Madlala Paradise, Singh Ravesh, An Ping, Werner Lise, Mlisana Koleka, Abdool Karim Salim S, Winkler Cheryl A, Ndungʼu Thumbi
*HIV Pathogenesis Programme, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; ‡Centre for the AIDS Programme of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; †Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD; and §KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
J Acquir Immune Defic Syndr. 2016 Aug 15;72(5):465-73. doi: 10.1097/QAI.0000000000001028.
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.
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.
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).
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.
由肽基脯氨酰异构酶A基因（PPIA）编码的人亲环素A（CypA）通过辅助衣壳解聚来增强HIV-1复制。PPIA调控区域的基因变异与南非有感染风险或感染了HIV-1的黑人中HIV-1感染易感性、疾病进展及基因表达之间的关联尚不清楚。
我们通过聚合酶链反应-限制性片段长度多态性对来自南非两个有感染风险或感染了HIV-1的黑人纵向研究队列的539名参与者进行PPIA调控单核苷酸多态性基因分型。
在南非艾滋病研究项目中心（CAPRISA）002队列中，单核苷酸多态性rs6850的次要等位基因（G）（rs6850 G）与感染急性期更高的病毒载量（平均4.85对4.46 log拷贝/mL，P = 0.0006）及更低的CD4 T细胞计数（平均506对557个细胞/μL，P = 0.0256）显著相关。同样，在CAPRISA 002队列感染早期慢性期，rs6850 G与更高的病毒载量（平均4.49对4.01 log拷贝/mL，P < 0.0001）及更低的CD4 T细胞计数（平均442对494个细胞/μL，P = 0.0002）显著相关；在CAPRISA 002队列（P = 0.0481）和Sinikithemba慢性感染队列（P = 0.0156）中，rs6850 G还与CD4 T细胞的快速下降显著相关。有趣的是，在HIV-1阳性个体中，rs6850 G与CypA mRNA水平升高显著相关（P = ）。
这些数据表明，rs6850 G通过在HIV-1感染后上调CypA表达来增强HIV-1复制。这些数据支持了正在进行的开发阻断HIV-1与细胞蛋白相互作用的抗HIV-1药物的努力。 （注：原文中“P = 0.0061”处的“）”疑似多余，译文保留原文状态）
