Activation of ISR/ATF4 signaling depletes HIV reservoir in CD4+ T cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210824 | GEO | 2022/12/05
REPOSITORIES: GEO
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Project description:HIV reservoirs in tissues form the major hurdle to an HIV cure. Despite major progress made on the understanding of the establishment and persistence of viral reservoirs, the characterization of composition and dynamics of the viral reservoir is still uncomplete. In addition, most studies in HIV infection are limited to blood. Here we take advantage of non-human primate models to provide a longitudinal analysis on potential viral target cells in distinct body compartments : blood, lymph nodes (LN), spleen ileum, jejunum and liver. We observed an increase in CD32+CD4+ T cells in secondary lymphoid tissues and intestine during primary and chronic pathogenic SIVmac infection. In the natural host (African green monkey, AGM), increase of the CD4+CD32+T cell levels was observed in tissues with higher replication and immune activation. CD32+CD4+ T cells expressed more often markers associated with HIV infected and/or reservoir cells (PD-1, CXCR5 for TFH cells in SLT, and CXCR3 for Th1 cells) than CD32- cells. The tissue CD32+CD4+T cells displayed higher levels of actively transcribed SIV RNA than CD32-CD4+T cells. The genome-wide transcriptome of CD32+CD4+ T cells in spleen from SIV-infected animals indicated that the CD32+CD4+ T cells shared B cell markers. The CD20+ expressing CD32+CD4+ T cells were increased in the tissues but not in the blood during SIV infection. Altogether, the study showed that SIV infection increases the frequencies of CD32+CD4+ T cells in tissues more than in blood. These cells might represent a not well-described subpopulation of activated CD4+ T cells.
2021-04-16 | GSE169736 | GEO
Project description:Resting CD4+ T cells that are both persistent and latently infected with HIV represent the most important challenge to HIV eradication. Estimates indicate the need for >70 years of continuous, fully suppressive, antiretroviral therapy (ART) to eliminate the HIV reservoir. Alternatively, induction of HIV from its latent state could accelerate the decline of the reservoir, thereby shortening the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in peripheral blood with minimal focus on tissue reservoirs and had limited effect. We found that activation of the non-canonical NF-B signaling pathway via AZD5582 results in induction of HIV- and SIV-RNA expression in the blood and tissues of ART-suppressed humanized mice and rhesus macaques. Analysis of resting CD4+ T cells from tissues after AZD55852 treatment revealed increased SIV-RNA in lymph nodes in macaques and robust induction of HIV in virtually all tissues analyzed in humanized mice including lymph nodes, thymus, bone marrow, liver, and lung. This promising new approach to latency reversal, in combination with the appropriate tools for systemic clearance of persistent HIV infection, greatly increases opportunities for HIV eradication.
2020-01-07 | GSE141546 | GEO
Project description:Persistent HIV-1 reservoirs of infected CD4 T-cells are a major barrier to HIV-1 cure, though the mechanisms by which they are established and maintained in vivo remain poorly characterized. To study host properties that govern productive cellular infection, we analyzed viral mRNA+ (vRNA) CD4 T-cells of untreated SIV-infected macaques by single-cell RNAseq. Transcriptionally active infected cells, defined by spliced vRNA, were highly enriched for vRNA: 10.3% and 7.5% of all mRNA in two animals. These cells expressed diminished FOS, a component of the Activator protein 1 (AP-1) transcription factor, relative to vRNA-low and -negative cells.
2023-06-05 | GSE232998 | GEO
Project description:Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH). Increased survival and aging of PLWH is associated with increased incidence of at-risk alcohol use and of metabolic comorbidities; and in women, menopause may be an additional factor contributing to metabolic dysregulation, particularly in adipose tissue. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome of simian immunodeficiency virus (SIV) infected macaques. Quantitative discovery-based proteomics identified 1429 differentially expressed proteins. Ingenuity Pathway Analysis calculated z-scores, or activation predictions for a disease or functional pathway. Results revealed functional pathways associated with protein changes centered around the “OmAT metaboproteome profile”. CBA did not affect functional pathways of metabolic disease; but dysregulated proteins involved in AMPK signaling and lipid metabolism. Based on IPA’s calculated z-score, OVX-mediated proteome changes promote pathways associated with glucose and lipid associated metabolic disease. Additionally, OVX was predicted to promote apoptosis, necrosis and reactive oxygen species (ROS) pathways, while CBA was predicted to inhibit these OVX-associated changes. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in HIV/SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administraton produced larger metabolic and cellular effects; which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.
