SDF-1 3'UTR MUTATION DELAYS PROGRESSION TO AIDS

HIV-1病毒使用两种主要的辅助受体CCR 5和CXCR 4， 加入CD 4以感染细胞。CCR 5是免疫调节剂的主要受体。 当使用CXCR 4时， 通过能够感染T细胞系的synctium诱导（SI）变体， (T-tropic）。T嗜性变异出现在无症状期， 感染，并与更快的疾病进展有关， CD 4 T细胞减少。CXCR 4的配体，基质衍生因子-1 （SDF-1）已被证明可引起CXCR 4的内化， 使用CXCR 4用于细胞的HIV-1变体不能结合的受体 进入和感染。几项研究表明，SDF-1是一种强大的 抗病毒剂并阻断T-嗜性/SI变体的融合。因为 趋化因子受体及其配体在HIV中的明显作用 发病机制，我们已经筛选了多态性的基因编码 受体和配体使用一组高风险患者， 未受感染，在不到5年或很长时间内迅速进展为艾滋病 幸存者（12年以上无艾滋病）。我们已经确定了一 SDF-1 β cDNA的3'非翻译区（UTR）突变， 纯合子，对艾滋病的发展和死亡具有高度保护作用 在感染后的头10年里。该SDF-1变体可 防止出现致病性更强的嗜T/SI菌株， 使用CXCR 4作为辅助受体，从而延迟免疫缺陷的发作 和艾滋病3' UTR突变的可能机制 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.