Reddy Kavidha, Ooms Marcel, Letko Michael, Garrett Nigel, Simon Viviana, Ndung'u Thumbi
aKwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH) bHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa cDepartment of Microbiology and Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, USA dCentre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa eRagon Institute of MGH, MIT and Harvard University, Cambridge, Massachusetts, USA fMax Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany. *Kavidha Reddy and Marcel Ooms contributed equally to this work.
AIDS. 2016 Jul 17;30(11):1723-9. doi: 10.1097/QAD.0000000000001113.
The human cytidine deaminase APOBEC3G (A3G) potently restricts HIV-1 but the virus, in turn, expresses a Vif protein which degrades A3G. A natural A3G-H186R variant, common in African populations, has been associated with a more rapid AIDS disease progression, but the underlying mechanism remains unknown. We hypothesized that differences in HIV-1 Vif activity towards A3G wild type and A3G-H186R contribute to the distinct clinical AIDS manifestation.
Vif variants were cloned from plasma samples of 26 South African HIV-1 subtype C infected patients, which either express wild type A3G or A3G-H186R. The Vif alleles were assessed for their ability to counteract A3G variants using western blot and single-cycle infectivity assays.
We obtained a total of 392 Vif sequences which displayed an amino acid sequence difference of 6.2-19.2% between patients. The intrapatient Vif diversities from patient groups A3G, A3G and A3G were similar. Vif variants obtained from patients expressing A3G and A3G were capable of counteracting both A3G variants with similar efficiency. However, the antiviral activity of A3G-H186R was significantly reduced in both the presence and absence of Vif, indicating that the A3G-H186R variant intrinsically exerts less antiviral activity.
A3G wild type and A3G-H186R are equally susceptible to counteraction by Vif, regardless of whether the Vif variant was obtained from A3G and A3G patients. However, the A3G-H186R variant intrinsically displayed lower antiviral activity, which could explain the higher plasma viral loads and accelerated disease progression reported for patients expressing A3G.
人类胞苷脱氨酶载脂蛋白B mRNA编辑酶催化多肽样蛋白3G（APOBEC3G，A3G）可有效限制HIV-1，但该病毒反过来会表达一种可降解A3G的Vif蛋白。一种在非洲人群中常见的天然A3G-H186R变体与艾滋病疾病进展更快有关，但其潜在机制仍不清楚。我们推测HIV-1 Vif对A3G野生型和A3G-H186R活性的差异导致了不同的临床艾滋病表现。
从26例感染HIV-1 C亚型的南非患者的血浆样本中克隆Vif变体，这些患者要么表达野生型A3G，要么表达A3G-H186R。使用蛋白质免疫印迹法和单循环感染性试验评估Vif等位基因对抗A3G变体的能力。
我们共获得392个Vif序列，患者之间的氨基酸序列差异为6.2%-19.2%。A3G、A3G和A3G患者组的患者体内Vif多样性相似。从表达A3G和A3G的患者中获得的Vif变体能够以相似的效率对抗两种A3G变体。然而，无论有无Vif，A3G-H186R的抗病毒活性均显著降低，这表明A3G-H186R变体本身的抗病毒活性较低。
无论Vif变体是从A3G和A3G患者中获得的，A3G野生型和A3G-H186R对Vif的对抗作用同样敏感。然而，A3G-H186R变体本身的抗病毒活性较低，这可以解释表达A3G的患者血浆病毒载量较高和疾病进展加速的原因。
