Additive contribution of HLA class I alleles in the immune control of HIV-1 infection

Abstract

Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

FIG. 1.

(A and B) Association of HLA allele expression with steady-state viral load (A) and absolute CD4 count (B) in a cohort of 1,211 HIV C-clade chronically infected individuals from KwaZulu-Natal, South Africa. Left-hand panels show association of all alleles occurring at a phenotypic frequency of greater than 1%. Associations with a P value of <0.05 (as measured by a Mann-Whitney U test) are highlighted in yellow, and those retaining significance after Bonferroni correction for multiple comparisons are highlighted in blue. Right-hand panels show the relative contribution of HLA-A, -B, and -C alleles to variation in viral load and CD4 count as measured by the Kruskal-Wallis test statistic (H). (C and D) Association of HLA allele expression with steady-state viral load (C) and absolute CD4 count (D), excluding the four alleles most strongly associated with differences in viral load and CD4 count (HLA-B*57, -B*5801, -B*18, and -B*5802). A total of 682 subjects were analyzed.

FIG. 2.

Effect of HLA haplotype on steady-state viral load (A) and absolute CD4 count (B). The presence (+) or absence (−) of alleles is indicated. All P values were generated by a nonparametric Mann-Whitney U test.

FIG. 3.

The effect of coexpression of protective and harmful HLA alleles on steady-state viral load (A) and absolute CD4 count (B). Protective/susceptible alleles are taken as those that remain significantly associated with viral load and/or CD4 count following stringent Bonferroni corrections for multiple comparisons (protective, HLA-B*57, -B*5801 and the -B*8101-Cw*0401 and -B*3910-Cw*1203 haplotypes; susceptible, HLA-B*18 and -B*5802). Remainder includes all the individuals in the cohort expressing none of these alleles. All P values were generated by a Mann-Whitney U test. Median VL/CD4 counts for each group are indicated by the red line.

FIG. 4.

Correlation between steady-state viral load and absolute CD4 count and HLA frequency. Panels A and B show the correlation of viral load (A) and CD4 count (B) with the total combined HLA frequency of each individual in the cohort, that is, the sum of the frequencies of each of the individual's HLA class I alleles. The Spearman's rank correlation coefficient, r, and the linear regression r² values are given with their corresponding P values. Panels C to H show the correlation of the combined frequencies of the HLA-B (C and D), HLA-C (E and F), and HLA-A (G and H) alleles with viral load and CD4 count.

FIG. 5.

Effect of homozygosity on steady-state viral load (A and C) and absolute CD4 count (B and D). Panels A and B compare all heterozygotes to individuals homozygous for at least one HLA allele. Homozygotes are further grouped into those individuals homozygous for the HLA-A, -B, or -C locus. In panels C and D, homozygotes are grouped according to whether they are homozygous at only one, two, or all three HLA class I alleles. No significant differences are observed between any groups. Median VL/CD4 counts for each group are indicated by the red line.