Effects of genetic variation on infectious disease

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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 human leukocyte antigen (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 that 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 submitted a manuscript showing that three distinct HLA alleles: B*27, B*57 and B*35Px, that are known to alter the overall rate of AIDS progression act during distinct 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 on 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 receptors (KIR). Genotyping of the MIC genes is also being considered for future studies. Thus far we have received approximately 1200 samples. HLA class I and class II genotyping have been completed on these samples. Preliminary analysis of the data suggests there are a number of significant associations between particular HLA alleles and prevalent HPV infection as well as squamous intraepithelial lesions. 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. We have previously shown 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.