Mentored Scientist Award

Modulating effects of HIV infection and early ART initiation on Immune dysfunction and TB risk

Headshot of Fatoumatta Darboe, PhD
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HIV infection increases risk of tuberculosis (TB) disease. Antiretroviral therapy (ART) decreases TB risk, yet it remains strikingly higher than in people without HIV. HIV increases immune dysfunction, impairing T helper (Th)1, Th17 cells and expanding regulatory responses, all of which likely increase TB risk. Furthermore, other immune activation pathways, such as the kynurenine pathway of tryptophan catabolism (KP) are upregulated in HIV and remain abnormal despite ART. KP catabolites suppress Th17 cells while expanding regulatory T cells (decreasing Th17/Treg ratio), potentially linking the KP to functional T cell defects associated with TB risk. It remains unknown how early initiation of ART regulates HIV-induced immune activation and dysfunction, since TB risk remains high despite viral suppression. We aim to determine the longitudinal kinetics of immune activation from pre-HIV acquisition up to 8 years after ART. We also aim to determine the impact of ART initiation timing on restoration of the immune function.

We hypothesize that whilst immediate ART initiation among people with recent HIV infection attenuates HIV-induced immune activation and dysfunction better than later ART initiation, these functions are not fully restored to pre-HIV infection levels even after long-term ART. We will leverage samples from the MERLIN study, which recruited at-risk Peruvian men who have sex with men (MSMs) and transgender women (TW) from an existing cohort, and randomized them during incident HIV infection to immediate or delayed ART (after 24 weeks after infection). They were followed for up to 8 years on ART. KP activity will be assessed pre-HIV acquisition and until 4 years after ART. Th17 and Treg function will be measured after stimulating cells with Mycobacterium tuberculosis (Mtb)-specific antigens using spectral flow.

This study will give insight into an important immune mechanism linking acute and long-term effects of HIV on the risk of TB.