Earlier this year the blog covered studies conducted by the Center for HIV/AIDS Vaccine Immunology (CHAVI), which identified a suite of genetic associations with control of HIV replication. Researchers from Sunil Ahuja’s group have now evaluated these associations in a different natural history cohort of HIV-infected individuals and found that the originally reported findings may need to be re-interpreted. Specifically, an association with a genetic polymorphism found in the ZNRD1 gene may be explained, at least in part, by an association with HLA A*10 (an immune response gene which has previously been associated with slowed disease progression). Also, as in the original CHAVI paper, this association was largely restricted to people of European descent and was not significant among African Americans.
Moving on to the other reported associations, the researchers found that the effect of a polymorphism in the HCP5 gene was entirely explained by its linkage with HLA B*57, an immune response gene that is strongly associated with long-term non-progression. When the effects of HCP5 and HLA B*57 were disentangled, the HCP5 polymorphism was associated with faster - not slower - disease progression. The third association identified by CHAVI was with a polymorphism in the HLA-C gene. Ahuja and colleagues also found evidence for this association, but discovered that the strength of the effect also relates to a linkage with HLA B*57. In the absence of HLA B*57, the HLA-C association with lower viral load was several fold less than initially reported. By evaluating HLA B*57 and HCP5 and HLA-C variants together, the researchers were able to identify combinations that ameliorate the protective effects of HLA B*57, which they suggest may explain why some people possessing this HLA allele do not experience slowed disease progression. They also show that the protective effects of HLA B*57 are not entirely mediated by a reduction in viral load, suggesting an impact on other parameters that influence disease progression, such as immune activation.
This type of study highlights the complexity and challenges of evaluating genetic associations with disease outcomes. Given this complexity, it’s possible that future research in additional cohorts will further alter the picture that has emerged regarding these particular genetic polymorphisms. Ahuja and colleagues also note that ethnicity appears to impact the associations independent of the altered frequency of the polymorphisms among different populations, suggesting that the evolutionary history of an ethnic group can alter the impact of gene variants in ways that have yet to be fully understood.
PLoS ONE 3(11): e3636 doi:10.1371/journal.pone.0003636
Gabriel Catano1,2#, Hemant Kulkarni1,2#, Weijing He1,2#, Vincent C. Marconi3,4, Brian K. Agan3,4,5, Michael Landrum3,4,5, Stephanie Anderson3,5, Judith Delmar3,4, Vanessa Telles1,2, Li Song1,2, John Castiblanco1,2, Robert A. Clark1,2, Matthew J. Dolan3,4,5*, Sunil K. Ahuja1,2,6,7*
1 Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, Texas, United States of America, 2 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, United States of America, 3 Infectious Disease Clinical Research Program (IDCRP), Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America, 4 Infectious Disease Service, San Antonio Military Medical Center (SAMMC), Ft. Sam Houston, Texas, United States of America, 5 Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland AFB, Texas, United States of America, 6 Department of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, Texas, United States of America, 7 Department of Biochemistry, University of Texas Health Science Center, San Antonio, Texas, United States of America
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.