Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA–viral peptide interaction as the major factor modulating durable control of HIV infection.

Background A T cell vaccine that lowers levels of HIV replication could significantly diminish the burden of the AIDS epidemic by attenuating disease progression and reducing the risk of HIV transmission. In order to learn which immune responses an effective HIV vaccine should elicit, we must first identify correlates of immune protection in vivo. Objective “Elite controllers” are rare HIV-infected individuals who are able to spontaneously control HIV replication without medication, maintaining viral loads that are consistently below the limits of detection by currently available commercial assays. The objective of this review is to examine studies of elite controllers that may help to elucidate mechanisms of HIV immune control that will be useful in designing a vaccine. Methods This review examines recent literature on HIV controllers as well as studies that have evaluated aspects of viral and host immunology that correlate with viral control. Results/Conclusions Although many elements of both innate and adaptive immunity are associated with control of HIV infection, the specific mechanism(s) by which HIV elite controllers achieve control remain undefined. Ongoing studies of elite controllers, including those examining host genetic polymorphisms, should facilitate the definition of an effective HIV-specific immune response and guide HIV vaccine design.