Although genetic variation in the virus itself can affect the outcome of infection, a growing number of host gene variants are being defined that impact the rate of progression of HIV infection toward AIDS. The implementation of genomewide association studies (GWAS) and, more recently, better highthroughput tools to define individual genetic variation (for example, exome and wholegenome sequencing) are accelerating discovery of genetic variations that distinguish highly susceptible and resistant individuals (Fig. 13.35). As discussed in Section 1330, one of the clearest cases of host genetic variation affecting HIV infection is a mutant allele of CCR5, CCR5Δ32, that when homozygous effectively blocks HIV1 infection, and when heterozygous may slow AIDS progression. Genetic polymorphisms in the HLA class I locus, particularly in HLA-B and HLA-C alleles, are another major factor in determining disease progression and are currently the strongest predictors of HIV control. Evidence from GWAS has mapped polymorphisms to the peptidebinding groove of HLA class I molecules as key determinants defining disease progression. Polymorphisms outside of the peptidebinding groove, as well as those in noncoding regions that control the expression levels of HLA molecules, are also implicated. The HLA class I alleles HLA-B57, HLA-B27, and HLA-B13, among others, are associated with a better prognosis, whereas HLA-B35 and HLA-B07 are associated with more rapid disease progression. Homozygosity of HLA class I alleles (HLA-A, HLA-B, and HLA-C) is also associated with more rapid progression, presumably because the Tcell response to infection is less diverse. Remarkably, one of the strongest associations with viral control is a singlenucleotide polymorphism (SNP) 35 kb upstream of the HLA-C locus; this polymorphism confers greater immune control that correlates with increased expression levels of HLAC—with the greater control presumably being due to enhanced presentation of viral peptides to CD8 T cells. Certain polymorphisms of the killercell immunoglobulinlike receptors (KIRs) present on NK cells (see Section 326), in particular the receptor KIR3DS1 in combination with certain alleles of HLA-B, also delay the progression to AIDS. Mutations that affect the production of cytokines such as IFNγ and IL10 have also been implicated in the restriction of HIV progression.
Fig. 13.35 Genes that influence progression to AIDS in humans.