The transcriptome of HIV-1 infected intestinal CD4+ T cells exposed to enteric bacteria

Abstract

Global transcriptome studies can help pinpoint key cellular pathways exploited by viruses to replicate and cause pathogenesis. Previous data showed that laboratory-adapted HIV-1 triggers significant gene expression changes in CD4+ T cell lines and mitogen-activated CD4+ T cells from peripheral blood. However, HIV-1 primarily targets mucosal compartments during acute infection in vivo. Moreover, early HIV-1 infection causes extensive depletion of CD4+ T cells in the gastrointestinal tract that herald persistent inflammation due to the translocation of enteric microbes to the systemic circulation. Here, we profiled the transcriptome of primary intestinal CD4+ T cells infected ex vivo with transmitted/founder (TF) HIV-1. Infections were performed in the presence or absence of Prevotella stercorea, a gut microbe enriched in the mucosa of HIV-1-infected individuals that enhanced both TF HIV-1 replication and CD4+ T cell death ex vivo. In the absence of bacteria, HIV-1 triggered a cellular shutdown response involving the downregulation of HIV-1 reactome genes, while perturbing genes linked to OX40, PPAR and FOXO3 signaling. However, in the presence of bacteria, HIV-1 did not perturb these gene sets or pathways. Instead, HIV-1 enhanced granzyme expression and Th17 cell function, inhibited G1/S cell cycle checkpoint genes and triggered downstream cell death pathways in microbe-exposed gut CD4+ T cells. To gain insights on these differential effects, we profiled the gene expression landscape of HIV-1-uninfected gut CD4+ T cells exposed to bacteria. Microbial exposure upregulated genes involved in cellular proliferation, MAPK activation, Th17 cell differentiation and type I interferon signaling. Our findings reveal that microbial exposure influenced how HIV-1 altered the gut CD4+ T cell transcriptome, with potential consequences for HIV-1 susceptibility, cell survival and inflammation. The HIV-1- and microbe-altered pathways unraveled here may serve as a molecular blueprint to gain basic insights in mucosal HIV-1 pathogenesis.

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

“…Despite a reduced expression of PRR, microbial exposure influenced how HIV-1 altered the gut CD4T cell transcriptome causing a strong upregulation of type I IFN and ISG production [80]. Surprisingly, the induction of multiple antiviral genes after microbial exposure was also associated with an enhanced TF HIV-1 replication [80]. In agreement, our previous study recorded a strong activation of IFNα/β and its receptor in the gut mucosa of HIV-1-infected subjects [52].…”

“…Besides the relationship between IFNα and TRAIL/DR5-mediated apoptosis, in chronic HIV-1 infection the pro-apoptotic Bak was found increased in CD4T cells and correlated positively with sensitivity to Fas/CD95-mediated apoptosis and negatively with CD4T cell numbers [79]. Moreover, a model in which CD4T cell-intrinsic type I IFN signaling due to microbial exposure was recently proposed to potentiate gut CD4T cells for accelerated HIV-1 by inhibiting CDK4/6, cyclins and c-Myc [80].…”

“…Decreased PRR expression was associated with increased abundance of numerous pathogenic bacterial taxa, including Pasteurellaceae members, Aggregatibacter and Actinobacillus, and the Mycoplasmataceae family, which in turn might be responsible for promoting persistent IFN activation, gut microbiota alterations, and limited viral clearance [29]. Despite a reduced expression of PRR, microbial exposure influenced how HIV-1 altered the gut CD4T cell transcriptome causing a strong upregulation of type I IFN and ISG production [80]. Surprisingly, the induction of multiple antiviral genes after microbial exposure was also associated with an enhanced TF HIV-1 replication [80].…”

The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

“…The majority of human studies listed above were performed with peripheral blood Th17 cells. Nevertheless, studies performed on cells infiltrating peripheral tissues in humans including the intestinal or vaginal mucosa also revealed a functional heterogeneity among CD4+ T-cell subsets in terms of Th17 and Th1Th17 polarization [ 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 ]. Emerging evidence exists now supporting the ability of specific components of intestinal microbiota in shaping the functional heterogeneity of CD4+ T-cells, including Th17 fate decision [ 28 , 29 , 32 , 61 , 62 , 63 ].…”

HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

“…Yoder et al showed reduced expression of canonical ISGs in LPMCs, infected with HIV [40], which might indicate differences in the IFN responsiveness following HIV infection. Another study observed differences in the ISG expression pattern following stimulation with different IFNα subtypes [9].…”