Influence of HLA-C expression level on HIV control

Abstract

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.

Fig. 1. The distribution in expression levels of HLA-C allotypes present in African Americans

Peripheral blood CD3⁺ cells from 200 healthy donors were analyzed by flow cytometry for HLA-C expression level using the monoclonal antibody DT9. MFI of HLA-C staining is plotted twice for each donor (i.e., once for each HLA-C allele present), with HLA-C homozygous individuals marked in red. Expression level correlates significantly with HLA-C allotypes in analysis of variance (P = 5 × 10⁻²¹).

Fig. 2. HLA-C expression level correlates with frequency of viral escape mutation and HIV-specific CTL responses

(A) Analysis of viral sequences from 1888 Clade B–infected individuals revealed 12 epitopes containing viral mutations that were associated independently with an HLA-C allele. Median ln(OR) for associations with each of the seven different HLA-C alleles involved correlated positively with the expression level of these alleles. (B) Clade C–infected Africans (n = 1010) were screened for CTL responses to overlapping peptides spanning the HIV proteome, and median log OR of all responses independently associated with each HLA-C allele are plotted. The number of peptide responses associated with each HLA-C allele is labeled next to each point (total number of CTL responses is 71). At least one HLA-C–restricted CTL response was detected in 71% of individuals in the population. (C) Differences in the odds of detecting a response to the same peptide when restricted by different HLA-C alleles correlate with the difference in expression level of these allelic pairs. Pearson coefficients are reported for each correlation.