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

Abstract

Previous studies have found an association between a single-nucleotide polymorphism 35 kb upstream of the HLA-C locus (؊35 SNP), HLA-C expression, and HIV-1 set point viral loads. We show that the difference in HLA-C expression across ؊35 SNP genotypes can be attributed primarily to the very low expression of a single allelic product, HLA-Cw7, which is a common HLA type. We suggest that association of the ؊35 SNP and HIV-1 load manifests as a result of linkage disequilibrium of this polymorphism with both favorable and unfavorable HLA-C and -B alleles.Infection with HIV-1 involves a complex interplay between virus and host. After the acute phase of infection, an equilibrium is reached between HIV-1 and the immune system, resulting in the decline of HIV-1 RNA levels to the widely variable viral set point, a known (though imperfect) predictor of time to progression to AIDS (36, 37). The early appearance of HIV-1-specific CD8 T cells and their rapid selection of escape mutants during the initial decline of viremia in primary infection imply that this T-cell response plays a central role in resolution of primary viremia and the long-term suppression of viral replication (21, 34).The major histocompatibility complex (MHC), located on chromosome 6, contains the HLA class I and II genes, which are the most polymorphic loci in humans (9). HLA class I molecules play a significant role in the immune response against HIV-1 by presenting viral peptides to CD8 T cells (adaptive immunity) and by serving as ligands for killer cell immunoglobulin-like receptors (KIRs) expressed on natural killer (NK) cells (innate immunity). The central role of the MHC region in HIV-1 control was highlighted by a recent genomewide association study of variants that influence the control of viral set point (17, 18). In Caucasian cohorts, two single-nucleotide polymorphisms (SNPs) were identified that associated with the HIV-1 set point, and a third was associated with disease progression. 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).One minor allelic variant of an SNP (rs2395029) associated with lower viral set points is located in the HLA complex P5 (HCP5) gene and is a tag for HLA-B*5701 (17), which is associated with slow disease progression (2, 9, 25, 40, 42). The second most significant polymorphism (rs9264942), accounting for 6.5% of the variation in viral set point (18), is located 35 kb upstream of the HLA-C gene (Ϫ35 SNP), with the minor allele (C) associating with a lower set point than the major allele (T). The Ϫ35 SNP is also present in African-American populations but does not correlate with viral set point (47, 49), which suggests that the Ϫ35 SNP is a marker for another polymorphism and is not the causal SNP. Although HLA-B*5701 is in linkage disequilibrium with the Ϫ35 SNP, both associate independently with the viral load set point (17,18).The Ϫ35 C variant was associated with higher HLA-C mRNA expression in Epstein...

Comment on “Influence of HLA-C Expression Level on HIV Control”

“…However, this finding has subsequently been challenged by Corrah et al, who have instead documented PBMC staining with another mAb to HLA-E, called 3D12 (4). Further adding to this controversy, and in agreement with Corrah et al, we have shown that mAb MEM-E/08 reacts with poorly expressed, unstable, unfolded HLA-E molecules free of their light chain subunit (b 2 m).…”

Relative Expression Levels of the HLA Class-I Proteins in Normal and HIV-Infected Cells

“…The mAb PA2.1 is specific to HLA-A*02:01, mAb 22E.1 is specific to B*44:02 and mAb DT9 is specific to C*05:01 in subjects homozygous for the A*02:01, B*44:02, C*05:01 haplotype. mAb DT9 is known to recognize HLA-E in addition to HLA-C [35], but we and others have previously determined that binding of DT9 to PBL is dominated by reactivity with HLA-C [14,42], likely because expression levels of HLA-E are very much lower than HLA-C. mAb BBM.1 recognizes the β 2 m molecule with which all HLA 45kDa heavy chains associate [30]. Binding of mAbs PA2.1, 22E.1 and DT9 was normalised to that of BBM.1 in our screening panel, in order to quantify the relative strength of antibody binding corrected for variation in the amount of each HLA allele present (Suppl Fig.…”

Genetic interplay betweenHLA-CandMIR148Ain HIV control and Crohn disease

“…Unambiguously distinguishing independent effects for the neighboring HLA-C and HLA-B loci, which map only 150 kb apart, has proven especially difficult and has questioned a direct causal effect of HLA-C expression levels on HIV control (23). The MIR148A gene is unlinked to the MHC in the human genome, so any effect of this locus on HIV control cannot be attributed to an HLA locus unless that locus contains variation in a binding site for miR-148a that results in regulation of some but not all of the alleles at that locus.…”