Regulatory variation in HIV-1 dependency factor ZNRD1 associates with host resistance to HIV-1 acquisition.
BACKGROUND
ZNRD1 was identified as a host protein required for the completion of the human immunodeficiency virus (HIV) lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4(+) T-cell depletion.


METHODS
We investigated the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes in 5 US-based HIV-1 longitudinal cohorts consisting of men who have sex with men, males with hemophilia, and injection drug users (IDUs) (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay.


RESULTS
A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI, .47-.89), independent of HLA-C rs9264942, in European Americans. The SNP rs3132130 tagging this haplotype, located in the ZNRD1 5' upstream region, caused a loss of nuclear factor binding and decrease in ZNRD1 promoter activity. ZNRD1 variants also affected HIV-1 disease progression in European- and African-American cohorts.


CONCLUSIONS
This study provides novel evidence that ZNRD1 polymorphism may confer host resistance to HIV-1 acquisition.
Basic Research Laboratory, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research.
Ping
P
An
Infections and Immunoepidemology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
James J
JJ
Goedert
Rho, Inc, Chapel Hill, North Carolina.
Sharyne
S
Donfield
San Francisco Department of Public Health, California.
Susan
S
Buchbinder
Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
Gregory D
GD
Kirk
Department of Epidemiology, School of Public Health, University of California, Los Angeles.
Roger
R
Detels
Basic Research Laboratory, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research.
Cheryl A
CA
Winkler
D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D060467:Disease Resistance; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014481:United States
D004268:DNA-Binding Proteins; C406241:POLR1H protein, human
AIDS; HIV-1; SNP; ZNRD1; genetic association; host susceptibility; infection; single nucleotide polymorphism