Host genetic variation and HIV disease: from mapping to mechanism

Abstract

This review aims to provide a summary of current knowledge of host genetic effects on human immunodeficiency virus (HIV) disease. Mapping of simple single nucleotide polymorphisms (SNP) has been largely successful in HIV, but more complex genetic associations involving haplotypic or epigenetic variation, for example, remain elusive. Mechanistic insights explaining SNP associations are incomplete, but continue to be forthcoming. The number of robust immunogenetic correlates of HIV is modest and their discovery mostly predates the genome-wide era. Nevertheless, genome-wide evaluations have nicely validated the impact of HLA and CCR5 variants on HIV disease, and importantly, made clear the many false positive associations that were previously suggested by studies using the candidate gene approach. We describe how multiple HIV outcome measures such as acquisition, viral control, and immune decline have been studied in adults and in children, but that collectively these identify only the two replicable loci responsible for modifying HIV disease, CCR5, and HLA. Recent heritability estimates in this disease corroborate the modest impact of genetic determinants and their oligogenic nature. While the mechanism of protection afforded by genetic variants that diminish CCR5 expression is clear, new aspects of HLA class I-mediated protection continue to be uncovered. We describe how these genetic findings have enhanced insights into immunobiology, been clinically translated into CCR5 antagonists, allowed prioritization of antigens for vaccination efforts, and identified targets for genome-editing interventions. Finally, we describe how studies of genetically complex parts of the genome using new tools may begin revealing additional correlates.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-017-1000-z) contains supplementary material, which is available to authorized users.

The HLA‐B landscape of Africa: Signatures of pathogen‐driven selection and molecular identification of candidate alleles to malaria protection

“…However, single HLA (more generally, MHC) loci may also display reduced levels of diversity that would not necessarily reduce the fitness of individuals thanks to the high polymorphism existing at other loci (Buhler, Nunes, & Sanchez‐Mazas, ; de Groot & Bontrop, ). In addition, specific HLA alleles are known or supposed to confer resistance or susceptibility to various auto‐immune (e.g., IDDM, coeliac disease) and infectious (e.g., HIV, tuberculosis, malaria) diseases (reviewed by Naranbhai & Carrington, ; Sollid, ; and Trowsdale & Knight, ; among others), indicating that directional selection may also drive the evolution of HLA genes. As an example, the HLA‐DRB1*12:02:01 allele has been suggested to have increased in frequency in a Mongolian population that migrated from the north to the southwest of China about 700 years ago as a consequence of its settlement in a new environment where this allele would have been protective (Sun et al., ).…”

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

“…The most robust immunogenetic associations with LTNP in HIV-1 are found in HLA alleles and CCR5 polymorphisms [60]. Few studies have reported on the impact of human leucocyte antigen (HLA) genotypes on HIV-2 infection outcomes.…”

Estimating HLA disease associations using similarity trees

“…A simple explanation for finding alleles that are associated with high SPVL is that they are less protective than the average allele. More interestingly, some alleles appear to have a truly detrimental effect [27], possibly explained by the interaction between HLA-E expression and the NK-cell response [33]. The distinction between relative and true detrimental effects is important for the subadditive dosage model.…”