Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE325004 | GEO | 2026/03/29
REPOSITORIES: GEO
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Project description:Impact of CD8 depletion on peripheral CD4+ T cells transcriptome during ART-treated SIV infection of rhesus macaques. Analysis of CD8+ T cells, CD4+ T cells, and NK cell transcriptomes following administration of HIV/SIV latency reversing agent IL-15 superagonist N-803 in ART-suppressed SIV infected rhesus macaques. Methods: RNA-Seq of sorted CD4+ T cells from SIV-infected, ART-suppressed rhesus macaques before intervention with the anti-CD8a depleting antibody MT807R1 and then again on day 3, week 2, and week 4 following the start of intervention. Some animals also had an intervention that includes four weekly administrations of the IL-15 superagonist complex N-803 initiated at the time of CD8 depletion. Methods: RNA-Seq of sorted CD4+ T cells, CD8+ T cells, and NK cells from SIV-infected, ART-suppressed rhesus macaques before intervention with four weekly administrations of the IL-15 superagonist complex N-803, then again on day 3, week 2, and week 4 following the start of intervention. Methods: RNA from sorted cells was collected and extracted and DNA was digested. Libraries were prepared and normalized, pooled, and clustered on a flow cells for sequencing. RNAseq data were aligned to the MacaM v7.8 assembly of the Indian rhesus macaque genome. To identify pathways differentially modulated, Gene Set Enrichment Analysis (GSEA)34 was performed on the ranked transcript lists using 1000 phenotype permutations and random seeding. Gene sets used included the MSigDB H (hallmark) gene sets
2020-01-06 | GSE128415 | GEO
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:Peripheral Blood Biomarkers in ART-Suppressed, SIV-Infected Rhesus Macaques Predict Viral Rebound Following ART Discontinuation
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Project description:Interleukin-21 treatment during ART was able to decrease residual immune activation and viral burden in SIV-infected rhesus macaques
2017-02-28 | GSE73232 | GEO
Project description:Despite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWH) experience persistent inflammation, immune dysfunction, and premature onset of cardiovascular and aging-related comorbidities. To define the underlying mechanisms, we performed longitudinal transcriptomic profiling in peripheral blood mononuclear cells (PBMCs) from a cohort of simian immunodeficiency virus (SIV)-infected rhesus macaques spanning four key stages: pre-infection, acute infection, short-term ART, and long-term ART. Bulk RNA sequencing revealed dynamic immune remodeling across infection and treatment. Acute SIV infection induced robust antiviral and inflammatory programs, with upregulation of interferon-stimulated genes (ISGs), IL-27, JAK/STAT, and NF-κB signaling, coupled with suppression of T- and B-cell activation pathways. Short-term ART effectively reversed these transcriptional perturbations, restoring adaptive immune gene expression and reducing innate antiviral responses to near-baseline levels. In contrast, chronic SIV infection on long-term ART maintained viral suppression but was characterized by reactivation of innate immune pathways, including TLR2/TLR4/MYD88, NF-κB, and inflammasome (NLRP3/NLRP12, caspase-1) signaling, along with sustained macrophage activation, platelet/coagulation signaling, and senescence-associated secretory phenotype. Protein analyses confirmed persistent CASPASE-1 and NF-κB activation in spleen tissue. Pathologic evaluation of a carotid artery from an SIV-infected, long-term ART–treated macaque revealed macrophage-rich plaques with p21⁺ senescent cells with intraluminal thrombus formation, recapitulating key features of HIV-associated atherogenesis. Together, these findings demonstrate that while ART normalizes acute infection–induced immune dysregulation, chronic SIV infection sustains a chronic, macrophage- and TLR-driven inflammatory state linked to vascular injury and aging process regardless of long-term suppression of viremia. Targeting inflammasome, NF-κB, and senescence pathways may mitigate non-AIDS comorbidities in PLWH.
2026-02-23 | GSE319957 | GEO
Project description:The earliest events of viral rebound following discontinuation of ART in persons living with HIV-1 (PLWH) remain largely unknown. Here we show that viral rebound in SIV-infected rhesus macaques following ART discontinuation involves serial clonal reactivation in gastrointestinal (GI) and lymph node (LN) tissues followed by rapid local and systemic spread. We investigated viral rebound dynamics in 18 SIV-infected rhesus macaques treated with antiretroviral therapy (ART) for 70 weeks and necropsied on day 12 after ART discontinuation. Using molecularly barcoded SIVmac239M, we tracked viral clonotypes following ATI in both peripheral blood and necropsy tissues. Viral rebound originated by reactivation of a single or a few clonotypes from a limited number of GI tissues and deep LNs, followed by replication of each clonotype and then serial reactivation of additional clonotypes from different anatomic sites, resulting in oligoclonal plasma viremia. Daily transcriptomic and proteomics profiling in peripheral blood identified early upregulation of pathways related to T cell signaling, cytokine responses, and cellular metabolism prior to detectable plasma viremia, presumably reflecting initial viral replication in tissues. Taken together, these data demonstrate the early clonal dynamics of viral rebound in SIV-infected macaques following ART discontinuation, which provides critical information for the development of next generation HIV-1 cure strategies.
2025-09-10 | GSE294867 | GEO
Project description:The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently-infected cells that persists despite long-term antiretroviral therapy (ART) and is maintained through cellular proliferation. Long-lived memory CD4+ T-cells with high self-renewal capacity such as central memory T-cells (CM) and T memory stem cells (SCM) are major contributors to the viral reservoir in HIV-infected individuals on ART. The Wnt/β-catenin signaling pathway regulates the balance between self-renewal and differentiation of SCM and CM T-cells and pharmacological manipulation of this pathway offers an opportunity to interfere with the proliferation of latently-infected cells. Here, we evaluated in vivo a novel approach to inhibit self-renewal of SCM and CM CD4+ T-cells in the rhesus macaque (RM) model of SIV infection. We used an inhibitor of the Wnt/β-catenin pathway, PRI-724, that blocks the interaction between the co-activator CREB binding protein (CBP) and β-catenin, resulting in the cell fate decision to differentiate rather than proliferate. Our study shows that PRI-724 treatment of ART-suppressed SIVmac251-infected RMs: (i) was well tolerated, with blood counts, liver enzymes, and renal function within normal limits and no alteration of tri-lineage hematopoiesis observed in bone marrow, (ii) resulted in decreased proliferation of SCM and CM T-cells, (iii) modified the SCM and CM CD4+ T-cell transcriptome towards a profile of more differentiated memory T-cells, and (iv) reduced SIV-DNA levels in CM and TFH CD4+ T-cells in the lymph nodes, but did not decrease the overall viral reservoir size. This work is the first demonstration in vivo that pharmacological modulation can effectively target T cell stemness in long-lived memory CD4+ T-cells, and represents a potential strategy to reduce HIV persistence.
2022-02-24 | GSE127330 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163442 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163441 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163440 | GEO