HIV-1 antibodies in the presence of tuberculosis and other coinfections

About This Grant

PROJECT SUMMARY Worldwide, tuberculosis (TB) is the most common disease in people living with HIV (PWH). Although, studies have conclusively demonstrated that HIV-1 enhances the development and progression of TB, there is limited understanding about TB effects on HIV-1 pathogenesis. We have observed that PWH and TB as compared to PWH/No TB have broader and more potent HIV-1 neutralizing antibodies (nAbs). We hypothesize that TB changes both the HIV-1 immune response and the characteristics of the viruses present in PWH. This is important because our knowledge about HIV-1 pathogenesis primarily comes from individuals that do not have concomitant TB; the ubiquitous HIV-1 TB syndemic provides an imperative to understand the effects of TB in PWH. TB influences multiple aspects of HIV-1 pathogenesis. Broad and more potent HIV-1 nAbs, observed in PWH and TB, provides selection pressure, and we will assess if TB leads to the emergence of more nAb resistant strains. Resistant viruses are a primary reason it has been difficult to prevent HIV-1 transmission through vaccination and induce virus remission with antibody-based therapies. We will also examine the impact of other diseases common in PWH, such as talaromycoses, histoplasmosis, cryptococcosis, and non- tuberculous mycobacteria. Comparing HIV-1 immune responses and virus characteristics in PWH and the various different opportunistic infections will provide insights into the pathogenesis of TB enhanced immune responses. These studies will highlight the importance of specific inflammatory programs, unique microbial antigens, and anatomic co-localization for the enhanced humoral response with TB. We hypothesize that TB and potentially other diseases increase the frequency and functionality of T follicular helper cells, which are an essential component of a broadly potent humoral response. Antibodies can also mediate effector cell function through Fc domains, such as antibody dependent cellular cytotoxicity (ADCC). We will also examine if TB selects for ADCC resistant strains because prior studies have shown that ADCC is important in preventing HIV-1 transmission and ameliorating disease outcomes after HIV-1 acquisition. Furthermore, neutralization resistant strains are often ADCC susceptible and vice-versa. We will also isolate and characterize antibodies that mediate broad and potent neutralization and ADCC. PWH and TB will harbor unique HIV-1 antibodies because they arise in the presence of highly resistant HIV-1 variants. TB mediated influence on HIV-1 immunity and the subsequent effect on the frequency of resistant strains has direct implications for future broadly potent nAb based vaccine strategies and therapies aimed at inducing virus remission in the absence of combination antiretroviral therapy. Our studies will highlight the importance of TB status for antibody based prevention and post-treatment control strategies and the type of antibodies that will work in HIV TB endemic regions of the world.