Clinical Implications of Basic Research

YTOTOXIC T lymphocytes control viral infections by lysing infected cells and secreting soluble factors (cytokines) that enhance antiviral immunity and suppress infection. The importance of antiviral killer cells in controlling acute infection with human immunodeficiency virus (HIV) and the related simian immunodeficiency virus (SIV) in macaque monkeys has clearly been demonstrated: resolution of the first wave of viremia coincides with the development of HIV-specific cytotoxic T lymphocytes, and macaques depleted of killer cells control SIV poorly. Some viruses, especially herpesviruses, hepatitis viruses, and immunodeficiency viruses, have devised clever strategies to outwit killer cells and thereby persist for the life of the host. Although HIV induces a very strong cytotoxicT-lymphocyte response, in which up to 1 in 10 circulating T lymphocytes is specific for the virus, the infection is not controlled in most untreated patients. This fact is particularly surprising because there are many more HIV-specific killer cells than cells infected with actively replicating HIV, except perhaps in the final stages of AIDS. Moreover, most in vitro assays of killer-cell function cannot distinguish between patients whose infection is controlled without antiviral drugs (long-term nonprogression) and those, treated or not, who have progressive disease. How does HIV outwit cytotoxic T lymphocytes? Two ways have been described, and others are likely. Killer cells recognize short viral peptides (called epitopes) presented to them by HLA class I molecules on infected cells. The nef protein of HIV causes the infected cell to down-regulate the HLA molecules that present viral peptides to cytotoxic T lymphocytes. The importance of this mechanism is unclear, since tens of thousands to hundreds of thousands of HLA molecules remain on the surface of HIV-infected cells, and it takes only a few peptide-laden HLA molecules to trigger a T lymphocyte. The second type of evasive action is mutation of viral sequences that specify immunogenic epitopes. By changing only a single amino acid in an epitope the virus can easily escape surveillance by the immune system. Moreover, cells expressing such altered peptides can even block the lysis of cells infected with unmutated virus.1 C