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(+)).
