The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control

Front Immunol. 2023 Dec 11:14:1305856. doi: 10.3389/fimmu.2023.1305856. eCollection 2023.

Abstract

Introduction: We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers.

Methods: We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region.

Results: Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort.

Discussion: These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control.

Keywords: AIDS; GWAS; HIV-1; MHC; elite controllers; genetics; haplotype; viral load.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • DNA-Binding Proteins / genetics
  • Genome-Wide Association Study
  • HIV Seropositivity* / genetics
  • HIV-1* / genetics
  • HLA-B Antigens / genetics
  • Humans
  • Major Histocompatibility Complex
  • Transcription Factors / genetics

Substances

  • HLA-B57 antigen
  • HLA-B Antigens
  • ZBTB12 protein, human
  • DNA-Binding Proteins
  • Transcription Factors

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Initial funding for the International Collaboration for the Genomics of HIV was provided by the NIH Office of AIDS Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. MT is recipient of a fellowship from the Foundation FundaMental. The Laboratory GBCM acknowledges the program Mécénat-Santé of Mutuelles AXA for funding its research. The funders had no role in study design, data analysis, decision to publish, or preparation of the manuscript.