Abstract:
As of 2019, approximately 62% of the 37.9 million individuals infected with Human Immunodeficiency Virus type 1 (HIV-1) underwent combination antiretroviral therapy (cART) treatment, which includes a cocktail of inhibitory drugs for nearly all parts of the viral life cycle. The lack of an FDA approved viral transcription inhibitor allows for persistent non-processive transcription which results in the production of short non-coding RNAs (TAR and TAR-gag). Our lab and others have shown that these RNAs are released from the cell in extracellular vesicles (EVs), specifically exosomes, and can induce production of proinflammatory cytokines in recipient myeloid cells; a factor that may contribute to the neuroinflammation observed in HIV-1 infected individuals with HIV associated neurocognitive disorder (HAND). Here, we demonstrate that EVs released from HIV-1 infected macrophages with and without cART induce the production of proinflammatory cytokines from astrocytes via activation of TLR3 by EV cargo (TAR) and have identified three TAR inhibitor candidates to inhibit this mechanism. Furthermore, we show that CBD can lower secretion of EVs and their viral cargo potentially through intracellular viral transcription inhibition. Overall, this study demonstrates the therapeutic potential for CBD usage on lowering EV-mediated neuroinflammation seen in HAND.