2022-08-12 | PXD023076 | Pride
Project description:Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and transcriptionally TRMlike profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are highly expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIVspecific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.
2022-10-12 | GSE215126 | GEO
Project description:Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and transcriptionally TRMlike profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are highly expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIVspecific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.
2022-10-12 | GSE215125 | GEO
Project description:HIV-1 usually utilize CCR5 as the co-receptor and rarely switches to CXCR4-tropic until late stage of infection. CCR5+CD4+ T cells are the major virus-producing cells in patients as well as SIV-infected non-human primates. The differentiation of CCR5+CD4+ T cells is associated with the availability of IL-15, which increases during acute HIV-1 infection. Here, we report that CCR5 is expressed by CD4+ T cells exhibiting effector or effector memory phenotype with high expression levels of the IL-2/IL-15 receptor common beta and gamma chains. IL-15 but not IL-7 improves the survival of CCR5+CD4+ T cells, drives their expansion, and facilitates HIV-1 infection in vitro and in humanized mice. Our study suggests that IL-15 plays confounding roles in HIV-1 infection, and future studies on the IL-15-based boosting of anti-HIV-1 immunity should carefully exam the potential effects on the expansion of HIV-1 reservoirs in CCR5+CD4+ T cells.
2022-04-03 | GSE199729 | GEO
Project description:Antiretroviral treatment regimens can effectively control HIV replication and some aspects of disease progression. However, molecular events in end-organ diseases such as central nervous system (CNS) disease are not yet fully understood, and routine eradication of latent reservoirs is not yet in reach. Regulatory RNAs have emerged as important participants in HIV disease pathogenesis. Using brain tissue from the simian immunodeficiency virus (SIV) model of HIV disease, we profiled messenger RNAs (mRNAs) and circular RNAs (circRNAs), seeking to identify possible networks of RNA interaction in SIV infection and neuroinflammation.
2023-09-25 | GSE236931 | GEO
Project description:Suppressive HAART does not eradicate HIV-1 and viral DNA persists as a stably integrated form in the absence of viral particle production. As a consequence, latent reservoirs are refractory to antiretroviral drugs and invisible to immune surveillance. The largest latent reservoir consists of resting memory CD4+ T cells. These cells can resume viral infection when activated through antigen recognition, causing bursts of viremia (blips). Current therapies targeting latent HIV-1 have focused primarily on the M-bM-^@M-^\shock and killM-bM-^@M-^] approach, which employs M-bM-^@M-^\anti-latencyM-bM-^@M-^] drugs M-bM-^@M-^S most notably histone deacetylase (HDAC) inhibitors M-bM-^@M-^S to reactivate and flush latent provirus from its cellular reservoirs in the absence of global T cell activation. This approach is predicated on the notions that viral reactivation will lead to the demise of the infected cell, and that HAART will prevent spreading of the infection. On the contrary, recent evidence indicates that latently infected CD4+ T cells of HIV-1 patients on HAART survive in vitro viral reactivation with the HDAC inhibitor, SAHA, even when co-cultured with autologous CD8+ cytotoxic T lymphocytes (CTL). Moreover, it remains to be addressed the impact of anti-latency drugs on viral reservoirs undergoing low-level ongoing replication, inherently more resistant to the cytopathic effects of HIV-1 and residing in anatomical sites hard to reach for some antiretroviral drugs (e.g. macrophages). As a consequence, there is a need to develop alternative therapeutic approaches aimed at eliminating or decreasing the latent reservoir. Progress in that direction has been hindered by the lack of biomarkers uniquely or differentially expressed on latently infected compared to their uninfected counterparts. To gain insight into the cellular mechanisms that take place in the context of latency, and with the goal of identifying distinctive markers that distinguish latently infected CD4+ T cells, we have used an in vitro model developed in our laboratory to study the expression profile of latently infected CD4+ T cells by microarray analysis. We have used a culture system, previously established in our laboratory, to generate and isolate quiescent latently infected CD4+ T cells in vitro. In this in vitro HIV-1 latency model, CD4+ T cells are activated, infected with full length, replication competent HIV-1, and then returned to quiescence in the presence of