Infection with <i>Mycobacterium tuberculosis</i> alters the antibody response to HIV-1

<b>Background: </b>Co-infection with Mycobacterium tuberculosis (MTB) differentially modulates untreated HIV-1 infection, with asymptomatic MTB reducing HIV-1 viremia and opportunistic infections and active tuberculosis (TB) accelerating AIDS progression. Here, we investigate antibody (Ab) responses to HIV-1 in people with HIV (PWH) without MTB, with asymptomatic MTB, and with later progression to active TB to elucidate MTB-associated effects on HIV-1 immune control. <b>Methods: </b>Using the Swiss HIV Cohort Study (SHCS), we conducted a retrospective study that included 2,840 PWH with data on MTB status and HIV-1-specific plasma binding-/neutralizing-responses. We evaluated associations between MTB status and binding-/neutralizing-responses while adjusting for key disease and demographic parameters. <b>Results: </b>Among the included 2,840 PWH, 263 PWH had asymptomatic MTB based on either a positive TST-/IGRA-test at the baseline (time of HIV-1 Ab measurement) or on later progression to active TB. Compared to PWH without MTB infection, PWH with asymptomatic MTB infection showed reduced HIV-1 Ab levels, both for Env binding (e.g., IgG1 BG505 trimer antigen, p = 0.024) and neutralization of a diverse panel of HIV-1 viruses (p = 0.012). Conversely, PWH (n = 32) who later progressed to active TB (&gt;180 days after baseline) demonstrated a significant shift towards IgG3 in their HIV-1 Ab repertoire (p = 0.011), detectable in median 3.8 years (IQR 2.4 - 8.7) before active TB onset. <b>Conclusion: </b>Our data indicate that asymptomatic MTB infection and active TB exert profound heterologous effects on HIV-1 specific Ab development. These findings advance our understanding of host-pathogen dynamics and may have implications for new diagnostic approaches in predicting future active TB.