SDF-1 3'UTR MUTATION DELAYS PROGRESSION TO AIDS

HIV-1病毒使用两个主要的辅助受体，CCR5和CXCR4，在 添加到CD4中以感染细胞。CCR5是该受体的主要受体 当使用CXCR4时，可传播的巨噬细胞嗜性(M嗜性)变体 通过能够感染T细胞系的合体诱导(SI)变异体 (T向)。T变异体出现在无症状期 感染，并与更快的疾病进展和 CD4T细胞丢失。CXCR4的配体基质衍生因子-1 (SDF-1)已被证明导致CXCR4的内化，使 使用CXCR4的HIV-1变异体无法与细胞结合的受体 进入和感染。多项研究表明，SDF-1是一种强大的 抗病毒药物，并通过T嗜性/SI变异体阻止融合。因为. 趋化因子受体及其配体在HIV中的明显作用 发病机制，我们已经对编码基因的多态性进行了筛选 受体和配体都使用了一组高危患者， 未受感染的、在不到5年或更长时间内迅速发展为艾滋病的人 幸存者(12年以上未感染艾滋病)。我们已经确定了一个 SDF-1β基因3‘非翻译区的突变 纯合子，对艾滋病和死亡具有很强的保护作用 在感染后的头10年。此SDF-1变种可能 防止出现更具致病性的T嗜性/SI病毒株 使用CXCR4作为辅助受体，从而延缓免疫缺陷的发生 和艾滋病。3‘端非编码区突变功能的可能机制 正在接受调查。

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.