Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

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Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease.

The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism1, lower expression on the cell surface2,3, and more extensive ligand-receptor interactions with killer cell immunoglobulin-like receptors (KIR)4. A single nucleotide polymorphism (SNP) 35Kb upstream of HLA-C (rs9264942; termed −35) associates with control of HIV5–7, and with levels of HLA-C mRNA transcripts8 and cell surface expression7, but the mechanism underlying its varied expression is unknown. We proposed that the −35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C7. Here we show that variation within the 3′ untranslated region of HLA-C regulates binding of the microRNA Hsa-miR-148a to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3′UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.

Certain major histocompatibility complex (MHC) class I alleles are associated with the control of human immunodeficiency virus and simian immunodeficiency virus (SIV) replication. We have designed sequence-specific primers for detection of the rhesus macaque MHC class I allele Mamu-B*08 by PCR and screened a cohort of SIV-infected macaques for this allele. Analysis of 196 SIV mac 239-infected Indian rhesus macaques revealed that Mamu-B*08 was significantly overrepresented in elite controllers; 38% of elite controllers were Mamu-B*08 positive compared to 3% of progressors (P ‫؍‬ 0.00001). Mamu-B*08 was also associated with a 7.34-fold decrease in chronic phase viremia (P ‫؍‬ 0.002). Mamu-B*08-positive macaques may, therefore, provide a good model to understand the correlates of MHC class I allele-associated immune protection and viral containment in human elite controllers.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.Correspondence should be addressed to M.C. (carringm@mail.nih.gov). Note: Supplementary information is available on the Nature Genetics website. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. AUTHOR CONTRIBUTIONS NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 December 1. Recently, however, a scan for genetic variants that influence the control of viral load indicated that a dimorphism 35 kb upstream of the HLA-C gene (-35C/T) had one of the two strongest genome-wide effects on the level of plasma viremia in early, established HIV infection as measured by viral load set-point, although no significant association of this variant was observed with progression to a CD4 cell count of <350 (ref.2 ). Notably, the -35C variant that associates with low viral load has also been shown to associate with high HLA-C mRNA levels in a codominant manner among a group of individuals of European ancestry 12,13 , although whether it associates with cell surface expression has not been tested. These findings suggest that certain HLA-C allotypes might have a primary role in restricting HIV replication through innate and/or acquired immune mechanisms that have previously been overlooked. Here we present data from 1,698 European American individuals, indicating that high levels of HLA-C confer strong protection early in the course of HIV infection and this early protection of high HLA-C extends to some extent into chronic infection. We propose a model in which highexpression HLA-C alleles might confer better innate and/or acquired immune responses than low-expression HLA-C alleles. RESULTS Effect of-35 on mean viral loadThe effect of -35 genotypes on mean plasma HIV load (mVL) measurements was tested in a group of 935 seroincident European American individuals (see Online Methods). Each individual was categorized into one of three groups based on their mVL (<2,000, 2,000-10,000 and >10,000 mean viral RNA copies per ml plasma), and the frequency of ea...

Without therapy, most persons infected with the human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (“elite controllers”) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA Class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B571. Since HLA molecules present viral peptides that activate CD8+ T cells, an immune mediated mechanism is likely responsible for superior control of HIV. We report that the peptide binding characteristics of HLA-B57 molecules impact thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naïve repertoire of B57-restricted clones recognizes a viral epitope and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide binding characteristics that impact thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, with implications for vaccination strategies.