Enhancement of HIV-1 infection and intestinal CD4+ T cell depletion ex vivo by gut microbes altered during chronic HIV-1 infection

Abstract

Background: Early HIV-1 infection is characterized by high levels of HIV-1 replication and substantial CD4 T cell depletion in the intestinal mucosa, intestinal epithelial barrier breakdown, and microbial translocation. HIV-1-induced disruption of intestinal homeostasis has also been associated with changes in the intestinal microbiome that are linked to mucosal and systemic immune activation. In this study, we investigated the impact of representative bacterial species that were altered in the colonic mucosa of viremic HIV-1 infected individuals (HIV-altered mucosal bacteria; HAMB) on intestinal CD4 T cell function, infection by HIV-1, and survival in vitro. Lamina propria (LP) mononuclear cells were infected with CCR5-tropic HIV-1 BaL or mock infected, exposed to high (3 gram-negative) or low (2 gram-positive) abundance HAMB or control gram-negative Escherichia coli and levels of productive HIV-1 infection and CD4 T cell depletion assessed. HAMB-associated changes in LP CD4 T cell activation, proliferation and HIV-1 co-receptor expression were also evaluated. Results:The majority of HAMB increased HIV-1 infection and depletion of LP CD4 T cells, but gram-negative HAMB enhanced CD4 T cell infection to a greater degree than gram-positive HAMB. Most gram-negative HAMB enhanced T cell infection to levels similar to that induced by gram-negative E. coli despite lower induction of T cell activation and proliferation by HAMB. Both gram-negative HAMB and E. coli significantly increased expression of HIV-1 co-receptor CCR5 on LP CD4 T cells. Lipopolysaccharide, a gram-negative bacteria cell wall component, up-regulated CCR5 expression on LP CD4 T cells whereas gram-positive cell wall lipoteichoic acid did not. Upregulation of CCR5 by gramnegative HAMB was largely abrogated in CD4 T cell-enriched cultures suggesting an indirect mode of stimulation. Conclusions:Gram-negative commensal bacteria that are altered in abundance in the colonic mucosa of HIV-1 infected individuals have the capacity to enhance CCR5-tropic HIV-1 productive infection and depletion of LP CD4 T cells in vitro. Enhanced infection appears to be primarily mediated indirectly through increased expression of CCR5 on LP CD4 T cells without concomitant large scale T cell activation. This represents a novel mechanism potentially linking intestinal dysbiosis to HIV-1 mucosal pathogenesis.

Brief Report: Inflammatory Colonic Innate Lymphoid Cells Are Increased During Untreated HIV-1 Infection and Associated With Markers of Gut Dysbiosis and Mucosal Immune Activation

“…Laboratory and analytic methods used to profile the intestinal microbiomes were as described 26,32,33,35 .…”

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…The role of ATRA in regulating tolerance and immunity via the modulation of regulatory and effector functions of CD4 + T cells, respectively, is well established (41) Considering the strategic location of Th17 cells at portal sites of HIV/SIV entry (6,24,27,28,63), as well as their important role in maintaining mucosal immunity homeostasis in the context of a complex microbiota (6,64,65), our results point to the potential beneficial use of mTOR inhibitors in preventing HIV infection/ persistence in gut-homing Th17 cells.…”

Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6 + CD4 + T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection

“…This group and others have also suggested that HIV-1 infection alters the gut microbiota of North American individuals in which Prevotella, a bacterial genus of the Bacteroidetes phylum, is significantly enriched (52,(57)(58)(59). Dillon and coworkers, for their part, have proposed that translocation of Prevotella species to mucosal tissues is significantly increased in HIV-1-infected subjects compared to uninfected individuals (5,52). Despite the heterogeneity in the composition of the gut microbiota, this high abundance of the Prevotella genus and its enhanced capacity to translocate to extraintestinal sites thus suggest the predominance of Gram-negative bacteria in GALT of HIV-1-infected persons.…”

“…Increased intraepithelial calcium concentrations (6,7) and reduced sodium glucose cotransport (6) were suggested as factors implicated in abnormal epithelial cell differentiation and organization. Ineffective glucose uptake mediated by the HIV-1 protein Tat (8) and microtubule disruption induced by the viral protein gp120 (7) are also thought to play a dominant role in the high level of enterocyte apoptosis observed in HIV-1-infected individuals (5,9). When associated with villous atrophy (10), this intestinal barrier disorganization causes disruption of epithelial tight junctions, resulting in the entry of microbial products into the bloodstream (a phenomenon also known as microbial translocation) (5,(11)(12)(13)(14)(15).…”

“…Immunological and structural alterations in the gut-associated lymphoid tissues (GALT) are seen and likely caused by direct and indirect effects of HIV-1 replication and the ensuing immune response (5,6). Increased intraepithelial calcium concentrations (6,7) and reduced sodium glucose cotransport (6) were suggested as factors implicated in abnormal epithelial cell differentiation and organization.…”