UC San Diego

Human immunodeficiency virus type-1 (HIV-1) is a global pandemic that has infected millions across the globe and is the precursor to acquired immunodeficiency syndrome (AIDS). Antiretroviral therapy (ART) allows HIV-1 infected individuals to live a full life; however, ART does not remove HIV-1 infected cells, allowing infected cells to become latent. These latent HIV-1 reservoirs cannot only reactivate once ART administration ends, but these latent HIV-1 reservoirs despite producing no replication competent virus can produce chronic inflammation in an individual leading to an assortment of other health conditions. A strategy to eradicate latent reservoirs is designed to reactivate HIV-1 from latently infected cells and kill the virus prior to it infecting uninfected bystander cells (often called “shock and kill”). Here, we identify Tat-Vpu peptide as a potential “shock” in the “shock and kill” cure strategy. We show that Tat-Vpu is able to increase HIV-1 viral release in infected macrophages through the LVEM66 amino acid sequence that is not observed in the tat-scramble. To analyze the inflammatory pathway induced by HIV-1, we used a GU-rich single stranded RNA (RNA40) derived from the long terminal repeat (LTR) region of HIV-1. We identified that TLR8 is critical in causing “bystander” CD4+ T cells to elicit IL-1β production. We also show a lack of cell death in RNA40 stimulated macrophages, and identify that caspase-8 and RIPK3 are involved in efficient IL-1β release suggesting the involvement of an alternative inflammasome. We also show that potassium efflux is essential in producing an inflammatory response in RNA40 stimulated macrophages. The involvement of TLR8, no pyroptosis, potassium efflux, and involvement of proteins in the alternative inflammasome indicate that a novel inflammatory pathway is involved with the induction of IL-1β by RNA40.