Biology subjects

Wiche Salinas, T. R.

Publications and source records attributed to Wiche Salinas, T. R..

4 recordsLinked to original sources

bioRxiv2023

A Blood Immunological Signature of Subclinical Coronary Artery Atherosclerosis in People Living with HIV-1 Receiving Antiretroviral Therapy

Cardiovascular disease (CVD) remains an important co-morbidity in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Our previous studies performed on the Canadian HIV/Aging Cohort Study (CHACS) (>40 years-old; Framingham Risk Score (FRS) >5%), revealed a 2-3-fold increase in non-calcified coronary artery atherosclerosis (CAA) plaque burden, measured by Computed tomography angiography scan (CTAScan) as total (TPV) and low attenuated plaque volume (LAPV) in ART-treated PLWH (HIV+) versus uninfected controls (HIV-). In an effort to identify novel correlates of subclinical CAA, markers of intestinal damage (sCD14, LBP, FABP2); cell trafficking/inflammation (CCL20, CX3CL1, MIF, CCL25); subsets of Th17-polarized and regulatory (Tregs) CD4+ T-cells, classical/intermediate/non-classical monocytes, and myeloid/plasmacytoid dendritic cells, were studied in relationship with HIV and TPV/LAPV status. The TPV detection/values coincided with higher plasma sCD14, FABP2, CCL20, MIF, CX3CL1 and triglyceride levels, lower Th17/Treg ratios, and classical monocyte expansion. Among HIV+, TPV+ versus TPV- exhibited lower Th17 frequencies, reduced Th17/Treg ratios, higher frequencies of non-classical CCR9lowHLADRhigh monocyte, and increased plasma fibrinogen levels. Finally, Th17/Treg ratios and non-classical CCR9lowHLADRhigh monocyte frequencies remained associated with TPV/LAPV after adjusting for FRS and HIV/ART duration in a logistic regression model. These findings point to Th17 paucity and non-classical monocyte abundance as novel immunological correlates of subclinical CAA that may fuel the CVD risk in ART-treated PLWH.

immunology↗

bioRxiv2023

Retinoic Acid Boosts HIV-1 Replication in Macrophages via CCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing elixir retinoic acid (RA), which transcriptionally reprograms CD4+ T-cells for increased HIV-1 permissiveness. Consistently, colon-infiltrating CD4+ T-cells carry replication-competent viral reservoirs in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by circulating monocytes, represents a rare event in ART-treated PLWH, thus questioning on HIV-1 permissiveness in gut-resident macrophages. Here, we demonstrate that RA significantly boosts R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA-Sequencing, Gene Set Variation Analysis, and HIV interactor NCBI database interrogation, revealed RA- mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations pointed to mechanisms of RA action, including CCR5 upregulation and SAMHD1 phosphorylation under the control of mTOR. These results support a model in which intestinal MDM contribute to viral replication/dissemination before ART and upon treatment interruption in mTOR-sensitive manner. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/561142v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@f966a0org.highwire.dtl.DTLVardef@1c0b4baorg.highwire.dtl.DTLVardef@992142org.highwire.dtl.DTLVardef@156a599_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO C_FIG

immunology↗

bioRxiv2022

Identification of Aryl Hydrocarbon Receptor as a Barrier to HIV-1 Infection and Outgrowth in CD4+ T-Cells

