Mycobacterium tuberculosis disease effect on HIV-1 immunity, evolution, and persistence - PROJECT SUMMARY Worldwide, Mycobacterium tuberculosis (Mtb) is the most common co-infection in people living with HIV (PWH). Although, studies have conclusively demonstrated that HIV-1 enhances the development and progression of Mtb disease, there is limited understanding into Mtb disease effects on HIV-1 pathogenesis. We have observed that PWH with pulmonary Mtb disease (PWH/Active Mtb) as compared to PWH/No Mtb have broader and more potent HIV-1 neutralizing antibodies (nAbs). We have also shown that PWH/Active Mtb as compared to PWH/No Mtb have lower levels of intracellular HIV-1 RNA, suggesting they have lower HIV-1 transcription in the latently infected cells. We hypothesize that Mtb disease 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 Mtb disease; the ubiquitous HIV-1 Mtb syndemic provides an imperative to understand the effects of Mtb in PWH. Mtb disease likely influences multiple aspects of HIV-1 pathogenesis. Broad and more potent HIV-1 nAbs select for resistant strains, and we will assess if Mtb disease leads to the emergence of more nAb resistant strains. We will also use ex-vivo and tonsil organoid models to examine if Mtb disease enhances nAbs by increasing 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 Mtb disease selects for ADCC resistant strains. Resistant viruses are a primary reason it has been difficult to prevent HIV-1 transmission through vaccination and induce virus remission. Achieving virus control without antiretroviral therapy will likely require the eradication of latently infected cells that have the ability to transcribe HIV-1 or remodeling that prevents HIV-1 transcription. The inflammation that accompanies Mtb disease largely accounts for the associated morbidity and mortality. We hypothesize that the Mtb immune dysfunction or the altered HIV immune response directly affects the characteristics of residual infectious latent HIV-1 reservoir. We will test whether Mtb disease associated inflammatory dysregulation either potentially enhances virus production which leads to elimination of infected cells through immune clearance, such as ADCC, or viral cytopathic effect, or it potentially induces a deeply latent state in infected cells. Mtb disease mediated influence on HIV-1 immunity and the subsequent effect on frequency of resistant strains has direct implications for future vaccine strategies that aim to elicit broadly potent nAbs. The frequency of antibody resistant strains also affects the use of broadly neutralizing antibodies for prevention and treatment. Furthermore, Mtb disease mediated changes to the HIV-1 latent reservoir will highlight the types of inflammatory and immune interventions that will be required to decrease the transcriptional capacity of the HIV-1 latent reservoir, in-vivo.
