Identification of aryl hydrocarbon receptor as a barrier to HIV-1 infection and outgrowth in CD4+ T cells

Chatterjee, Debashree; Zhang, Yuwei; Ngassaki-Yoka, Christ-Dominique; Dutilleul, Antoine; Khalfi, Soumia; Hernalsteens, Olivier; Salinas, Tomas Raul Wiche; Dias, Jonathan; Chen, Huicheng; Smail, Yasmine; Goulet, Jean-Philippe; Bell, Brendan; Routy, Jean Pierre; Lint, Carine Van; Ancuța, Petronela

doi:10.1016/j.celrep.2023.112634

Cited by 11 publications

(8 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a first set of experiments, MDMs were treated with ATRA before HIV VSV-G exposure (Figure 2A). At day 3 post-infection, levels of early (RU5) and late (Gag) reverse transcripts, as well as levels of integrated HIV-DNA (proviral HIV-DNA), measured as we previously reported 73,76,83 , were significantly increased by ATRA (Figure 2B), indicative of a superior efficacy in reverse transcription and/or integration. Consistently, HIV-p24 levels in cell-culture supernatants, indicative of viral production, were significantly increased by ATRA (n=14; p=0.0009) (Figure 2C).…”

Section: Resultssupporting

confidence: 67%

See 1 more Smart Citation

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

Dias,

Cattin,

Goulet

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

The intestinal environment facilitates HIV-1 infectionviamechanisms 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.Figure 1:

show abstract

Section: Resultssupporting

confidence: 67%

“…The RNA sequencing and analysis was performed, as we recently reported 83 . Briefly, total RNA was extracted from ATRA-MDMs and DMSO-MDMs harvested prior HIV infection (Figure 1A) using AllPrep DNA/RNA/miRNA universal kit (Qiagen; Hilden/Germany), according to the manufacturer’s protocol.…”

Section: Experimental Model and Study Participant Detailsmentioning

confidence: 99%

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

Dias,

Cattin,

Goulet

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

“…The AhR is strongly linked to viral pathogenesis 39 , though there is ongoing controversy whether the AhR pathway promotes or restrains these infections 38,39 . These discrepancies may relate to the role of AhR signaling varying in a virus- 39,50–53 , cell type- 50,54,55 , and ligand-specific manner 54,56,57 . Consistent with these findings, we found that ILA—but not I3A—robustly suppresses viral infection even though both are AhR agonists that are produced in an ArAT-dependent manner 31 .…”

Section: Discussionmentioning

confidence: 99%

Commensal bacteria inhibit viral infections via a tryptophan metabolite

Jiang,

Soo,

Tan

et al. 2024

Preprint

View full text Add to dashboard Cite

There is growing appreciation that commensal bacteria impact the outcome of viral infections, though the specific bacteria and their underlying mechanisms remain poorly understood. Studying a simian-human immunodeficiency virus (SHIV)-challenged cohort of pediatric nonhuman primates, we bioinformatically associated Lactobacillus gasseri and the bacterial family Lachnospiraceae with enhanced resistance to infection. We experimentally validated these findings by demonstrating two different Lachnospiraceae isolates, Clostridium immunis and Ruminococcus gnavus, inhibited HIV replication in vitro and ex vivo. Given the link between tryptophan catabolism and HIV disease severity, we found that an isogenic mutant of C. immunis that lacks the aromatic amino acid aminotransferase (ArAT) gene, which is key to metabolizing tryptophan into 3-indolelactic acid (ILA), no longer inhibits HIV infection. Intriguingly, we confirmed that a second commensal bacterium also inhibited HIV in an ArAT-dependent manner, thus establishing the generalizability of this finding. In addition, we found that purified ILA inhibited HIV infection by agonizing the aryl hydrocarbon receptor (AhR). Given that the AhR has been implicated in the control of multiple viral infections, we demonstrated that C. immunis also inhibited human cytomegalovirus (HCMV) infection in an ArAT-dependent manner. Importantly, metagenomic analysis of individuals at-risk for HIV revealed that those who ultimately acquired HIV had a lower fecal abundance of the bacterial ArAT gene compared to individuals who did not, which indicates our findings translate to humans. Taken together, our results provide mechanistic insights into how commensal bacteria decrease susceptibility to viral infections. Moreover, we have defined a microbiota-driven antiviral pathway that offers the potential for novel therapeutic strategies targeting a broad spectrum of viral pathogens.

show abstract

“…Early and late HIV-1 reverse transcripts, as well as integrated HIV-DNA levels were quantified using specific primers and probes (Supplemental Table 2), as we previously described 20,111,112 . Briefly, cell lysates, generated by proteinase K digestion, were used to quantify HIV-DNA copies.…”

Section: Star Methodsmentioning

confidence: 99%

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

Fert,

Richard,

Raymond Marchand

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The mechanistic target of rapamycin (mTOR) positively regulates multiple steps of the HIV-1 replication cycle. We previously reported that a 12-weeks supplementation of antiretroviral therapy (ART) with metformin, an indirect mTOR inhibitor used in type-2 diabetes treatment, reduced mTOR activation and HIV transcription in colon-infiltrating CD4+ T-cells, together with systemic inflammation in nondiabetic people with HIV-1 (PWH). Herein, we investigated the antiviral mechanisms of metformin. In a viral outgrowth assay performed with CD4+ T-cells from ART-treated PWH, and upon infection in vitro with replication-competent and VSV-G-pseudotyped HIV-1, metformin decreased virion release, but increased the frequency of productively infected CD4lowHIV-p24+ T-cells. These observations coincided with increased BST2/Tetherin (HIV release inhibitor) and Bcl-2 (pro-survival factor) expression, and improved recognition of productively infected T-cells by HIV-1 Envelope antibodies. Thus, metformin exerts pleiotropic effects on post-transcription/translation steps of the HIV-1 replication cycle and may be used to accelerate viral reservoir decay in ART-treated PWH.

show abstract

Identification of aryl hydrocarbon receptor as a barrier to HIV-1 infection and outgrowth in CD4+ T cells

Cited by 11 publications

References 87 publications

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

Retinoic Acid Boosts HIV-1 Replication in MacrophagesviaCCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

Commensal bacteria inhibit viral infections via a tryptophan metabolite

Metformin Enhances Antibody-Mediated Recognition of HIV-Infected CD4+ T-Cells by Decreasing Viral Release

Contact Info

Product

Resources

About