HIV-induced bystander cell death in astrocytes requires cell-to-cell viral transmission

Human immunodeficiency virus (HIV) neuroinvasion occurs early after infection through the trafficking of virus-infected immune cells into the central nervous system (CNS) and viral dissemination into the brain. There, it can infect resident brain cells including astrocytes, the most abundant cell type that is crucial to brain homeostasis. In this report, we examined the HIV-related mechanism able to induce bystander cell death in astrocytes mediated by cell-to-cell contact with productively infected (PI) ones. We first demonstrate that HIV-induced bystander cell death involves mitochondrial dysfunction that promotes exacerbated reactive oxygen species production. Such a phenomenon is a contagious cell death that requires contact with HIV-PI astrocytes that trigger caspase-dependent (apoptosis and pyroptosis) and caspase-independent cell death pathways. The HIV accessory proteins Nef, Vpu, and Vpr counteract astrocyte death among PI cells but, in contrast, participate to promote contagious bystander cell death by inducing mitochondrial reactive oxygen species production. Our findings indicate that astrocytes PI by HIV became capable to counteract infection-derived death signals, surviving, and spreading the bystander cell death into neighboring uninfected cells by a cell-to-cell contact-dependent mechanism. Considering that astrocytes have been proposed as a long-term HIV reservoir in the CNS, ascertaining the mechanism of survival and contagious bystander death will afford clear targets in the current goal to achieve a functional cure.