<i>Mycobacterium tuberculosis</i> infection, immune activation, and risk of HIV acquisition

Abstract Background Although immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis ( Mtb ) infection, are not well characterized. Methods We conducted a nested case-control study within the Step MRKAd5 HIV-1 vaccine study. PBMCs from the last HIV-negative sample from incident HIV cases and controls who did not acquire HIV were stimulated with Mtb -specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining. Com binatorial p olyfunctionality analysis of a ntigen- s pecific T-cell s ubsets (COMPASS) determined overall Mtb -antigen-specific T cell activation. We measured inflammatory profiles with five Correlates of TB Risk (CoR) peripheral blood transcriptomic signatures. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether either cellular markers of TB-associated immune activation or transcriptomic predictors of TB disease states were associated with HIV acquisition. Results Among 465 participants, latent Mtb infection (LTBI) prevalence (21.5% controls vs 19.1% cases, p=0.51) and Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.76 (0.60, 0.95)), were associated with HIV acquisition in multivariable analysis. The Sweeney3 signature best predicted odds of acquiring HIV in unadjusted and adjusted analyses, including when restricted to LTBI-negative participants. Conclusions LTBI and Mtb polyfunctional antigen-specific CD4+ T cell immune activation were not identified as risk factors for HIV acquisition, but transcriptomic analyses demonstrated that two CoR signatures predicted HIV risk after adjustment for known behavioral and clinical risk factors. CoR signatures can demonstrate host gene expression associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.