Precursor loss triggers AIDS

Abstract

HIV and its simian counterpart, SIV, replicate rapidly after infection but often take many years to subdue the immune system and cause AIDS. Okoye et al. (page 2171) now find that these slow burner viruses only cause disease after they deplete the precursor cells that give rise to pathogen-fighting effector cells. Figure 1 Loss of TCM cells during chronic SIV infection (bottom) depletes pathogen-fighting TEM cells and triggers AIDS. The effector memory T (TEM) cells that battle these viruses at infection sites develop from a pool of CD4+ central memory (TCM) cells that are stored in secondary lymphoid organs. Although the virus infects both types of cells simultaneously, TEM cells are the first casualties. This early depletion of TEM cells is not completely devastating; the TCM population quickly cranks out more TEM cells. But this defensive strategy is obviously not foolproof: infected individuals eventually develop AIDS. Okoye et al. now identify the glitch in the strategy by tracking disease progression in SIV-infected rhesus macaques. Newly generated TEM cells were short lived, they found, as persistent activation by the virus induced their death. And unlike in earlier stages of infection, TCM cells no longer came to the rescue, as they were also crippled by viral infection. The virus thus tamed the immune system by stimulating one population to death and destroying its back-up. Based on these results, stabilizing the TCM pool may be a more effective way to prevent the onset of AIDS than controlling viral load—the goal of current vaccination strategies. Rising viral loads might not be the trigger for AIDS, as viral loads remained constant while CD4+ T cell levels declined during the later stages of disease. Recent studies from other groups show that survival of patients with AIDS correlates with more circulating TCM cells, supporting the idea that protecting the TCM niche might keep AIDS at bay. The team is now trying to identify the factors that bolster TCM cell levels and how HIV/SIV dismantles them.