Gut Protein Expression in Immune Cells Linked to HIV Risk, Progression

Researchers recently uncovered a strong link between the prevalence of immune cells that express high levels of a gut-homing protein at HIV infection and related clinical outcomes, according to a study published by Science Translational Medicine.

The authors previously discovered a link between alpha-4 beta-7-expressing immune cells and HIV in monkey models of the infection.

In the current study, women whose CD4+ T cells had a high level of alpha-4 beta-7 on the surface were more likely to develop HIV compared with women who have fewer of these cells. Additionally, these patients were also more likely to experience rapid immune damage resulting from infection.

“Our findings suggest that having a high frequency of alpha-4 beta-7-expressing CD4+ T cells, which HIV preferentially infects, leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells,” said co-author Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases.

Included in the study were blood samples from 59 women prior to HIV infection and 106 HIV-negative women. Patients were participants in the CAPRISA 004 study, which examined the efficacy of an HIV prevention treatment in sub-Saharan Africa.

The researchers compared the percentage of CD4+ T cells with high levels of alpha-4 beta-7 in the blood samples.

The number of immune cells with high levels of alpha-4 beta-7 was observed to have a moderate effect on HIV risk among both the general study population and among a cohort of 41 female sex workers in Kenya, according to the study.

The risk of HIV skyrocketed 18% for every 1% increase in alpha-4 beta-7 protein, which was similar to preclinical findings.

The number of the CD4+ T cells expressing high levels of alpha-4 beta-7 was also observed to strongly affect how quickly the immune system sustained damage. CD4+ T cell levels dropped twice as fast among patients with high pre-infection levels of alpha-4 beta-7 compared with patients who had lower levels, according to the study.

Notably, the HIV viral load a few months after infection was much higher among women with increased pre-infection levels compared with women who had lower pre-infection levels.

The authors hypothesize that the immune system damage was likely the result of HIV-related damage to the gut because higher pre-infection levels of alpha-4 beta-7 were linked to higher levels of a biomarker for gut damage.

Further investigation revealed that HIV targets CD4+ T cells expressing alpha-4 beta-7 early in the infection, especially in the gut, according to the study.

The authors then analyzed data from the RV254 clinical trial and discovered that early initiation of antiretroviral therapy (ART) was unable to prevent CD4+ T cells depletion from the gut or reconstitute the immune cells.

“These findings suggest that interventions in addition to ART may be needed to restore CD4+ T cells in the [gastrointestinal] tracts of people living with HIV,” said study co-lead Lyle McKinnon, PhD. “One such intervention could be an anti-alpha-4 beta-7 antibody called vedolizumab, which is FDA-approved for the treatment of ulcerative colitis and Crohn’s disease.”