HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C

Abstract

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.Correspondence should be addressed to M.C. (carringm@mail.nih.gov). Note: Supplementary information is available on the Nature Genetics website. Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. AUTHOR CONTRIBUTIONS NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 December 1. Recently, however, a scan for genetic variants that influence the control of viral load indicated that a dimorphism 35 kb upstream of the HLA-C gene (-35C/T) had one of the two strongest genome-wide effects on the level of plasma viremia in early, established HIV infection as measured by viral load set-point, although no significant association of this variant was observed with progression to a CD4 cell count of <350 (ref.2 ). Notably, the -35C variant that associates with low viral load has also been shown to associate with high HLA-C mRNA levels in a codominant manner among a group of individuals of European ancestry 12,13 , although whether it associates with cell surface expression has not been tested. These findings suggest that certain HLA-C allotypes might have a primary role in restricting HIV replication through innate and/or acquired immune mechanisms that have previously been overlooked. Here we present data from 1,698 European American individuals, indicating that high levels of HLA-C confer strong protection early in the course of HIV infection and this early protection of high HLA-C extends to some extent into chronic infection. We propose a model in which highexpression HLA-C alleles might confer better innate and/or acquired immune responses than low-expression HLA-C alleles. RESULTS Effect of-35 on mean viral loadThe effect of -35 genotypes on mean plasma HIV load (mVL) measurements was tested in a group of 935 seroincident European American individuals (see Online Methods). Each individual was categorized into one of three groups based on their mVL (<2,000, 2,000-10,000 and >10,000 mean viral RNA copies per ml plasma), and the frequency of ea...

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

“…Interestingly, most of those alleles are in strong LD with a polymorphism termed 235C, located 35 kb upstream of the HLA-C locus (59). This polymorphism is associated with increased expression of HLA-C and is genetically linked with delayed onset to AIDS (59). Alleles in LD with the polymorphic form associated with rapid onset (termed 235T) overall displayed weaker binding (Supplemental Fig.…”

“…Interestingly, most alleles carrying Cys 1 are in strong LD with a polymorphism known as 235C, which is associated with delayed onset to AIDS (59). Conversely, most alleles carrying Gly 1 display strong LD with the variant associated with rapid onset (termed 235T).…”

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

“…Functional education of human NK cells by HLA class I is well established (13,15,(39)(40)(41)(42), and a quantitative influence of HLA on NK cell responsiveness may explain, for example, how a single nucleotide polymorphism associated with a higher HLA-C expression levels is beneficial in acute HIV infection (43,44). The role of HLA class I molecules on the human NK cell repertoire is less clear, but is implied from studies showing that specific compound genotypes of KIR and HLA may provide protection or susceptibility to infections, cancers, and successful pregnancy (45).…”

Surface expression, peptide repertoire, and thermostability of chicken class I molecules correlate with peptide transporter specificity

“…Class I molecules are also polymorphic in expression at the cell surface, discovered in chickens (6,7), but more recently found for HLA-C in humans (8,9). It has also become clear that the diversity of peptides bound by particular class I alleles varies significantly, again described first in chickens (10,11) and later in humans (12,13).…”