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Goulet, J.-P.

Publications and source records attributed to Goulet, J.-P..

2 recordsLinked to original sources
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↗