The mitochondriotoxic domain of Vpr determines HIV-1 virulence

Most patients infected with HIV-1 develop AIDS unless they receive antiretroviral medication. However, a small number of HIV-infected individuals with high viral titers remain disease free and do not experience progressive immunosuppression, even in the absence of therapy. Such individuals are labeled long-term nonprogressors (LTNPs) and are characterized by a series of laboratory parameters that are usually compromised in HIV-1 carriers who ultimately develop AIDS. In particular, LTNPs possess a high frequency of peripheral CD4plus; T cells, as well as a low level of spontaneous apoptosis, correlating with a normal mitochondrial transmembrane potential (Δψm) among circulating T cells. It has long been assumed that, as an experimentum naturae, LTNPs might furnish valuable clues for the identification of molecular determinants of HIV-1 pathogenesis. A study by Badley and colleagues involving LTNPs, reported in this issue of the JCI (1), strongly suggests that viral protein R (Vpr) is a major HIV-1 virulence factor.