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
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.
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