Effects of HLA and KIR genotype on HIV and HCV

描述（由申请方提供）：本申请旨在研究女性中人类白细胞抗原（HLA）和杀伤免疫球蛋白样受体（KIR）多态性对（i）HIV感染风险、（ii）HCV感染风险和（iii/iv）HIV和HCV感染病程的影响。HLA分子是多态性蛋白质，其通过将抗原呈递给T细胞而在对病毒的免疫应答中发挥核心作用，并且充当KIR（帮助调节自然杀伤细胞功能的多态性分子）的配体。由于共同的风险因素，HIV和HCV影响相似的人群，合并感染很常见。对于HIV和HCV，先前的流行病学研究表明HLA类型与感染过程有关。然而，HLA和KIR的已知生物学相互作用只是最近才被考虑到。我们小组在男性中进行的一项大型研究发现，HLA和KIR之间的相互作用与HIV/AIDS进展相关。在其他免疫相关疾病中也观察到HLA/KIR相互作用。因此，重要的是要知道HLA和KIR，以充分解释任何一个的数据;在HIV和HCV的先前研究中不完整的数据。关键的差距，我们的知识的影响，HLA类型大大超出了需要考虑KIR，迄今为止，有一个缺乏的HLA数据在妇女尽管性别差异，在艾滋病毒的自然史，令人惊讶的是，也很少有人知道有关的HLA等位基因与响应HAART，甚至成为艾滋病毒感染的风险。我们对HCV和HLA类型的了解更不完整。HCV清除的研究几乎完全集中在HLA II类，但它是HLA Ia类在细胞毒性T细胞对HCV的反应中发挥核心作用。感染HCV的风险从未被仔细研究过。这项计划中的研究将是第一个仔细评估HLA和KIR对女性HIV/AIDS进展、HAART反应、HIV感染风险、HCV病毒血症和HCV感染风险的独立影响和相互作用的研究。为了解决这些问题，我们将在妇女跨机构艾滋病研究（WIHS）中进行高分辨率HLA和KIR基因分型。WlHS是HIV（+）（n=2761，-40%HCV（+））和具有相似风险因素的HIV（-）妇女（n=942，-25%HCV（+））的一个大的、种族和地理上多样化的队列。

DESCRIPTION (provided by applicant): This application is to study the effects of human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) polymorphisms in women on (i) risk of infection by HIV, (ii) risk of infection by HCV, and (iii/iv) the course of HIV and HCV infections. HLA molecules are polymorphic proteins that play a central role in the immune response to viruses through the presentation of antigens to T-cells, and act as ligand for KIR (polymorphic molecules that help regulate natural killer cell function). Due to shared risk factors, HIV and HCV affect similar populations, and coinfection is common. For both HIV and HCV, previous epidemiologic studies have indicated that HLA type is related to course of infection. However, the known biologic interaction of HLA and KIR has only recently been taken into consideration. A large study in men conducted by our group found strong significant interactions between HLA and KIR associated with HIV/AIDS progression. HLA/KIR interactions have also been observed in other immune-related diseases. Thus, it is important to know both HLA and KIR to fully interpret the data for either; data that were incomplete in prior studies of HIV and HCV. Critical gaps in our knowledge regarding the effects of HLA type go substantially beyond the need to consider KIR, To date, there is a paucity of HLA data in women despite gender differences in HIV natural history and, surprisingly, little is also known regarding the HLA alleles associated with response to HAART, or even risk of becoming HIV infected. Our understanding of HCV and HLA type is even more incomplete. Studies of HCV clearance have focused almost entirely on HLA class II, but it is HLA class Ia that plays a central role in the cytotoxic T-cell response to HCV. Risk of becoming HCV infected has never been carefully studied. The planned study will be the first to carefully assess the independent effects and interactions of HLA and KIR on HIV/AIDS progression among women, response to HAART, risk of HIV infection, HCV viremia, and risk of HCV infection. To address these issues, we will conduct high resolution HLA and KIR genotyping in the Women's Interagency HIV Study (WIHS). WlHS is a large, racially and geographically diverse cohort of HIV(+) (n=2761 with - 40% HCV(+)), and HIV(-) women who share similar risk factors (n=942 with - 25%HCV(+)).