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Antiretroviral therapy (ART) has dramatically prolonged the lives of people living with HIV (PLWH), but it is not curative as it cannot eliminate integrated HIV-1 proviruses in different tissue reservoirs. Even though subtype C HIV-1 accounts for almost half of global HIV-1 infections, few studies had evaluated HIV-1 reservoirs for this subtype. Many co-factors, including the lifestyle factor cannabis use, have been investigated for their potential effects in HIV-1 infection. However, only limited information exists regarding cannabis’s effects on HIV-1 infections in vivo, and the impact of cannabis use on HIV-1 parenchymal tissue reservoirs is unexplored. This dissertation aims to deepen our understanding of subtype C HIV-1, which is predominant in resource-limited settings and presents unique challenges in management and treatment. Specifically, it explores the landscape of subtype C HIV-1 tissue reservoirs, particularly identifying the human appendix as a novel reservoir, and assessed the effects of cannabis use on these reservoirs. To map the distribution of subtype C HIV-1 tissue reservoirs, we conducted systematically sample collections from autopsies in Zambia, sub-Saharan Africa (SSA), and employed advanced molecular techniques to map the distribution and viral burden of subtype C HIV-1 within different tissue compartments. We discovered significant viral persistence in the lymphoid and gastrointestinal (GI) tract tissues, but unlike well-documented subtype B HIV-1, subtype C HIV-1 poorly accessed the brain. Interestingly, subtype C proviruses were readily detected in the appendix, a previously unrecognized tissue reservoir. This finding suggests that the appendix may play a crucial role in the long-term persistence of HIV-1, challenging existing paradigms of reservoir locations. To evaluate the impact of cannabis use on subtype C HIV-1 tissue reservoirs, we analyzed viral load and immune modulation, via analyses of inflammatory cytokine mRNA expression in cannabis-using and non-using individuals. Results demonstrated that cannabis use is associated with a reduced size of viral reservoirs and altered inflammatory responses, indicating potential therapeutic implications in exploiting lifestyle factors in managing HIV-1. Overall, this dissertation provides critical insights into the unique characteristics of subtype C HIV-1 reservoirs and the modulatory effects of cannabis. These findings not only contribute to the field of HIV research by identifying new targets for potential eradication strategies but also highlight the importance of considering behavioral factors in the clinical management of HIV. The research underscores the need for a comprehensive approach that includes both molecular characterization of HIV reservoirs and evaluation of lifestyle influences on disease dynamics.