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.
Highlights
CD4+ T cells are the major targets of HIV-1 infection, and their preferential depletion during the course of infection is the hallmark feature of progression to AIDS [1]
The gastrointestinal (GI) tract is a major site of early HIV-1 replication and death of CD4 + T cells
We obtained the first gene expression profiles of primary gut CD4+ T cells infected in cell culture with HIV-1 in the context of microbes found in the GI tract of HIV-1 infected patients
Summary
CD4+ T cells are the major targets of HIV-1 infection, and their preferential depletion during the course of infection is the hallmark feature of progression to AIDS [1]. Major efforts have been made to understand the molecular events that occur following HIV-1 infection of CD4+ T cells. Microarray studies reported that infection of CD4+ T cells with laboratory-adapted, CXCR4-tropic HIV-1 altered pathways associated with DNA repair, T cell activation, cell cycle control, subcellular trafficking, programmed cell death, RNA processing and nucleic acid metabolism (reviewed in [2]). Those studies used either CD4+ T cell lines or mitogen-activated CD4+ T cells from peripheral blood, which are resistant to killing by primary, CCR5-tropic HIV-1 strains in vitro [3]. The CD4+ T cell-intrinsic pathways altered by transmitted/founder (TF) HIV-1, which best approximate the initial strains, i.e. those identified to have established clinical infection in vivo [4, 5], remain unknown
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