Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS.
Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4(+) T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5' UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.
An
Ping
P
Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, United States of America.
Wang
Li Hua
LH
Hutcheson-Dilks
Holli
H
Nelson
George
G
Donfield
Sharyne
S
Goedert
James J
JJ
Rinaldo
Charles R
CR
Buchbinder
Susan
S
Kirk
Gregory D
GD
O'Brien
Stephen J
SJ
Winkler
Cheryl A
CA
D000163:Acquired Immunodeficiency Syndrome / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D000090103:Antiviral Restriction Factors; D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D002352:Carrier Proteins / Q000235:genetics; D021984:Cyclophilin A / Q000235:genetics*; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D020022:Genetic Predisposition to Disease; D015497:HIV-1; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A