{"doi":"10.1101/2024.12.07.625684","title":"Deep analysis of the Major Histocompatibility Complex associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS","abstract":"Abstract Introduction We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC). Methods A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR. Results 2,626 SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396. Conclusion Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with a partially functional NK cell response which could also explain this marker’s involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":507263,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":0.0,"corpus_rank":10062,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":true,"is_dataset_confidence":0.6853,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":709667,"name":"Sigrid Le Clerc","orcid":null,"position":1,"is_corresponding":false},{"id":1078478,"name":"Jean‐Louis Spadoni","orcid":null,"position":2,"is_corresponding":false},{"id":1078481,"name":"Taoufik Labib","orcid":null,"position":3,"is_corresponding":false},{"id":1078479,"name":"Maxime Tison","orcid":null,"position":4,"is_corresponding":false},{"id":1078480,"name":"Raissa Medina‐Santos","orcid":null,"position":5,"is_corresponding":false},{"id":1078025,"name":"Armand Bensussan","orcid":"0000-0002-0409-2497","position":6,"is_corresponding":false},{"id":495402,"name":"Ryad Tamouza","orcid":"0000-0003-3992-9565","position":7,"is_corresponding":false},{"id":850200,"name":"Jean-François Deleuze","orcid":null,"position":8,"is_corresponding":false},{"id":41015,"name":"Jean‐François Zagury","orcid":null,"position":9,"is_corresponding":false},{"id":1078022,"name":"Myriam Rahmouni","orcid":"0009-0003-6681-7136","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:10:58.484528Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}