Transcriptome analysis in primary cell models of HIV latency and cells from HIV-infected ART-suppressed individuals
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144585 | GEO | 2020/10/28
REPOSITORIES: GEO
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Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.
2020-01-08 | GSE137438 | GEO
Project description:Transcriptome analysis in primary cell models of HIV latency and cells from HIV-infected ART-suppressed individuals
| PRJNA604101 | ENA
Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression This study evaluated PBMC gene expression in cells from 36 (4 dropped from analysis) recently HIV-infected individuals to identify differentially expressed genes following 48 weeks of ART
2013-09-10 | E-GEOD-44228 | biostudies-arrayexpress
Project description:The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research.
2023-08-30 | GSE203603 | GEO
Project description:Molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latency in vitro and ex vivo without the pleotropic cellular effects seen with other LRAs. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFκB pathway as exemplified by rapid degradation of cIAP1, followed by a slower conversion of inactive p100 into active p52. A potent representative of this class, AZD5582, increases cell-associated HIV gag RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of SMACm in preclinical animal models.
2020-01-11 | GSE142774 | GEO
Project description:Latency reversal and clearance strategies for HIV cure are beginning to employ IAP antagonists (IAPi) to induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with Bromodomain and Extra-Terminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single cell-RNAseq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bromodomain (BD)-selective BET, or selective BET isoform targeting in CD4 T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA but lesser induction of fully elongated and tat-rev RNA, especially compared to T cell activation positive controls. IAPi/BETi resulted in HIV protein induction in bulk cultures of CD4 T cells using an ultrasensitive p24 assay, but did not translate to enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. Overall, this study defines HIV transcriptional elongation and splicing as key barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their bromodomains in HIV latency, and provides rationale for testing of IAPi+BETi in animal models of HIV latency.
2022-02-10 | GSE196091 | GEO
Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression
2013-09-10 | GSE44228 | GEO
Project description:Metabolic alterations, such as oxidative stress, are hallmarks of HIV-1 infection. However, their influence on the development of viral latency, and thus on HIV-1 persistence during antiretroviral therapy (ART), have just begun to be explored. We analyzed omics profiles of in-vitro and in-vivo models of infection by HIV-1 and its simian homolog SIVmac. We found that cells survive retroviral replication by upregulating antioxidant pathways and intertwined iron import pathways. These changes are associated with remodeling of the redox sensitive promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML is depleted in productively infected cells and restored by ART. Moreover, we identified intracellular iron as a key link between oxidative stress and PML depletion, thus supporting iron metabolism modulators as pharmacological tools to impair latency establishment.
2020-01-30 | GSE127468 | GEO
Project description:In study NCT00594880, we successfully administered weekly doses of pegylated interferon-α-2a (Peg-IFN-α2a) with antiretroviral therapy (ART) for 5 weeks, before continued Peg-IFN-α2a monotherapy to 12 weeks (primary endpoint) in chronic HIV-infected subjects. Subjects maintaining HIV viral load <400 copies/ml by primary endpoint were defined as responders. We now describe innate immune correlates and transcriptional profiles associated with viral control and decrease in integrated HIV DNA after Peg-IFN-α2a immunotherapy. Peripheral blood samples were obtained prior to Peg-IFN-α2a administration (ART), after 5 weeks of ART+Peg-IFN-α2a dual treatment, and after 12 weeks of Peg-IFN-α2a monotherapy. Cell subset modulation, natural killer cell (NK) function and signaling, as well as inflammatory mediators and gene expression were assessed. Results were analyzed using R.2.5.1 or MATLAB 7.10.0. Five weeks of ART+Peg-IFN-α2a preserved the frequency of immune subsets and NK cytotoxicity, while increased the levels of inflammatory mediators, and decreased cell-responsiveness to in vitro IFN-α re-stimulation. Gene expression analysis showed that induction of host restriction factors after ART+Peg-IFN-α2a was not solely predictive of a virologic response, and revealed a 108 gene signature that identified subjects who did not modulate genes after ART+Peg-IFN-α2a. A 29 gene signature along with higher NK cell activation and IFN-γ-induced protein 10 (IP-10) levels on ART, as well as higher in vitro responses to IFN-γ-induced NK cytotoxicity, and decrease in the frequency of NK bearing inhibitory receptors [i.e. killer cell immunoglobulin-like receptor, two domains, long cytoplasmic tail 1 (KIR2DL1) or KIR2DL2/DL3] and C-C chemokine receptor type 7+ (CCR7) myeloid dendritic cells after ART+Peg-IFN-α2a distinguished responders from non-responders. Reductions in integrated HIV DNA after immunotherapy were associated with expression patterns of genes that are associated with activated cell-mediated response and NK cytotoxicity. In summary, innate activation and NK cell cytotoxicity are identified as correlates of HIV control and reduction after Peg-IFN-α2a immunotherapy in ART-suppressed subjects.
2019-06-03 | GSE107549 | GEO
Project description:HIV reservoirs persist despite successful antiretroviral therapy (ART) and are a major obstacle to the eradication and cure of HIV. The mature monocyte subset, CD14+CD16+, contributes to viral reservoirs and HIV-associated comorbidities. Only a subset of monocytes harbors HIV (HIV+), while the rest remain uninfected, exposed cells (HIVexp). We developed an innovative single cell RNA sequencing (scRNAseq) pipeline that detects HIV and host transcripts simultaneously, enabling us to examine differences between HIV+ and HIVexp mature monocytes. Using this, we characterized uninfected, HIV+, and HIVexp primary human mature monocytes with and without ART. We showed that HIV+ mature monocytes do not form their own cluster separately from HIVexp but can be distinguished by significant differential gene expression. We found that ART decreased levels of unspliced HIV transcripts potentially by modulating host transcriptional regulators shown to decrease viral infection and replication. We also identified and characterized mature monocyte subpopulations differentially impacted by HIV and ART. We identified genes dysregulated by ART in HIVexp monocytes compared to their uninfected counterpart and, of interest, the junctional protein ALCAM, suggesting that ART impacts monocyte functions. Our data provide a novel method for simultaneous detection of HIV and host transcripts. We identify potential targets, such as those genes whose expression is increased in HIV+ mature monocytes compared to HIVexp, to block their entry into tissues, preventing establishment/replenishment of HIV reservoirs even with ART, thereby reducing and/or eliminating viral burden and HIV-associated comorbidities. Our data also highlight the heterogeneity of mature monocyte subsets and their potential contributions to HIV pathogenesis in the ART era.
2020-07-08 | GSE153958 | GEO