Project Summary One of the hallmarks of HIV infection is chronic immune activation/inflammation, which is strongly associated with and predictive of HIV disease progression, even in patients that were successfully treated with anti-retroviral therapy (ART). We and other have shown that chronic elevation of type I IFN signaling in HIV+ individuals is a major driver in immune activation. Alleviating chronic activation may reduce disease progression and prevent or slow down progression of HIV-associated diseases, including HIV-associated neurocognitive disorders (HAND), which is fueled by inflammation in the central nervous system (CNS). In recent years, studies have suggested that major components of cannabis, namely THC and CBD, may have anti-inflammatory properties. However, the individual and combined effects and mechanisms of THC and CBD on immune activation during HIV infection remain elusive. In this project, we aim to study the individual and combined effects of THC and CBD on immune cell activation and CNS inflammation during HIV infection. We hypothesize that THC and CBD regulate IFN-I mediated inflammation differently by binding to and signaling through diverse cannabinoid receptors. We will carefully evaluate if treatment of THC and CBD have the potential to reduce chronic inflammation and improve immune function against HIV infection.