CTL AND HIV POLYMORPHISMS IN HETEROSEXUAL TRANSMISSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的目标是：(1)在人群和个人水平上对HIV对人类白细胞抗原I类限制性免疫反应的适应性进行横断面分析，以确定与人类白细胞抗原I类基因相关的HIV-1多态是否聚集在已知的人类白细胞抗原I类特定CD8+CTL表位内，以及我们是否能够识别出针对非洲人类白细胞抗原等位基因的新表位；(2)确定150对涉及最近传播的夫妇的CTL表位逃逸和逆转的动力学，因为病毒适应从供者的一个人类白细胞抗原I类环境转移到接受者的环境，(3)在40对高危非传播性伴侣中，确定长期非传播性伴侣是否在逃避特征上表现出偏见，这是导致缺乏传播性的原因之一。 这些研究阐明了艾滋病毒逃避宿主免疫反应的机制，有利于未来的疫苗设计。来自200个慢性感染的非传播者和150个慢性感染的传播者的Gag和nef序列已经完成，并用于全面的HLA连锁多态分析。对这些受试者也进行了HLAI类配型和病毒载量分析。在新感染的受试者中，从捐赠者遗传的Gag特异性逃逸突变与早期病毒载量呈负相关，这表明这些突变对病毒适合性产生了不利影响。在HLA-B*5703阳性受试者中，三个p24 Gag逃逸突变以可预测的顺序发生，并且突变伴随着病毒载量的增加，表明失去了免疫控制。对205名血清转换者和224名暴露的未感染伙伴进行了KIR基因分型，以检查KIR和人类白细胞抗原基因表达如何影响病毒保护。近200对夫妇完成了II类DRB1和DQB1基因分型。 最后，来自9个队列的研究结果显示，某些表位变异的频率与限制人类白细胞抗原等位基因的丰度高度相关，这表明病毒在人群中适应了人类白细胞抗原的压力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this project were to: (1) Perform a cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses at population and individual levels to determine if HIV-1 polymorphisms associated with HLA alleles cluster within known HLA class I specific CD8+ CTL epitopes and if we can identify novel epitopes that are specific to African HLA alleles, (2) Determine the kinetics of CTL epitope escape and reversion in 150 couples involving recent transmission as the virus adapts in moving from one HLA class I environment in the donor to that of the recipient, (3) Determine in 40 high-risk non-transmitting couples if long-term non-transmitting partners display a bias in escape signatures that contribute to the lack of transmission. These studies elucidated mechanisms by which HIV escapes the host's immune response, benefiting future vaccine design. Gag and nef sequences from 200 chronically infected non-transmitters and 150 chronically infected transmitters have been completed and are used for a comprehensive HLA-linked polymorphism analysis. Class I HLA typing and viral load analyses were also completed for these subjects. In newly infected subjects, gag-specific escape mutations inherited from the donor were inversely correlated with early viral loads, suggesting these mutations adversely affected viral fitness. Three p24 Gag escape mutations in HLA-B*5703 positive subjects occurred in a predictable order and mutations were accompanied by increased viral loads suggesting a loss of immune control. KIR genotyping was completed for 205 seroconverters and 224 exposed uninfected partners to examine how KIR and HLA gene expression might affect viral protection. Class II DRB1 and DQB1 genotyping were completed in nearly 200 couples. Finally, results from a 9-cohort study showed the frequency of certain epitope variants was highly correlated with the abundance of the restricting HLA allele, suggesting viral adaptation to HLA pressure within the population.