Research Article: Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction

Date Published: February 27, 2017

Publisher: Public Library of Science

Author(s): Ekaterina Maidji, Ma Somsouk, Jose M. Rivera, Peter W. Hunt, Cheryl A. Stoddart, Dirk P. Dittmer.

http://doi.org/10.1371/journal.ppat.1006202

Abstract

Although invasive cytomegalovirus (CMV) disease is uncommon in the era of antiretroviral therapy (ART), asymptomatic CMV coinfection is nearly ubiquitous in HIV infected individuals. While microbial translocation and gut epithelial barrier dysfunction may promote persistent immune activation in treated HIV infection, potentially contributing to morbidity and mortality, it has been unclear whether CMV replication in individuals with no symptoms of CMV disease might play a role in this process. We hypothesized that persistent CMV replication in the intestinal epithelium of HIV/CMV-coinfected individuals impairs gut epithelial barrier function. Using a combination of state-of-the-art in situ hybridization technology (RNAscope) and immunohistochemistry, we detected CMV DNA and proteins and evidence of intestinal damage in rectosigmoid samples from CMV-positive individuals with both untreated and ART-suppressed HIV infection. Two different model systems, primary human intestinal cells differentiated in vitro to form polarized monolayers and a humanized mouse model of human gut, together demonstrated that intestinal epithelial cells are fully permissive to CMV replication. Independent of HIV, CMV disrupted tight junctions of polarized intestinal cells, significantly reducing transepithelial electrical resistance, a measure of monolayer integrity, and enhancing transepithelial permeability. The effect of CMV infection on the intestinal epithelium is mediated, at least in part, by the CMV-induced proinflammatory cytokine IL-6. Furthermore, letermovir, a novel anti-CMV drug, dampened the effects of CMV on the epithelium. Together, our data strongly suggest that CMV can disrupt epithelial junctions, leading to bacterial translocation and chronic inflammation in the gut and that CMV could serve as a target for therapeutic intervention to prevent or treat gut epithelial barrier dysfunction during HIV infection.

Partial Text

Immune activation and intestinal epithelial barrier dysfunction are major hallmarks of HIV infection that persist in spite of potent combination antiretroviral therapy (ART) [1–6]. The barrier properties of mucosal intestinal epithelium are maintained by a monolayer of columnar epithelial cells that are firmly connected by intercellular tight junctions [7]. Disruption of these junctions was proposed as a mechanism for the increased colonic permeability in ART-suppressed patients [8]. In HIV infection, impaired integrity of the intestinal epithelial barrier facilitates bacterial translocation, a major contributor to chronic immune activation [4, 6, 9–11]. The precise mechanisms by which HIV perturbs the intercellular tight junctions of intestinal epithelia remain an active area of investigation [12–14].

During HIV infection, immune activation linked to intestinal epithelial barrier dysfunction persists despite potent suppressive ART [5, 6, 10, 67–69]. The underlying mechanisms are complex and remain unclear, but the role of opportunistic viral pathogens in the gut has yet to be fully appreciated. Here we report that CMV persists in the rectosigmoid tissues of asymptomatic CMV-positive individuals with both untreated and ART-suppressed HIV infection and that CMV infection coexists with discontinuous epithelial tight junctions. Independent of HIV, CMV impairs the integrity of polarized human intestinal cells, significantly reducing transepithelial electrical resistance and enhancing epithelial barrier permeability. CMV-associated disruption of intestinal epithelium integrity was mediated, at least in part, by CMV-induced IL-6. These observations suggest that CMV reactivation in the gastrointestinal epithelium of HIV-infected individuals could be a potent cofactor that stimulates release of proinflammatory cytokines from intestinal epithelial cells, compromising barrier function and locally initiating bacterial translocation that leads to chronic inflammation in the gut (Fig 10).

 

Source:

http://doi.org/10.1371/journal.ppat.1006202

 

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