PROJECT SUMMARY Infections with Human Immunodeficiency Virus (HIV) remain a major global public health concern. The HIV reservoirs are a leading reason for which HIV infection remains without a cure. HIV integrates its viral DNA into the host cell DNA. Cell activation leads to transcription of archived viral information, which can refuel viral replication even in the presence of antiretroviral therapy (ART). This may be problematic when cellular reservoirs of HIV involve cell types that are in continuous functional activation. Research conducted by others and us have shown that pvSMC are susceptible to HIV infection. In addition, people living with HIV (PLWH) are more prone to comorbidities that involve chronic vascular constriction. Our preliminary studies suggest that pulmonary arterial smooth muscle cells are susceptible to HIV infection, sustain the infection during ART-induced viral suppression, and are capable to release infectious viruses that can infect bystander T cells. Our preliminary findings have significant importance because identifying and eliminating HIV reservoirs such as pvSMC is critical to the success of global efforts to cure HIV. The fact that PLWH are more prone to pulmonary vasoconstrictive diseases implies that the persistent cell activation and vasoconstriction of pvSMC are likely to provide transcriptionally active HIV leading to reseeding of reservoirs. The pulmonary vasculature is heavily overlooked as an important source of HIV, leading to a significant gap in the literature about non-immune cell sources such as pvSMC as HIV reservoirs. Herein, we propose to determine the ability of pvSMC to support chronic HIV infection and their ability to spread HIV to bystander immune cells in the presence of ART. We also propose to investigate the cellular mechanisms for the resiliency of pvSMC to the cytopathic effects of HIV. This work should provide new insights into the potential of pulmonary vascular as SMC as reservoirs in the era of advanced ART. Knowing the characteristics of pvSMC as HIV reservoirs is imperative to further strategize for the effective eradication of a previously unappreciated HIV reservoir.