HIV-1 Disease-Influencing Effects Associated with ZNRD1, HCP5 and HLA-C Alleles Are Attributable Mainly to Either HLA-A10 or HLA-B*57 Alleles

Abstract

A recent genome-wide association study (GWAS) suggested that polymorphisms in or around the genes HCP5, HLA-C and ZNRD1 confer restriction against HIV-1 viral replication or disease progression. Here, we also find that these alleles are associated with different aspects of HIV disease, albeit mainly in European Americans. Additionally, we offer that because the GWAS cohort was a subset of HIV-positive individuals, selected based in part on having a low viral load, the observed associations for viral load are magnified compared with those we detect in a large well-characterized prospective natural history cohort of HIV-1-infected persons. We also find that because of linkage disequilibrium (LD) patterns, the dominant viral load- and disease-influencing associations for the ZNRD1 or HLA-C and HCP5 alleles are apparent mainly when these alleles are present in HLA-A10- or HLA-B*57-containing haplotypes, respectively. ZNRD1 alleles lacking HLA-A10 did not confer disease protection whereas ZNRD1-A10 haplotypes did. When examined in isolation, the HCP5-G allele associates with a slow disease course and lower viral loads. However, in multivariate models, after partitioning out the protective effects of B*57, the HCP5-G allele associates with disease-acceleration and enhanced viral replication; these associations for HCP5-G are otherwise obscured because of the very strong LD between this allele and a subset of protective B*57 alleles. Furthermore, HCP5 and HLA-C alleles stratify B*57-containing genotypes into those that associate with either striking disease retardation or progressive disease, providing one explanation for the long-standing conundrum of why some HLA-B*57-carrying individuals are long-term non-progressors, whereas others exhibit progressive disease. Collectively, these data generally underscore the strong dependence of genotype-phenotype relationships upon cohort design, phenotype selection, LD patterns and populations studied. They specifically demonstrate that the influence of ZNRD1 alleles on disease progression rates are attributable to HLA-A10, help clarify the relationship between the HCP5, HLA-C and HLA-B*57 alleles, and reaffirm a critical role of HLA-B*57 alleles in HIV disease. Furthermore, as the protective B*57-containing genotypes convey striking salutary effects independent of their strong impact on viral control, it is conceivable that T cell-based therapeutic vaccine strategies aimed at reducing viral loads may be inadequate for limiting AIDS progression, raising the potential need for complementary strategies that target viral load-independent determinants of pathogenesis.

Reappraisal of the Relationship between the HIV-1-Protective Single-Nucleotide Polymorphism 35 Kilobases Upstream of theHLA-CGene and Surface HLA-C Expression

“…All three SNPs were located in the MHC region on chromosome 6. These findings have been replicated with other independent Caucasian cohorts (10,15,31,53,55).…”

Comparative Analysis of the Capacity of Elite Suppressor CD4 + and CD8 + T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

“…This idea has long been supported by both functional studies examining the response and quality of ES CD8 ϩ T cells (2, 3, 5, 10, 36-40) and genome-wide association studies identifying major histocompatibility complex class I alleles (such as HLA-B*57 and HLA-B*27) (41)(42)(43)(44)(45)(46). In addition, these protective HLA alleles have been shown to be overrepresented in multiple ES cohorts (5,41,(47)(48)(49)(50)(51)(52).…”

ZNRD1 (Zinc Ribbon Domain–Containing 1) Is a Host Cellular Factor That Influences HIV‐1 Replication and Disease Progression

“…In the middle of such an intricate picture, however, several genetic polymorphisms have been described that clearly influence the outcome of HIV infection, specially in the HLA region, where ZNRD1 is located [7,31,36,37]. Genetic complexity and the high linkage disequilibrium of the region challenges the effect of ZNRD1 on HIV disease progression [32,37]. Unlike the findings of these studies, our data point to a role for the ZNRD1 gene in HIV disease progression independent of the HLA-A10 allele, a factor proposed to be responsible for much of the effect of ZNRD1 [32].…”

“…Genetic complexity and the high linkage disequilibrium of the region challenges the effect of ZNRD1 on HIV disease progression [32,37]. Unlike the findings of these studies, our data point to a role for the ZNRD1 gene in HIV disease progression independent of the HLA-A10 allele, a factor proposed to be responsible for much of the effect of ZNRD1 [32]. Polymorphisms in the ZNRD1 gene remained statistically significantly associated with the LTNP phenotype when HLA-A10 was introduced as a covariable in the analysis.…”