Rulli Samuel J, Mirro Jane, Hill Shawn A, Lloyd Patricia, Gorelick Robert J, Coffin John M, Derse David, Rein Alan
HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, MD 12702-1201, USA.
J Virol. 2008 Jul;82(13):6566-75. doi: 10.1128/JVI.01357-07. Epub 2008 Apr 30.
APOBEC3 proteins are cytidine deaminases which help defend cells against retroviral infections. One antiviral mechanism involves deaminating dC residues in minus-strand DNA during reverse transcription, resulting in G-to-A mutations in the coding strand. We investigated the effects of mouse APOBEC3 (mA3) and human APOBEC3G (hA3G) upon Moloney murine leukemia virus (MLV). We find that mA3 inactivates MLV but is significantly less effective against MLV than is hA3G. In contrast, mA3 is as potent against human immunodeficiency virus type 1 (HIV-1, lacking the protective Vif protein) as is hA3G. The two APOBEC3 proteins are packaged to similar extents in MLV particles. Dose-response profiles imply that a single APOBEC3 molecule (or oligomer) is sufficient to inactivate an MLV particle. The inactivation of MLV by mA3 and hA3G is accompanied by relatively small reductions in the amount of viral DNA in infected cells. Although hA3G induces significant levels of G-to-A mutations in both MLV and HIV DNAs, and mA3 induces these mutations in HIV DNA, no such mutations were detected in DNA synthesized by MLV inactivated by mA3. Thus, MLV has apparently evolved to partially resist the antiviral effects of mA3 and to totally resist the ability of mA3 to induce G-to-A mutation in viral DNA. Unlike the resistance of HIV-1 and human T-cell leukemia virus type 1 to hA3G, the resistance of MLV to mA3 is not mediated by the exclusion of APOBEC from the virus particle. The nature of its resistance and the mechanism of inactivation of MLV by mA3 are completely unknown.
载脂蛋白B mRNA编辑酶催化多肽样蛋白3（APOBEC3）家族蛋白是胞苷脱氨酶，可帮助细胞抵御逆转录病毒感染。一种抗病毒机制是在逆转录过程中使负链DNA中的胞嘧啶（dC）残基脱氨，导致编码链上发生G到A的突变。我们研究了小鼠APOBEC3（mA3）和人类APOBEC3G（hA3G）对莫洛尼氏鼠白血病病毒（MLV）的影响。我们发现mA3可使MLV失活，但对MLV的作用明显弱于hA3G。相比之下，mA3对1型人类免疫缺陷病毒（HIV-1，缺乏保护性的Vif蛋白）的作用与hA3G相当。两种APOBEC3蛋白在MLV颗粒中的包装程度相似。剂量反应曲线表明，单个APOBEC3分子（或寡聚体）足以使一个MLV颗粒失活。mA3和hA3G使MLV失活的同时，受感染细胞中病毒DNA的量仅有相对较小的减少。尽管hA3G可在MLV和HIV DNA中诱导产生高水平的G到A突变，mA3可在HIV DNA中诱导此类突变，但在被mA3失活的MLV合成的DNA中未检测到此类突变。因此，MLV显然已经进化到能够部分抵抗mA3的抗病毒作用，并完全抵抗mA3诱导病毒DNA发生G到A突变的能力。与HIV-1和1型人类T细胞白血病病毒对hA3G的抗性不同，MLV对mA3的抗性不是通过将APOBEC排除在病毒颗粒之外介导的。其抗性的本质以及mA3使MLV失活的机制完全未知。
