Disruption of gastrointestinal integrity in patients with HIV infection

Primary infection with HIV leads to severe depletion of CD4 T cells. This effect is conveniently measured in the blood compartment, but is even more pronounced in the gastrointestinal tract, which may be the initial site of acquisition of HIV for some people. Persistent HIV gastrointestinal infection impairs local immune defences, leads to immune activation and disrupts the epithelial barrier. The epithelial dysfunction is not completely repaired by anti‐retroviral therapy (ART) that is effective enough to suppress HIV viral load in the blood to undetectable levels. At the microscopic level, disruption of tight junctions between adjacent columnar epithelial cells is seen as a component. The resulting loss of integrity of the epithelium allows translocation of bacteria into the bloodstream, and this has been investigated as a potential contributor to the chronic systemic inflammation seen in HIV patients. These studies have now been supplemented by investigations to detect a viral pathogen in the gastrointestinal tract. Cytomegalovirus is found in the vast majority of HIV‐positive patients. Opportunistic diseases, usually retinitis, caused by high viral loads of CMV are nowadays mostly prevented by ART, where this is available. However, there is extensive evidence that CMV infection, as opposed to overt disease, is not completely controlled by ART. It is known to infect endothelial, stromal and intestinal epithelial cells and may form ulcers to compromise the barrier function of the mucosa. It is known to disrupt tight junctions of retinal pigment epithelial cells, so might be able to do the same in epithelial cells of the gastrointestinal tract. It is possible therefore that it may contribute to the chronic gastrointestinal and systemic inflammation seen in HIV‐positive patients. A recent publication combined immunohistochemistry with in situ hybridisation on primary intestinal cells differentiated to form monolayers of polarised cells. In this system, CMV decreased trans‐epithelial electrical resistance, a method used to assess the integrity of an epithelial monolayer. Permeability was also changed when assessed by the ability of dextran labelled with a fluorescent dye to migrate across cells held in the compartments of a trans‐well apparatus. Only a few cells were CMV positive, raising the question of how an infection of limited scale could produce an effect across the whole epithelium. A contribution from interleukin‐6 was identified, with the effect on epithelial integrity partially reduced by an antibody that blocked interleukin‐6. The antiviral drugs ganciclovir or letermovir reduced the effect of CMV on the epithelium. Parallel studies on biopsies of rectosigmoid tissue provided evidence that similar effects take place in vivo. The CMV proteins were readily detected in untreated