Background: Intestinal microbial dysbiosis is evident in chronic HIV-infected individuals and may underlie inflammation that persists even during antiretroviral therapy (ART). It remains unclear, however, how early after HIV infection gut dysbiosis emerges and how it is affected by early ART. Methods: Fecal microbiota were studied by 16s rDNA sequencing in 52 Thai men who have sex with men (MSM), at diagnosis of acute HIV infection (AHI), Fiebig Stages 1-5 (F1-5), and after 6 months of ART initiation, and in 7 Thai MSM HIV-uninfected controls. Dysbiotic bacterial taxa were associated with relevant inflammatory markers. Results: Fecal microbiota profiling of AHI pre-ART vs HIV-uninfected controls showed a mild dysbiosis. Transition from F1-3 of acute infection was characterized by enrichment in pro-inflammatory bacteria. Lower proportions of Bacteroidetes and higher frequencies of Proteobacteria and Fusobacteria members were observed post-ART compared with pre-ART. Fusobacteria members were positively correlated with levels of soluble CD14 in AHI post-ART. Conclusions: Evidence of gut dysbiosis was observed during early acute HIV infection and was partially restored upon early ART initiation. The association of dysbiotic bacterial taxa with inflammatory markers suggests that a potential relationship between altered gut microbiota and systemic inflammation may also be established during AHI.
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[This corrects the article DOI: 10.1093/ofid/ofz367.].