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Association of Polymorphisms in the Regulatory Region of the Cyclophilin a Gene (PPIA) with Gene Expression and HIV/AIDS Disease Progression.

Association of Polymorphisms in the Regulatory Region of the Cyclophilin a Gene (PPIA) with Gene Expression and HIV/AIDS Disease Progression.
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Madlala P, Singh R, An P, Werner L, Mlisana K, Abdool Karim SS, Winkler CA, Ndungʼu T,


Madlala P, Singh R, An P, Werner L, Mlisana K, Abdool Karim SS, Winkler CA, Ndungʼu T, (click to view)

Madlala P, Singh R, An P, Werner L, Mlisana K, Abdool Karim SS, Winkler CA, Ndungʼu T,

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Journal of acquired immune deficiency syndromes (1999) 72(5) 465-73 doi 10.1097/QAI.0000000000001028

Abstract
BACKGROUND
Human cyclophilin A (CypA) encoded by peptidyl prolyl isomerase A gene (PPIA), enhances HIV-1 replication by aiding capsid uncoating. The association of genetic variation in the PPIA regulatory region with susceptibility to HIV-1 infection, disease progression, and gene expression among black South Africans at risk for infection or infected with HIV-1 is unknown.

METHODS
We genotyped 539 participants from 2 longitudinal study cohorts of black South Africans at high risk for infection or infected with HIV-1 for PPIA regulatory single nucleotide polymorphisms by polymerase chain reaction-restriction fragment length polymorphism.

RESULTS
Minor allele (G) of SNP rs6850 (rs6850 G) significantly associated with higher viral loads (mean 4.85 versus 4.46 log copies/mL, P = 0.0006) and lower CD4 T-cell counts (mean 506 versus 557 cells/μL, P = 0.0256) during the acute phase of infection in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 cohort. Consistently, rs6850 G significantly associated with higher viral loads (mean 4.49 versus 4.01 log copies/mL, P < 0.0001) and lower CD4 T-cell counts (mean 442 versus 494 cells/μL, P = 0.0002) during the early chronic phase of infection in the CAPRISA 002 cohort; rs6850 G further associated significantly with rapid CD4 T-cell decline in the CAPRISA 002 cohort (P = 0.0481) and Sinikithemba chronic infection cohort (P = 0.0156). Interestingly, rs6850 G significantly associated with elevated CypA mRNA levels in HIV-1-positive individuals (P = 0.0061). CONCLUSIONS
These data suggest that rs6850 G enhances HIV-1 replication through upregulation of CypA expression following HIV-1 infection. The data support ongoing efforts to develop anti-HIV-1 drugs that block interaction of HIV-1 and cellular proteins.

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