IL-7, yielding a culture of quiescent latently infected and uninfected cells. We showed that HIV-1 p24gag expressed during viral replication persists in the cytoplasm of latently infected cells for several days before being degraded. Therefore, we exploited the presence of cytoplasmic p24gag to sort latently infected from uninfected cells by FACS from the same initial cell culture. Total RNA was isolated from sorted latently infected and uninfected cells generated from CD4+ T cells of four different donors. Paired RNA samples from infected and uninfected cells were labeled with Cy3 and Cy5 to allow dual-color competitive hybridization. Moreover, to control for the dye bias in our experiments, we implemented a dye swap protocol (reciprocal labeling) for paired RNA samples from 2 donors. Samples were analyzed by dual-color competitive hybridization on the Agilent whole human genome microarrays (41,000 unique probes). This is the first comparative genomic profiling of primary latently infected resting memory CD4+ T cells versus their uninfected counterparts sorted from the same culture. Microarray analyses performed in this study revealed profound differences between latently infected and uninfected cells. Of relevance are genes involved, not only in previously described pathways related with transcriptional and post-transcriptional regulation, but affecting proliferation, survival, cell cycle progression and cell metabolism. This could explain why latently infected cells have been resistant to reactivation with current anti-latency approaches. Thus, targeting of more downstream steps, such as the ones identified in this study, may be able to enhance viral flushing from refractory latent reservoirs. In addition, we identified a panel of surface makers differentially expressed in latently infected cells, which seem worth investigating for their potential use as biomarkers. Indeed, they might allow the enrichment of this latent reservoir for molecular in depth studies, for monitoring the size of the latent reservoir in the clinical setting, as well as for the development of new therapeutic strategies aimed at eradicating this reservoir.
2013-03-15 | E-GEOD-40550 | biostudies-arrayexpress
Project description:Background: Atherosclerosis (AS)-associated cardiovascular disease is an important cause of mortality in an aging population of people living with HIV (PLWH). This elevated risk of atherosclerosis has been attributed to viral infection, prolonged usage of anti-retroviral therapy, and subsequent chronic inflammation. Methods: To investigate dysregulated immune signaling in PLWH with and without AS, we sequenced 9368 peripheral blood mononuclear cells (PBMCs) from 8 PLWH, 4 of whom also had atherosclerosis (AS+). To develop executable models of signaling pathways that drive cellular states in HIV-associated atherosclerosis, we developed the single-cell Boolean Omics Network Invariant Time Analysis (scBONITA) algorithm. ScBONITA (a) uses single-cell RNA sequencing data to infer Boolean rules for topologically characterized networks, (b) prioritizes genes based on their impact on signaling, (c) performs pathway analysis, and (d) maps sequenced cells to characteristic signaling states. We used scBONITA to identify dysregulated pathways in different cell-types from AS+ PLWH and AS- PLWH. To compare our findings with pathways associated with HIV infection, we used scBONITA to analyze a publicly available dataset of PBMCs from subjects before and after HIV infection. Additionally, the executable Boolean models characterized by scBONITA were used to analyze observed cellular states corresponding to the steady states of signaling pathways Results: We identified an increased subpopulation of CD8+ T cells and a decreased subpopulation of monocytes in AS+ PLWH. Dynamic modeling of signaling pathways and pathway analysis with scBONITA provided a new perspective on the mechanisms of HIV-associated atherosclerosis. Lipid metabolism and cell migration pathways are induced by AS rather than by HIV infection. These pathways included AGE-RAGE and PI3K-AKT signaling in CD8+ T cells, and glucagon and cAMP signaling pathways in monocytes. Further analysis of other cell subpopulations suggests that the highly interconnected PI3K-AKT signaling pathway drives cell migratory state in response to dyslipidemia. scBONITA attractor analysis mapped cells to pathway-specific signaling states that correspond to distinct cellular states. Conclusions: Dynamic network modeling and pathway analysis with scBONITA indicates that dysregulated lipid signaling regulates cell migration into the vascular endothelium in AS+ PLWH. Attractor analysis with scBONITA facilitated pathway-based characterization of cellular states that are not apparent in gene expression analyses.
2022-09-06 | GSE198339 | GEO