Cytomegalovirus Still a Problem for Patients with HIV Treated with ART

Cytomegalovirus (CMV) disease is a rarity in the age of antiretroviral therapy (ART), but CMV coinfection without symptoms is common in people with HIV. The results of a new study appear to show CMV can disrupt epithelial junctions and bring about chronic inflammation of the gut. Conducted by Ekaterina Maidji, PhD, (picture) of the Division of Experimental Medicine at Zuckerberg San Francisco General, and colleagues, the study suggests that therapeutic intervention of CMV could prevent or treat epithelial barrier dysfunction in people with HIV.

Even patients with HIV receiving ART often have epithelial barrier dysfunction in the intestines. The exact mechanisms that cause this dysfunction is an active area of research. Some scientists attribute it to an increased production of what the authors described as “inflammatory cytokines by activated mucosal T cells and mucosal epithelial cells directly responding to HIV-1 gp 120.” However, that is not a universally accepted explanation. The authors said that CMV has been suspected of being a cofactor for HIV disease progression and noted that “the gastrointestinal tract experiences severe CD4+ T cell depletion at all stages of the disease” and that those cells are not restored following ART.

The current study investigated the presence of CMV in the rectosigmoid tissues of both patients with HIV treated with ART and untreated individuals. The researchers used what they described as “state-of-the-art techniques in dual immunohistochemistry (IHC) and in situ hybridization (ISH).” They used two models, a murine model of the human gut and polarized monolayers formed from human intestinal cells differentiated in vitro.

There were several findings, including that CMV disrupts the junctions of polarized intestinal cells with or without HIV and that, in turn, significantly reduced transepithelial electrical resistance (TER)—which is a measure of epithelial monolayer integrity, as well as enhanced epithelial barrier permeability. An additional finding was that at least some of the disruption of the intestinal epithelium integrity was due to the proinflammatory cytokine interleukin-6 (IL-6), which is induced by CMV. Finally, the researchers found that a novel drug currently being developed, letermovir, preserved epithelial polarity in the system that they tested.

These findings could indicate that CMV reactivation could be a cofactor, which stimulates the release of cytokines causing the compromise of the barrier function and leading, ultimately, to chronic inflammation. The team also reported finding CMV proteins and DNA in 47% of the intestinal biopsies, which they said could suggest “that the intestinal epithelium supports CMV replication.”

Although CMV induces IL-6, the researchers said that HIV does not in vitro, but that the reasons for elevated plasma IL-6 remain unclear and could be attributed to multiple factors, including CMV. They call the changes in IL-6 levels observed in this study “highly intriguing,” but avoided theorizing until larger studies can be conducted.

“Altogether, our results provide further evidence that CMV remains an important cofactor in HIV pathogenesis even during ART-mediated HIV suppression and suggest new antiviral interventions to prevent gut epithelial barrier dysfunction in treated HIV infection,” the team concluded.

The study, “Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction,” was published in PLOS Pathogens.

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