PMID- 31651980
OWN - NLM
STAT- MEDLINE
DCOM- 20201112
LR  - 20240423
IS  - 1537-1719 (Electronic)
IS  - 0737-4038 (Print)
IS  - 0737-4038 (Linking)
VI  - 37
IP  - 3
DP  - 2020 Mar 1
TI  - HLA Heterozygote Advantage against HIV-1 Is Driven by Quantitative and 
      Qualitative Differences in HLA Allele-Specific Peptide Presentation.
PG  - 639-650
LID - 10.1093/molbev/msz249 [doi]
AB  - 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.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      Society for Molecular Biology and Evolution.
FAU - Arora, Jatin
AU  - Arora J
AD  - Research Group for Evolutionary Immunogenomics, Max Planck Institute for 
      Evolutionary Biology, Plon, Germany.
FAU - Pierini, Federica
AU  - Pierini F
AD  - Research Group for Evolutionary Immunogenomics, Max Planck Institute for 
      Evolutionary Biology, Plon, Germany.
FAU - McLaren, Paul J
AU  - McLaren PJ
AD  - JC Wilt Infectious Diseases Research Center, National HIV and Retrovirology 
      Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
AD  - Department of Medical Microbiology and Infectious Diseases, University of 
      Manitoba, Winnipeg, MB, Canada.
FAU - Carrington, Mary
AU  - Carrington M
AD  - Basic Science Program, Frederick National Laboratory for Cancer Research, 
      Frederick, MD.
AD  - Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of 
      Technology and Harvard University, Cambridge, MA.
FAU - Fellay, Jacques
AU  - Fellay J
AD  - Global Health Institute, School of Life Sciences, Ecole Polytechnique Federale de 
      Lausanne, Lausanne, Switzerland.
AD  - Swiss Institute of Bioinformatics, Lausanne, Switzerland.
AD  - Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, 
      Lausanne, Switzerland.
FAU - Lenz, Tobias L
AU  - Lenz TL
AD  - Research Group for Evolutionary Immunogenomics, Max Planck Institute for 
      Evolutionary Biology, Plon, Germany.
LA  - eng
GR  - HHSN261200800001C/RC/CCR NIH HHS/United States
GR  - HHSN261200800001E/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Biol Evol
JT  - Molecular biology and evolution
JID - 8501455
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B*57:01 antigen)
RN  - 0 (Peptides)
RN  - 0 (Viral Proteins)
SB  - IM
MH  - Antigen Presentation
MH  - Genetic Variation
MH  - Genome, Viral
MH  - HIV Infections/genetics/*immunology/virology
MH  - HIV-1/immunology/*physiology
MH  - HLA Antigens/*genetics/immunology
MH  - HLA-B Antigens/genetics
MH  - Heterozygote
MH  - Humans
MH  - Peptides/*immunology
MH  - Viral Load
MH  - Viral Proteins/*chemistry
PMC - PMC7038656
OTO - NOTNLM
OT  - MHC evolution
OT  - antigen presentation
OT  - divergent allele advantage
OT  - human leukocyte antigen
OT  - major histocompatibility complex
OT  - pathogen-mediated balancing selection
EDAT- 2019/10/28 06:00
MHDA- 2020/11/13 06:00
PMCR- 2019/10/22
CRDT- 2019/10/26 06:00
PHST- 2019/10/28 06:00 [pubmed]
PHST- 2020/11/13 06:00 [medline]
PHST- 2019/10/26 06:00 [entrez]
PHST- 2019/10/22 00:00 [pmc-release]
AID - 5607306 [pii]
AID - msz249 [pii]
AID - 10.1093/molbev/msz249 [doi]
PST - ppublish
SO  - Mol Biol Evol. 2020 Mar 1;37(3):639-650. doi: 10.1093/molbev/msz249.