SDF-1 3'UTR MUTATION DELAYS PROGRESSION TO AIDS

点击翻译按钮获取中文摘要

The HIV-1 virus uses two primary coreceptors, CCR5 and CXCR4, in addition to CD4 to infect cells. CCR5 is the primary receptor for the transmissible, macrophage-tropic (M-tropic) variants while CXCR4 is used by the synctium-inducing (SI) variants capable of infecting T-cell lines (T- tropic). T-tropic variants emerge during the asymptomatic period of infection and are associated with more rapid disease progression and loss of CD4 T cells. The ligand for CXCR4, stromal derived factor-1 (SDF-1) has been shown to cause internalization of CXCR4, making the receptor unavailable for binding by HIV-1 variants using CXCR4 for cell entry and infection. Several studies have shown that SDF-1 is a powerful antiviral agent and blocks fusion by T- tropic/SI variants. Because of the obvious role of chemokine receptors and their ligands in HIV pathogenesis, we have screened for polymorphisms in the genes encoding both receptors and ligands using a panel of patients that are high risk, uninfected, rapid progressors to AIDS in less than 5 years, or long time survivors (no AIDS for more than 12 years). We have identified a mutation in the 3' untranslated region (UTR) of SDF-1beta cDNA that when homozygous, is highly protective against progression to AIDS and death in the first 10 years following infection. This SDF-1 variant may prevent the emergence of the more pathogenic T-tropic/SI strains that use CXCR4 as a coreceptor, thus delaying the onset of immunodeficiency and AIDS. Possible mechanisms for the function of the 3' UTR mutation are under investigation.