Extracellular Vesicles activation of latent HIV-1 is driven by EV-associated c-Srca

POSTER - Abstract: HIV-1 is the causative agent of AIDS, infecting nearly 37 million people worldwide. Currently, no cure exists, mainly due to HIV-1’s ability to enact latency. Our previous work has shown that exosomes, small extracellular vesicles (EVs), from uninfected cells can activate HIV-1 in latent cells, leading to increased mostly short and some long HIV-1 RNA transcripts. This is consistent with the notion that none of the FDAapproved antiretroviral drugs used today in the clinic are transcription inhibitors. Furthermore, these HIV-1 transcripts can be packaged into EVs and released from the infected cell. In this study, we investigated the specific mechanism behind the activation of latent HIV-1 by EVs. We observed that the EV-associated kinase c-Src is able to activate latent HIV-1 in infected cells via the PI3K/AKT/mTOR pathway and SRC1/p300-driven chromatin remodeling. We discovered that upon inhibiting each of the proteins involved in the PI3K/AKT/mTOR pathway, HIV-1 transcription, as well as levels of HIV-1 Gag p24 in the cell supernatant, was decreased. Collectively, our data suggests that the EV activation of latent HIV-1 is initially started by EV-associated c-Src being delivered into a recipient cell, where it is able to activate the PI3K/AKT/mTOR pathway, eventually leading to the activation and translocation of SRC-1 to the nucleus, promoting a pro-transcription state.

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