Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection

CD8 T cells play an important role in protection and control of HIV-1 by di rect cytolysis of infected cells and by suppression of viral replication by secreted factors. However, although HIV-1-infected individuals have a high frequency of HIV-1-specific CD8 T cells, viral reservoirs persist and prog ressive immunodeficiency generally ensues in the absence of continuous pote nt antiviral drugs. Freshly isolated HIV-specific CD8 T cells are often una ble to lyse HIV-1-infected cells. Maturation into competent cytotoxic T lym phocytes may be blocked during the initial encounter with antigen because o f defects in antigen presentation by interdigitating dendritic cells or HIV -Infected macrophages. The molecular basis for impaired function is multifa ctorial, due to incomplete T-cell signaling and activation (in part related to CD3 zeta and CD28 down-modulation), reduced perforin expression, and in efficient trafficking of HIV-specific CD8 T cells to lymphoid sites of infe ction. CD8 T-cell dysfunction can partially be corrected in vitro with shor t-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a significant causal or exacerbating role. Func tional defects are qualitatively different and more severe with advanced di sease, when interferon gamma production also becomes compromised. (C) 2001 by The American Society of Hematology.