CORRELATES OF HIV-1 PROTECTION

趋化因子现已被确定为体外巨噬细胞嗜性HIV感染的有效可溶性抑制因子。对多次暴露的未感染个体的研究表明，在许多情况下，β趋化因子升高在艾滋病毒耐药性中的作用与趋化因子受体的基因突变无关。猕猴研究也表明-趋化因子在使用多种候选疫苗和活病毒攻击的疫苗诱导保护性免疫中的作用。HIV-2与HIV-1密切的遗传和抗遗传关系以及不一致的生物学表型，使我们假设HIV-2可能对后续的HIV-1攻击提供保护。我们报告了52-74%的感染了HIV-2的妇女在随后感染了HIV-1后得到了保护，我们的观察期现在已经延长到13年以上。在我们探索这种保护机制的过程中，我们最近证明，与X4病毒相比，大约60%的HIV-2感染刺激pbmc对HIV-1 R5感染具有抗性。这种相对抗性是可转移的，CD8依赖性的，并且与培养基中β趋化因子的产生密切相关。通过添加趋化因子抗体，所有相对耐药的培养物都变得易感。我们的具体目标包括体外和体内研究。1. 我们将进一步确定和表征HIV-2耐药表型，研究β趋化因子的细胞来源，并评估每种β趋化因子对相对耐药表型的贡献。2. 我们将在体外确定β趋化因子的分泌是否被HIV-2感染特异性诱导，并将β趋化因子信息与分泌的趋化因子信息与分泌的趋化因子联系起来。-我们将确定HIV-2包膜/CD8相互作用是否有助于HIV-2特异性诱导β趋化因子和HIV-1相对抗性。3. 我们将确定HIV-2感染的妇女是否继续表现出对HIV-1感染的保护作用，将以HIV-1病毒RNA 14水平作为次要结果来评估部分保护作用。4. 我们将在评估的HIV-2感染妇女中确定β趋化因子信息和蛋白的特征，并研究β趋化因子与体内保护HIV-1感染的关系。

Beta chemokines have now been identified as potent soluble suppressors of macrophage-tropic HIV infection, in vitro. Studies of multiply exposed uninfected individuals have implicated the role of elevated beta chemokines in HIV resistance, in many cases, independent of genetic mutations in the chemokine receptor. Macaque studies have also suggested a role for beta-chemokines in vaccine induced protective immunity using a variety of vaccine candidates and live virus challenge. The close genetic and antigenetic relationship of HIV-2 with HIV-1 and the discordant biological phenotypes, led us to hypothesize that HIV-2 might afford protection from subsequent HIV-1 challenge. We have reported 52-74% protection in HIV-2 infected women that were observed for subsequent infection with HIV-1, our observation period has now been extended to over 13 years. In our quest for identifying the mechanism of this protection, we have recently demonstrated that approximately 60% of HIV-2 infected stimulated PBMCs are resistant to HIV-1 R5 infection compared with X4 viruses. This relative resistance was transferable, CD8 dependent and strongly correlated with beta chemokine production in the media. All relatively resistant cultures were rendered susceptible by addition of antibodies to beta chemokines. Our specific aims include in vitro and in vivo studies. 1. We will further identify and characterize the HIV-2 resistant phenotype the cellular sources of beta chemokines will be studied and each beta chemokine's contribution to the relative resistance phenotype will be assessed. 2. We will determine if beta chemokine secretion is specifically induced by HIV-2 infection, and correlate beta chemokine message with the secreted chemokine message with the secreted chemokine, in vitro. - we will determine if HIV-2 envelope/CD8 interactions contribute to an HIV-2 specific induction of beta chemokines and HIV-1 relative resistance. 3. We will determine if HIV-2 infected women continue to demonstrate protection from HIV-1 infection, partial protection will be evaluated with HIV-1 viral RNA l4evels as a secondary outcome. 4. We will determine the profile of beta chemokine message and protein in the evaluated HIV-2 infected women and study the association of beta chemokines with in vivo protection from HIV-1 infection.