PMID- 38236978 OWN - NLM STAT- MEDLINE DCOM- 20240202 LR - 20240202 IS - 1095-9203 (Electronic) IS - 0036-8075 (Linking) VI - 383 IP - 6680 DP - 2024 Jan 19 TI - Impact of HLA class I functional divergence on HIV control. PG - 319-325 LID - 10.1126/science.adk0777 [doi] AB - Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs. FAU - Viard, Mathias AU - Viard M AUID- ORCID: 0000-0002-1737-8021 AD - Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA. FAU - O'hUigin, Colm AU - O'hUigin C AUID- ORCID: 0000-0001-5404-5173 AD - Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA. FAU - Yuki, Yuko AU - Yuki Y AUID- ORCID: 0000-0003-1721-6003 AD - Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA. FAU - Bashirova, Arman A AU - Bashirova AA AUID- ORCID: 0000-0001-9188-0178 AD - Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA. FAU - Collins, David R AU - Collins DR AUID- ORCID: 0000-0001-7903-346X AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. FAU - Urbach, Jonathan M AU - Urbach JM AUID- ORCID: 0000-0003-0597-2848 AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. FAU - Wolinsky, Steven AU - Wolinsky S AUID- ORCID: 0000-0002-9625-6697 AD - Division of Infectious Diseases, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. FAU - Buchbinder, Susan AU - Buchbinder S AUID- ORCID: 0000-0003-2404-0712 AD - Bridge HIV, San Francisco Department of Public Health, San Francisco, CA, USA. AD - Department of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. FAU - Kirk, Gregory D AU - Kirk GD AD - Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. FAU - Goedert, James J AU - Goedert JJ AUID- ORCID: 0000-0001-6134-1472 AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. FAU - Michael, Nelson L AU - Michael NL AUID- ORCID: 0000-0001-5882-5548 AD - US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA. FAU - Haas, David W AU - Haas DW AUID- ORCID: 0000-0002-5813-1594 AD - Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. FAU - Deeks, Steven G AU - Deeks SG AUID- ORCID: 0000-0001-6371-747X AD - Department of Medicine, University of California, San Francisco, CA, USA. FAU - Walker, Bruce D AU - Walker BD AUID- ORCID: 0000-0001-6122-9245 AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. AD - Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. FAU - Yu, Xu AU - Yu X AUID- ORCID: 0000-0002-8295-884X AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. FAU - Carrington, Mary AU - Carrington M AUID- ORCID: 0000-0002-2692-2180 AD - Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute Bethesda, MD, USA. AD - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. LA - eng PT - Journal Article DEP - 20240118 PL - United States TA - Science JT - Science (New York, N.Y.) JID - 0404511 RN - 0 (HLA-B Antigens) RN - 0 (Peptides) SB - IM MH - Humans MH - Alleles MH - Disease Progression MH - *Heterozygote MH - *HIV Infections/genetics/pathology MH - *HLA-B Antigens/genetics MH - Peptides/genetics/immunology MH - Male MH - Female MH - Young Adult MH - Adult MH - Middle Aged MH - Aged EDAT- 2024/01/18 18:42 MHDA- 2024/01/22 06:42 CRDT- 2024/01/18 14:04 PHST- 2024/01/22 06:42 [medline] PHST- 2024/01/18 18:42 [pubmed] PHST- 2024/01/18 14:04 [entrez] AID - 10.1126/science.adk0777 [doi] PST - ppublish SO - Science. 2024 Jan 19;383(6680):319-325. doi: 10.1126/science.adk0777. Epub 2024 Jan 18.