HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and Qualitative Differences in HLA Allele-Specific Peptide Presentation

Abstract

Pathogen-mediated balancing selection is regarded as a key driver of host immunogenetic diversity. A hallmark for balancing selection in humans is the heterozygote advantage at genes of the human leukocyte antigen (HLA), resulting in improved HIV-1 control. However, the actual mechanism of the observed heterozygote advantage is still elusive. HLA heterozygotes may present a broader array of antigenic viral peptides to immune cells, possibly resulting in a more efficient cytotoxic T-cell response. Alternatively, heterozygosity may simply increase the chance to carry the most protective HLA alleles, as individual HLA alleles are known to differ substantially in their association with HIV-1 control. Here, we used data from 6,311 HIV-1-infected individuals to explore the relative contribution of quantitative and qualitative aspects of peptide presentation in HLA heterozygote advantage against HIV. Screening the entire HIV-1 proteome, we observed that heterozygous individuals exhibited a broader array of HIV-1 peptides presented by their HLA class I alleles. In addition, viral load was negatively correlated with the breadth of the HIV-1 peptide repertoire bound by an individual’s HLA variants, particularly at HLA-B. This suggests that heterozygote advantage at HLA-B is at least in part mediated by quantitative peptide presentation. We also observed higher HIV-1 sequence diversity among HLA-B heterozygous individuals, suggesting stronger evolutionary pressure from HLA heterozygosity. However, HLA heterozygotes were also more likely to carry certain HLA alleles, including the highly protective HLA-B*57:01 variant, indicating that HLA heterozygote advantage ultimately results from a combination of quantitative and qualitative effects in antigen presentation.

Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: A pilot study in a cohort of Covid-19 Spanish patients

“…In addition, they present a greater percentage of heterozygosity. Although these findings are consistent with the bioinformatic predictions and previous works [ 13 , 21 , 24 ], these data must be interpreted with caution mainly due to the limited sample size. In this sense, global efforts are currently being made to collect samples from different types of patients, including asymptomatic individuals, in order to carry out studies with greater statistical power.…”

“…The degree of HLA homozygosity is associated with poorer disease resistance [ 21 ]. In our study, it was found that the percentage of homozygous individuals for loci A and C was higher in the group of patients with severe evolution compared to those with moderate evolution (20% vs. 10% in locus A, 15% vs. 5% in locus C).…”

HLA tapasin independence: broader peptide repertoire and HIV control

“…We previously reported genetic epidemiological observations indicating an HLA class I heterozygote advantage against HIV (32), supporting a theory originally put forth by Doherty and Zinkernagel proposing that heterozygosity at class I results in a greater repertoire of viral peptides to which an individual can respond (33). These studies are further supported by recent theoretical data (34). Thus, there are at least two mechanisms by which HLA class I genotypes can enhance the breadth of the peptide binding repertoire and protect against viral disease: heterozygosity and tapasin independence.…”

HLA class I genotypes customize vaccination strategies in immune simulation to combat COVID-19

“…For example, HLA-B*46:01 that was predicted to bind to two low-affinity peptides from ORF1ab-encoded proteins, in comparison to B*15:03 and B*07:02 predicted to bind 1538 and 158 peptides derived from the same SARS-CoV-2 proteins (Fig. 4), likely supports the theory of heterozygous advantage 68 , if these HLA class I alleles express in an individual. This study provided an example of immune simulation that CD8 + T cell responses in an individual expressing a weak peptide binder HLA-B*46:01 protein can be enhanced and rescued by the heterozygous expression of B*07:02 protein, which provided complementary capacity in peptide presentation to enhance CD8 + T cell activation (Fig.…”

“…Heterozygosity of HLA alleles is considered as a result of balancing selection to shape exceptional polymorphism of HLA proteins and increase host immunocompetence against highly diverse pathogens 67,68 . In this study, HLA class I heterozygosity was demonstrated to provide an advantage in presenting additional high-affinity peptides complementarily (Figs.…”