Mycobacterium Tuberculosis impact on HIV reservoir Clearance (MyTHIC) - PROJECT SUMMARY/ABSTRACT Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death and illness among people with HIV-1 (PWH) globally. However, its impact on HIV-1 latent reservoirs, which require lifelong combination antiretroviral treatment (cART), is not well understood. Mtb lipid antigens trigger strong immune responses and sustained inflammation, which affects HIV-1 reservoirs. Understanding this impact is crucial for developing future HIV-1 cure strategies. PWH with TB disease (PWH/TB) show lower HIV-1 transcriptional activity compared to those without TB (PWH/No TB), and we hypothesize that TB associated inflammation induces cellular changes and effects HIV-1 establishment, transcription, and maintenance. These TB-induced changes will influence strategies for achieving virus remission without cART, such as shock and kill or block and lock. Various latency-reversing agents (LRAs) are being investigated to induce HIV-1 expression in latently infected cells for subsequent killing using cytotoxic therapeutics like broadly neutralizing antibodies (bnAbs). We hypothesize that TB-induced epigenetic changes will affect LRA efficacy. Furthermore, PWH/TB have significantly broader and more potent HIV-1 neutralizing antibodies and more neutralization resistant HIV- 1 envelopes, and this will affect bnAbs’ effectiveness in remission strategies. For this study, we will recruit 200 PWH, half with TB disease, and follow them for up to 18 months. In Aim 1, we will examine provirus levels, proviral integrity, transcriptional activity, and HIV-1 integration sites in PWH/TB and PWH/No TB and correlate these provirus characteristics with TB disease extent, bacterial burden, inflammation, and timing of TB onset with cART. In Aim 2, we will assess the impact of TB disease on HIV-1 latency reversal and examine HIV-1 transcription ex-vivo in PWH/TB and PWH/No TB peripheral blood mononuclear cells (PBMCs) and in-vitro in HIV-1 latently infected cells after exposure to a broad array of current LRAs. We will further compare cellular pathways involved in HIV-1 latency after exposure to different LRAs. In Aim 3, we will characterize the antibody susceptibility of the HIV-1 reservoir between PWH/TB and PWH/No TB. We will isolate HIV-1 reservoir Envs and compare their sensitivity to diverse HIV-1 bnAbs. We will examine Env susceptibility association with the extent of TB disease, bacterial burden, baseline inflammation, and cART status. TB and HIV-1 are a worldwide syndemic. This research will provide insights into the effects of TB on HIV-1 reservoirs and inform the development of future remission strategies relevant globally.
