HIV: Not-so-innocent bystanders

Abstract

A new mechanism to explain massive depletion of CD4⁺ T cells in HIV-1 infection despite the low frequency of productively infected cells involves innate immune sensing of HIV 1 by abortively infected “bystander” CD4⁺ T cells. The result is death of the bystander cells through an inflammatory process known as pyroptosis. These findings may provide long sought explanations for both CD4⁺ T cell depletion and HIV-associated inflammation. See Article on page X.

Figure 1. Following HIV-1 infection, most lymphoid CD4⁺ T cell death is mediated by caspase-1 activation and pyroptosis in abortively infected quiescent CD4⁺ T cells

A. Productively infected CD4⁺ T cells represent the minority of dying CD4⁺ T cells and undergo death via caspase-3 mediated apoptosis. B. The majority of CD4⁺ T cell death results from caspase-1 mediated pyroptosis in quiescent CD4⁺ T cells. Abortive infection of quiescent CD4⁺ T cells, in which incomplete HIV-1 transcripts accumulate and are sensed by the host DNA sensor IFI16, results in caspase-1 cleavage and activation with 1) selective depletion of CD4⁺ T cells via pyroptosis and 2) release of the highly inflammatory cytokine IL-1β. HIV-1-induced CD4⁺ T cell death via pyroptosis was blocked by a caspase-1 inhibitor and antiretroviral agents that act on early stages of the HIV-1 life cycle.