TY - JOUR
T1 - Host genetic variation and HIV disease
T2 - from mapping to mechanism
AU - Naranbhai, Vivek
AU - Carrington, Mary
N1 - Funding Information:
This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research.
Publisher Copyright:
© 2017, The Author(s).
PY - 2017/8
Y1 - 2017/8
N2 - This review aims to provide a summary of current knowledge of host genetic effects on human immunodeficiency virus (HIV) disease. Mapping of simple single nucleotide polymorphisms (SNP) has been largely successful in HIV, but more complex genetic associations involving haplotypic or epigenetic variation, for example, remain elusive. Mechanistic insights explaining SNP associations are incomplete, but continue to be forthcoming. The number of robust immunogenetic correlates of HIV is modest and their discovery mostly predates the genome-wide era. Nevertheless, genome-wide evaluations have nicely validated the impact of HLA and CCR5 variants on HIV disease, and importantly, made clear the many false positive associations that were previously suggested by studies using the candidate gene approach. We describe how multiple HIV outcome measures such as acquisition, viral control, and immune decline have been studied in adults and in children, but that collectively these identify only the two replicable loci responsible for modifying HIV disease, CCR5, and HLA. Recent heritability estimates in this disease corroborate the modest impact of genetic determinants and their oligogenic nature. While the mechanism of protection afforded by genetic variants that diminish CCR5 expression is clear, new aspects of HLA class I-mediated protection continue to be uncovered. We describe how these genetic findings have enhanced insights into immunobiology, been clinically translated into CCR5 antagonists, allowed prioritization of antigens for vaccination efforts, and identified targets for genome-editing interventions. Finally, we describe how studies of genetically complex parts of the genome using new tools may begin revealing additional correlates.
AB - This review aims to provide a summary of current knowledge of host genetic effects on human immunodeficiency virus (HIV) disease. Mapping of simple single nucleotide polymorphisms (SNP) has been largely successful in HIV, but more complex genetic associations involving haplotypic or epigenetic variation, for example, remain elusive. Mechanistic insights explaining SNP associations are incomplete, but continue to be forthcoming. The number of robust immunogenetic correlates of HIV is modest and their discovery mostly predates the genome-wide era. Nevertheless, genome-wide evaluations have nicely validated the impact of HLA and CCR5 variants on HIV disease, and importantly, made clear the many false positive associations that were previously suggested by studies using the candidate gene approach. We describe how multiple HIV outcome measures such as acquisition, viral control, and immune decline have been studied in adults and in children, but that collectively these identify only the two replicable loci responsible for modifying HIV disease, CCR5, and HLA. Recent heritability estimates in this disease corroborate the modest impact of genetic determinants and their oligogenic nature. While the mechanism of protection afforded by genetic variants that diminish CCR5 expression is clear, new aspects of HLA class I-mediated protection continue to be uncovered. We describe how these genetic findings have enhanced insights into immunobiology, been clinically translated into CCR5 antagonists, allowed prioritization of antigens for vaccination efforts, and identified targets for genome-editing interventions. Finally, we describe how studies of genetically complex parts of the genome using new tools may begin revealing additional correlates.
KW - CCR5
KW - HIV
KW - HLA
KW - Host genetics
KW - Immunology
UR - http://www.scopus.com/inward/record.url?scp=85022202636&partnerID=8YFLogxK
U2 - 10.1007/s00251-017-1000-z
DO - 10.1007/s00251-017-1000-z
M3 - Review Article
C2 - 28695282
AN - SCOPUS:85022202636
SN - 0093-7711
VL - 69
SP - 489
EP - 498
JO - Immunogenetics
JF - Immunogenetics
IS - 8-9
ER -