Extracellular Vesicle-Associated c-Src Activates Latent HIV-1
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Mensah, Gifty
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Abstract
HIV-1 is a retrovirus that has infected more than 37 million people worldwide. Latent reservoirs throughout the body have proven to be a major hurdle when it comes to completely eradicating the virus. In our previous study, we found that exosomes, small membrane-bound vesicles, from uninfected cells activate the transcription of HIV-1 in latent infected cells regardless of combination antiretroviral therapy (cART) leading to increased mostly short and some long HIV-1 RNA transcripts. This is consistent with the notion that none of the FDA-approved antiretroviral drugs used today in the clinic are transcription inhibitors. These HIV-1 transcripts can then be packaged into extracellular vesicles (EVs), including exosomes, and released from the infected cell potentially eliciting detrimental effects in recipient cells such as increased susceptibility to infection. In this study, we investigated the specific mechanism behind the EV activation of latent HIV-1. We discovered that phosphorylated c-Src (Y-416; active) is present in EVs from various cell lines and has the ability to activate epidermal growth factor receptor (EGFR), initiating a downstream signaling cascade. We proposed that EGFR is able to activate the PI3K/AKT/mTOR pathway, STAT3, and SRC-1 following activation by c-Src. This was verified by examining the levels of HIV-1 TAR, genomic RNA and HIV-1 Gag p24 protein in the presence of inhibitors of each of the specific proteins involved in our proposed pathway. We discovered that upon inhibiting each of the proteins involved in the aforementioned pathway, HIV-1 transcription, as well as levels of HIV-1 Gag p24 in the cell supernatant, was decreased. Furthermore, we found that EVs containing c-Src were able to rescue HIV-1 despite the presence of the inhibitors, validating the importance of EV-associated c-Src in reversing HIV-1 latency. Collectively, our data suggests that the EV activation of latent HIV-1 is initiated by EV-associated c-Src being delivered to a recipient cell, where it is able to activate the PI3K/AKT/mTOR pathway and STAT3, eventually leading to the activation and translocation of SRC-1 to the nucleus, promoting a pro-transcription state.
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HIV-1, C-Src, Extracellular vesicles, Nanoparticles, Combine of Antiretroviral Therapy, Signaling cascade