HLA and HIV-1: Heterozygote Advantage and B*35 - Cw*04 Disadvantage

Abstract

A selective advantage against infectious disease associated with increased heterozygosity at the human major histocompatibility complex [human leukocyte antigen (HLA) class I and class II] is believed to play a major role in maintaining the extraordinary allelic diversity of these genes. Maximum HLA heterozygosity of class I loci (A, B, and C) delayed acquired immunodeficiency syndrome (AIDS) onset among patients infected with human immunodeficiency virus-type 1 (HIV-1), whereas individuals who were homozygous for one or more loci progressed rapidly to AIDS and death. The HLA class I alleles B*35 and Cw*04 were consistently associated with rapid development of AIDS-defining conditions in Caucasians. The extended survival of 28 to 40 percent of HIV-1-infected Caucasian patients who avoided AIDS for ten or more years can be attributed to their being fully heterozygous at HLA class I loci, to their lacking the AIDS-associated alleles B*35 and Cw*04, or to both.

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

“…37 One of them (Mamu-DQB1*1801-DRB1*0303-DRB1*1007) was also linked to class I configurations associated with slow disease progression, including configuration 4. This finding indicates that Mhc class I genotypes have a much more marked influence upon disease progression than class II genotypes, thereby corroborating previous reports on HIV-infected humans 20 and SIV-infected macaques. 38 Mhc region configurations explain at least 48% of the variation in disease progression In order to somehow quantify the overall influence of the Mhc genotype on disease progression in our study cohort, we performed a post hoc unbalanced one-way analysis of variance (ANOVA) of the 60 observed event times (that is, euthanizations with AIDS …”

“…Several studies have shown (1) a temporal relationship between the decline of viral load and the emergence of CTL responses in both infected humans and infected monkeys, [3][4][5][6] (2) an increase of viral load after the appearance of CTL-escape HIV/SIV mutants during chronic and acute infection [7][8][9][10][11][12][13] and (3) a dramatic rise of viral load after CD8 þ T-cell depletion. [14][15][16] Additional indirect evidence for a CTL effect upon viral replication came from genetic association studies showing that Mhc class I alleles are strongly associated with survival time in HIV-infected humans [17][18][19][20] .…”

MHC polymorphism under host-pathogen coevolution

“…Since different MHC molecules bind different peptides, MHC heterozygous hosts can present a greater variety of peptides, and hence defend themselves against a larger variety of pathogens compared with MHC homozygous individuals (Penn et al 2002). It has indeed been shown that MHC heterozygosity correlates negatively with disease in HIV-infected patients (Carrington et al 1999), with HTLV-1 infection in humans (Jeffery et al 2000), and with LCMV infection in mice (Weidt et al 1995).…”

Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study

“…[24][25][26][27] Molecular genetic epidemiological studies have identified polymorphisms in more than 20 human genes, including several chemokines and their receptors, that are associated with HIV-1 infection and/or AIDS disease pathogenesis. [28][29][30][31][32][33][34][35][36][37][38][39][40] Given the importance of SDF-1 in various metabolic and developmental activities, we examined the allele frequencies and haplotype structure of nine SNPs in and around the SDF-1 gene. In addition, given the important role played by SDF-1 and CXCR4 in HIV-1/AIDS, we looked for the influence of genetic variation in these SNPs and haplotypes on disease in over 3000 subjects enrolled in five USA-based natural history HIV-1/AIDS cohorts.…”