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 direct 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 progressive immunodeficiency generally ensues in the absence of continuous potent antiviral drugs. Freshly isolated HIV-specific CD8 T cells are often unable to lyse HIV-1-infected cells. Maturation into competent cytotoxic T lymphocytes may be blocked during the initial encounter with antigen because of defects in antigen presentation by interdigitating dendritic cells or HIV-infected macrophages. The molecular basis for impaired function is multifactorial, due to incomplete T-cell signaling and activation (in part related to CD3zeta and CD28 down-modulation), reduced perforin expression, and inefficient trafficking of HIV-specific CD8 T cells to lymphoid sites of infection. CD8 T-cell dysfunction can partially be corrected in vitro with short-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a significant causal or exacerbating role. Functional defects are qualitatively different and more severe with advanced disease, when interferon gamma production also becomes compromised.
Lieberman
J
J
Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA. lieberman@cbr.med.harvard.edu
Shankar
P
P
Manjunath
N
N
Andersson
J
J
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D017951:Antigen Presentation; D002465:Cell Movement; D017635:Clonal Anergy; D018450:Disease Progression; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D011971:Receptors, Immunologic / Q000378:metabolism; D054340:Receptors, KIR; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D007376:Interleukin-2; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D007371:Interferon-gamma