Ikeda Terumasa, Yue Yuan, Shimizu Ryo, Nasser Hesham
Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Front Microbiol. 2021 Jun 15;12:686357. doi: 10.3389/fmicb.2021.686357. eCollection 2021.
The introduction of combination antiretroviral therapy (cART) has managed to control the replication of human immunodeficiency virus type 1 (HIV-1) in infected patients. However, a complete HIV-1 cure, including a functional cure for or eradication of HIV-1, has yet to be achieved because of the persistence of latent HIV-1 reservoirs in adherent patients. The primary source of these viral reservoirs is integrated proviral DNA in CD4 T cells and other non-T cells. Although a small fraction of this proviral DNA is replication-competent and contributes to viral rebound after the cessation of cART, >90% of latent viral reservoirs are replication-defective and some contain high rates of G-to-A mutations in proviral DNA. At least in part, these high rates of G-to-A mutations arise from the APOBEC3 (A3) family proteins of cytosine deaminases. A general model has shown that the HIV-1 virus infectivity factor (Vif) degrades A3 family proteins by proteasome-mediated pathways and inactivates their antiviral activities. However, Vif does not fully counteract the HIV-1 restriction activity of A3 family proteins , as indicated by observations of A3-mediated G-to-A hypermutation in the proviral DNA of HIV-1-infected patients. The frequency of A3-mediated hypermutation potentially contributes to slower HIV-1/AIDS disease progression and virus evolution including the emergence of cytotoxic T lymphocyte escape mutants. Therefore, combined with other strategies, the manipulation of A3-mediated mutagenesis may contribute to an HIV-1 functional cure aimed at cART-free remission. In this mini-review, we discuss the possibility of an HIV-1 functional cure arising from manipulation of A3 mutagenic activity.
联合抗逆转录病毒疗法（cART）的引入成功控制了1型人类免疫缺陷病毒（HIV-1）在感染患者体内的复制。然而，由于在坚持接受治疗的患者中存在潜伏的HIV-1储存库，尚未实现完全治愈HIV-1，包括功能性治愈或根除HIV-1。这些病毒储存库的主要来源是CD4 T细胞和其他非T细胞中的整合前病毒DNA。虽然这一小部分前病毒DNA具有复制能力，并在cART停止后导致病毒反弹，但>90%的潜伏病毒储存库存在复制缺陷，其中一些在原病毒DNA中含有高比例的G到A突变。这些高比例的G到A突变至少部分源于胞嘧啶脱氨酶的载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3，A3）家族蛋白。一个通用模型表明，HIV-1病毒感染性因子（Vif）通过蛋白酶体介导的途径降解A3家族蛋白，并使其抗病毒活性失活。然而，正如在HIV-1感染患者的原病毒DNA中观察到的A3介导的G到A超突变所示，Vif并不能完全抵消A3家族蛋白对HIV-1的限制活性。A3介导的超突变频率可能导致HIV-1 /艾滋病疾病进展和病毒进化变慢，包括细胞毒性T淋巴细胞逃逸突变体的出现。因此，结合其他策略，操纵A3介导的诱变可能有助于实现旨在无cART缓解的HIV-1功能性治愈。在这篇小型综述中，我们讨论了通过操纵A3诱变活性实现HIV-1功能性治愈的可能性。
