January 29, 2018HIV/AIDS
According to a study published online in Science Translational Medicine (24 January 2018), for the first time, a relationship has been shown between health outcomes and the proportion of key immune cells, at the time of HIV infection, that display high levels of a gut-homing protein called alpha-4 beta-7. Previous research illustrated this relationship in monkeys infected with a simian form of HIV. The new study found that women who had more CD4+ T cells displaying high levels of alpha-4 beta-7 on their surface were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly, than women with fewer such cells. The National Institutes of Health co-funded the study with the South African Medical Research Council as part of the U.S.-South Africa Program for Collaborative Biomedical Research.
For the study, the authors compared the percentage of CD4+ T cells displaying high levels of alpha-4 beta-7 in blood samples drawn from 59 women shortly before they acquired HIV to the percentage of such cells in 106 women who remained HIV negative. The women, 18 to 40 years of age, were selected from participants in the CAPRISA 004 study, which evaluated the safety and efficacy of tenofovir gel for HIV prevention in KwaZulu-Natal, South Africa, from 2007 to 2010. Understanding HIV acquisition and disease progression among African women is especially important because women accounted for nearly 60% of new HIV infections among adults in sub-Saharan Africa in 2016.
Results showed that the proportion of CD4+ T cells with high levels of alpha-4 beta-7 had an effect, albeit modest, on the risk of acquiring HIV among both the women in the CAPRISA 004 study and a separate cohort of 41 high-risk females in Kenya. The risk of HIV acquisition rose by 18% for each 1% increase in alpha-4 beta-7 protein. The authors showed a similar association in monkeys that were exposed to a simian form of HIV. The proportion of CD4+ T cells with high levels of alpha-4 beta-7 strongly affected how quickly HIV damaged the immune system. CD4+ T cell levels declined twice as fast among women with higher pre-infection levels of alpha-4 beta-7 as among women with lower pre-infection levels. In addition, the amount of HIV in the blood within a few months of infection was greater in women with higher pre-infection levels of alpha-4 beta-7 than in women with lower pre-infection levels. According to the authors, the mechanism for the immune system damage likely was HIV-related damage to the gut, as higher pre-infection levels of alpha-4 beta-7 were associated with higher levels of a biological marker of gut damage. The authors also found that HIV targets CD4+ T cells displaying alpha-4 beta-7 very early in infection, particularly in the gut. In this regard, the authors looked at data from the U.S. Military HIV Research Program-led RV254 clinical trial at the Thai Red Cross in Bangkok, Thailand, and found that starting antiretroviral therapy (ART) right after HIV diagnosis did not prevent the depletion of CD4+ T cells from the gut or facilitate reconstitution of the depleted cells. According to the authors, these findings suggest that interventions in addition to ART may be needed to restore CD4+ T cells in the GI tracts of people living with HIV, and that 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.
In previous studies, a monkey-adapted form of vedolizumab contributed to the near-replenishment in monkeys of CD4+ T cells that had been destroyed by a simian form of HIV. Based on this and related findings, NIAID initiated an early-phase clinical trial in 2017 to determine whether short-term treatment with vedolizumab in combination with ART could generate sustained HIV remission in people living with HIV. The study is taking place at the NIH Clinical Research Center in Bethesda, Maryland. Preliminary results are expected later this year. More information about the study is available at ClinicalTrials.gov under study identifier NCT02788175.