The Aryl hydrocarbon receptor (AhR) identifies "non-pathogenic" Th17-polarized CD4+ T-cells in autoimmune models. Thus, we explored whether AhR restricts HIV-1 in Th17-cells, consistent with its antiviral role in macrophages. AhR-specific CRISPR/Cas9-mediated knockout and pharmacological blockade decreased AhR target gene expression (CYP1A1/IL-22/IL-17A/IL-10/ ITGB7), while increasing HIV-1 replication in CD4+ T-cells. Pharmacological AhR activation caused opposite effects. AhR agonism/antagonism modulated HIV-1 replication mainly in Th17/Th22-polarized CCR6+CD4+ T-cells. Single-round VSV-G-pseudotyped HIV-1 infection demonstrated that AhR acts at post-entry levels, with AhR blockade increasing the efficacy of early/late reverse transcription steps and subsequently integration/translation. In viral outgrowth assay, the AhR blockade boosted the detection of replication-competent viral reservoirs in CD4+ T-cells of people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Finally, RNA-Sequencing revealed genes/pathways modulated by AhR blockade in CD4+ T-cells of ART-treated PLWH, with known HIV-1 interactor activities (NCBI HIV Interactor Database) and AhR responsive elements in their promoters (ENCODE). Among them, HIC1, a repressor of Tat-mediated HIV-1 transcription and a tissue-residency inducer, represents a putative AhR mechanism of action. These results demonstrate that AhR governs an antiviral transcriptional program in CD4+ T-cells and point to the use of AhR inhibitors to boost viral outgrowth in "shock and kill" HIV-1 remission/cure strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/512596v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@ddd99org.highwire.dtl.DTLVardef@4fa24eorg.highwire.dtl.DTLVardef@28e66forg.highwire.dtl.DTLVardef@130b2bb_HPS_FORMAT_FIGEXP M_FIG Model of AhR-mediated transcriptional reprogramming with implications for "silent" HIV-1 reservoir persistence and gut homing/residency.RNA-Sequencing revealed genes sets modulated by AhR blockade in CD4+ T-cells of ART-treated PLWH, with known HIV-1 interactor activities (NCBI HIV Interactor Database) and AhR responsive elements in their promoters (ENCODE). Among them, HIC1, a repressor of Tat-mediated HIV-1 transcription and a tissue-residency regulator, represents a putative AhR mechanism of action. These results support a model in which AhR activation favors the gut homing and residency via the induction of ITGB7 and CXCR6 expression, respectively, and fuels the persistence of silent" HIV-1 reservoirs in CD4+ T-cells of ART-treated PLWH. At the opposite, pharmacological AhR blockade facilitates viral outgrowth, and by interfering with tissue residency, likely promotes the mobilization of << reactivated >> reservoir cells from deep tissues into the circulations. C_FIG BRIEF SUMMARYWe identified the aryl hydrocarbon receptor as a barrier to HIV-1 infection/outgrowth in Th17-polarized CD4+ T-cells and a novel therapeutic target in HIV-1 cure/remission interventions.

immunology↗

bioRxiv2021

Th17 cell master transcription factor RORC2 regulates HIV-1 gene expression and viral outgrowth

Among CD4+ T-cells, T helper 17 (Th17) cells are particularly susceptible to HIV-1 infection and are depleted from mucosal sites, which causes damage to the gut barrier resulting in microbial translocation-induced systemic inflammation, a hallmark of disease progression. Furthermore, a proportion of latently infected Th17 cells persist long-term in the gastro-intestinal lymphatic tract, where low-level HIV-1 transcription is observed. This residual viremia contributes to chronic immune activation. Thus, Th17 cells are key players in HIV pathogenesis and viral persistence, however it is unclear why these cells are highly susceptible to HIV-1 infection. Th17 cell differentiation depends on expression of the master transcriptional regulator RORC2, a retinoic acid-related nuclear hormone receptor that regulates specific transcriptional programs by binding to promoter/enhancer DNA. Here, we report that RORC2 is a key host-cofactor for HIV replication in Th17 cells. We found that specific inhibitors that bind to the RORC2 ligand-binding domain reduced HIV replication in CD4+ T-cells. Depletion of RORC2 inhibited HIV-1 infection, whereas RORC2 overexpression enhanced it. RORC2 was found to promote HIV-1 gene expression. Chromatin immune precipitation revealed that RORC2 binds to the nuclear receptor responsive element (NRRE) in the HIV-1 LTR. In treated HIV-1 patients, RORC2+ CD4 T cells contained more proviral DNA than RORC2- cells. Pharmacological inhibition of RORC2 potently reduced HIV-1 outgrowth in CD4+ T-cells from antiretroviral-treated patients. Altogether, these results provide a new explanation as to why Th17 cells are highly susceptible to HIV-1 infection and point to RORC2 as a cell-specific target for HIV-1 therapy. Significance statementHIV-1 infects CD4 T cells and among these, Th17 cells are known to be particularly permissive for virus replication. Infection of Th17 cells is critical for AIDS pathogenesis and viral persistence, however it is not clear why these cells are highly permissive to HIV-1. We found that Th17 cell permissiveness depends on expression of the hormone receptor RORC2, which is the master transcriptional regulator of Th17 cell differentiation. We identify RORC2 as a new, cell-specific host-dependency factor that can be targeted by small molecules. Our results point to RORC2 as a cell-specific target for HIV-1 therapy, an entirely new concept in the field, and suggest HIV-1 might have evolved to exploit RORC2 to promote its own persistence.

microbiology↗