The clinical course and outcome of HIV-1 infection are highly variable among individuals, depending on a combination of viral, host, and environmental determinants. Genetic resistance to HIV-1 clearly involves a complex array of host genetic effects involving variants that have subtle, but significant consequences on gene expression or protein function. Overall, the strongest genetic associations with HIV-1 disease progression have involved the HLA class I loci, which appear to influence resistance/susceptibility to AIDS in a highly multifarious manner through both acquired and innate immune responses. The effects of HLA on outcome to HIV-1 exposure and infection have been studied more thoroughly than those pertaining to any other infectious disease. Many of the associations reported have not been confirmed in multiple studies, but consistent patterns of susceptibility or resistance conferred by certain HLA class I alleles or genotypes have emerged. In addition, an effective acquired immune response to infectious agents mediated by HLA restricted T cell recognition can target different stages of disease pathogenesis. We have recently begun to address the specific timing at which alleles known to affect disease progression exert their influence. Our initial analysis indicates that three distinct HLA alleles: B27, B57 and B35Px that have been previously shown to alter the overall rate of AIDS progression act during different intervals following HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. A few studies have examined the relationship between HLA risk of HIV-1 infection, primarily involving individuals from Africa. Effects of HLA on highly active anti-retroviral therapy (HAART) are only just being considered and nearly all studies of HLA on progression to AIDS have been performed in men. To address these deficiencies in our understanding of HIV-1 pathogenesis, we have established a collaboration with Dr. Howard Strickler and the Women's Interagency Health Study (WIHS) to investigate effects of immune response genes on three disease outcomes to HIV-1 exposure: 1) risk of becoming infected in groups of HIV+ and HIV- individuals matched for site of enrollment and risk factors; 2) progression to AIDS from specific ranges of baseline CD4 counts and viral loads; and 3) response to HAART. The WIHS cohort is the largest multicenter prospective cohort study of HIV and its complications in women, involving individuals with high rates of hepatitis C virus (HCV) and human papilloma virus (HPV) infection (see below). The cohort has enrolled about 4,000 women of varied ethnic backgrounds in the U.S. and detailed clinical data is collected on the participants every six months. Patients participating in the WIHS will be typed for HLA class I, class II, and killer immunoglobulin-like receptor genes (KIR). Genotyping of the MIC genes is also being considered for future studies. Thus far we have received approximately 1200 samples. HLA class I genotyping has been completed on these samples and HLA class II genotyping is in progress. Preliminary analysis of the data has also begun. HLA class I molecules have also been shown to participate in innate immune responses as ligands for KIR molecules expressed on natural killer (NK) cells and a subset of CD8+ cells. NK cells defend against viral infections by producing cytokines and killing virally infected cells, functions that are regulated by activating and inhibitory KIR molecules through recognition of specific class I allotypes on target cells. Like HLA, the KIR locus is extremely diverse in terms of the number and types of genes present on a given haplotype. Using the largest sample size reported to date (352 individuals with HCV clearance and 685 matched persistently infected individuals), we studied the effects of HLA class I and KIR on HCV clearance/persistence. We showed that genes encoding the inhibitory NK cell receptor KIR2DL3 and its HLA-C1 ligand, which transmit relatively weak inhibitory signals, enhance resolution of HCV infection. The protection was observed only among individuals presumably receiving low-dose HCV inocula, suggesting that the difference in the ability of distinct KIR-HLA genotypes to regulate NK cell activity is great enough to alter the outcome when faced with low-dose, but not high-dose infection. The data demonstrate the importance of inhibitory NK cell interactions in anti-viral immunity, and suggest that diminished inhibitory responses confer protection against HCV. We are also studying the potential influence of several polymorphic immune response genes on HIV-1 infection and disease pathogenesis as well as other viral infections including Hepatitis B Virus (HBV) and HCV. The studies include: 1) an extension of previous studies addressing effects of HLA; 2) analyses of KIR haplotypic and allelic effects that take into account functionally relevant combinations of HLA and KIR genetic variants; and 3) identification of potential MICA allelic effects. Virtually all seroconverters (patients who had enrolled in at-risk AIDS cohort studies when their HIV-1 antibody status was negative and subsequently became HIV-1 antibody positive), all high-risk seronegative patients (those who are at high risk for HIV-1 infection based on a history of likely chronic exposure, but remain HIV-1 negative), and a subset of seroprevalent patients (those who were HIV-1 antibody-positive before enrollment) from six cohorts have now been typed using high-resolution methods for HLA class I and II. Typing for the presence/absence of KIR genes and subtyping of KIR3DL1 is completed in our seroconverter and high-risk seronegative samples. Subtyping of KIR3DL2 and KIR2DL4 has also begun. A typing system for MICA has been established and we have typed this gene in our HBV and HCV cohorts. Analysis of the data indicate that MICA015 was associated with clearance of HCV and recovery from HBV infection. We recently completed typing of MICA in the AIDS cohorts, as well. A number of studies have suggested that HLA diversity is an important determinant in progression to HPV-associated cervical neoplasia. We performed high-resolution typing of 1,321 individuals participating in three large disease studies. A single consistent association across all three studies was observed, involving a protective effect conferred by HLA-Cw0202. The primary role of HLA-C as ligand for receptors that regulate NK cell activity, the KIR molecules, suggests the possibility that the basis for the Cw0202 association with decreased risk of cervical neoplasia may involve an effective NK cell response. To test the possibility that the KIR genes are involved in risk of developing cervical neoplasia, a cancer caused by HPV, we also genotyped KIR in these individuals, and analyzed the influence of KIR/HLA combinations on development of cervical neoplasia. HLA and KIR genotypes determined from 257 women with cancer (squamous cell carcinoma) or CIN3 and 675 normal controls were analyzed for their influence on cervical disease. HLA-B Bw4, HLA-Cw Group 1 and 2, and KIR genotype frequencies were calculated for cases and controls; the magnitude and significance of differences between the patient groups were measured by determining odds ratios (ORs) and 95% confidence intervals (CIs). Both HLA-Cw group 2 and HLA-B Bw4 allelic groups, which encode molecules that serve as ligands for the inhibitory receptors KIR2DL1 and KIR3DL1, respectively, were significantly associated with decreased risk of disease. Alternatively, the activating receptor KIR3DS1 was significantly associated with risk of disease development, particularly when the protective inhibitory combinations were missing.