Regulatory Polymorphisms in the Cyclophilin A Gene, PPIA, Accelerate Progression to AIDS

Abstract

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. Individual risk of acquiring HIV type 1 (HIV-1) infection and developing AIDS is not equal; some people are more prone to HIV/AIDS than others. Susceptibility to HIV-1/AIDS is likely determined by a combination of environmental, viral, and host genetic factors. Genetic variations in host cellular factors involved in HIV-1 cell entry, replication, and host defense have been found to affect susceptibility to HIV-1/AIDS. In this report, we focused on the gene PPIA that encodes cyclophilin A, a human cellular protein that is incorporated into the HIV-1 virion and promotes viral replication. We studied genetic variation in the PPIA gene in persons with different susceptibility levels to HIV-1 infection or different rates of disease progression. We found that individuals who processed two functional variants in the promoter region of PPIA had higher risk of CD4⁺ T-cell loss or progression to AIDS-defining diseases. We also observed that an additional variant occurred more frequently in HIV-1-infected individuals compared to HIV-1-exposed, but uninfected, individuals. These results suggest that genetic variation in PPIA may influence host susceptibility to HIV-1 infection or disease progression and targeting PPIA might provide therapeutic benefit.