CORRELATES OF HIV-1 PROTECTION

β趋化因子现已被鉴定为体外嗜巨噬细胞HIV感染的有效可溶性抑制剂。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HIV耐药性中的作用与趋化因子受体的基因突变无关。猕猴研究还表明，β-趋化因子在使用各种候选疫苗和活病毒攻击的疫苗诱导的保护性免疫中的作用。HIV-2与HIV-1的遗传和抗遗传关系密切，生物学表型不一致，这使我们假设HIV-2可能提供保护，免受随后的HIV-1的挑战。我们报告了52-74%的艾滋病毒-2感染的妇女，观察到随后感染艾滋病毒-1的保护，我们的观察期现在已经延长到13年以上。在我们寻求确定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感染的刺激PBMC对HIV-1 R5感染具有抗性。这种相对抗性是可转移的，CD 8依赖性的，并且与培养基中的β趋化因子产生强烈相关。通过添加β趋化因子抗体，使所有相对耐药的培养物变得敏感。我们的具体目标包括体外和体内研究。1.我们将进一步鉴定和表征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.我们将确定β趋化因子分泌是否由HIV-2感染特异性诱导，并在体外将β趋化因子信息与分泌的趋化因子信息相关联。- 我们将确定HIV-2包膜/CD 8相互作用是否有助于HIV-2特异性诱导β趋化因子和HIV-1相对耐药性。3.我们将确定HIV-2感染的女性是否继续表现出对HIV-1感染的保护，部分保护将以HIV-1病毒RNA 14水平作为次要结局进行评估。4.我们将确定β趋化因子的信息和蛋白质在评估的HIV-2感染的妇女和研究β趋化因子与体内保护HIV-1感染的关联。

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.