Abstract
HIV-1 is a global health crisis that has infected more than 37 million people. Latent reservoirs throughout the body are a major hurdle when it comes to eradicating the virus. In our previous study, we found that exosomes, a type of extracellular vesicle (EV), from uninfected cells activate the transcription of HIV-1 in latent infected cells, regardless of combination antiretroviral therapy (cART). In this study, we investigated the specific mechanism behind the EV activation of latent HIV-1. We found that phosphorylated c-Src is present in EVs of various cell lines and has the ability to activate downstream proteins such as EGFR, initiating a signal cascade. EGFR is then able to activate the PI3K/AKT/mTOR pathway, resulting in the activation of STAT3 and SRC-1, culminating in the reversal of HIV-1 latency. This was verified by examining levels of HIV-1 TAR, genomic RNA and HIV-1 Gag p24 protein in cell lines and primary cells. We found that EVs containing c-Src rescued HIV-1 despite the presence of inhibitors, validating the importance of EV-associated c-Src in latent HIV-1 activation. Lastly, we discovered an increased recruitment of p300 and NF-κB in the nucleus of EV-treated infected cells. Collectively, our data suggest that EV-associated c-Src is able to activate latent HIV-1 via the PI3K/AKT/mTOR pathway and SRC-1/p300-driven chromatin remodeling. These findings could aid in designing new strategies to prevent the reactivation of latent HIV-1 in patients under cART.
Highlights
Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that has infected more than 37 million people worldwide [1]
In an effort to better understand how exosomes and extracellular vesicle (EV) could be responsible for activation of latent HIV-1-infected cells, we examined the kinase, cellular Src (c-Src), which was previously reported to be in exosomes [23]
Our past studies have shown a relationship between EVs and viral infection, especially in the context of HIV-1
Summary
Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that has infected more than 37 million people worldwide [1]. There is no cure for HIV-1; the introduction of combined antiretroviral therapy (cART) suppresses the replication of the virus and prevents the onset of AIDS. CART lowers HIV-1 viral loads to undetectable levels in plasma but is unable to cure or eliminate latent infected cells [2]. The viral infection reactivates upon the discontinuation of cART, leading to viral rebound and an increase in opportunistic infections and the advancement of HIV-1 into AIDS [3,4]. Latent reservoirs throughout the body, primarily in resting memory CD4+ T-cells and macrophages, have proven to be a major hurdle when it comes to completely eradicating HIV-1. The immune system is incapable of distinguishing these latent cells from healthy cells and is unable to Viruses 2020, 12, 665; doi:10.3390/v12060665 www.mdpi.com/journal/viruses
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