Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2007 Sep 12;2(9):e893. doi: 10.1371/journal.pone.0000893.
The human APOBEC3G protein is an innate anti-viral factor that can dominantly inhibit the replication of some endogenous and exogenous retroviruses. The prospects of purposefully harnessing such an anti-viral defense are under investigation. Here, long-term co-culture experiments were used to show that porcine endogenous retrovirus (PERV) transmission from pig to human cells is reduced to nearly undetectable levels by expressing human APOBEC3G in virus-producing pig kidney cells. Inhibition occurred by a deamination-independent mechanism, likely after particle production but before the virus could immortalize by integration into human genomic DNA. PERV inhibition did not require the DNA cytosine deaminase activity of APOBEC3G and, correspondingly, APOBEC3G-attributable hypermutations were not detected. In contrast, over-expression of the sole endogenous APOBEC3 protein of pigs failed to interfere significantly with PERV transmission. Together, these data constitute the first proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. These studies suggest that human APOBEC3G-transgenic pigs will provide safer, PERV-less xenotransplantation resources and that analogous cross-species APOBEC3-dependent restriction strategies may be useful for thwarting other endogenous as well as exogenous retrovirus infections.
人类 APOBEC3G 蛋白是一种先天抗病毒因子，可显著抑制某些内源性和外源性逆转录病毒的复制。目前正在研究有目的地利用这种抗病毒防御机制的前景。在这里，通过在产生病毒的猪肾细胞中表达人 APOBEC3G，长期共培养实验表明，猪内源性逆转录病毒（PERV）从猪向人细胞的传播减少到几乎无法检测的水平。抑制作用是通过一种非脱氨酶依赖的机制发生的，可能发生在颗粒产生后但病毒整合到人类基因组 DNA 之前，从而使病毒永生化之前。APOBEC3G 的 DNA 胞嘧啶脱氨酶活性不需要 PERV 抑制，并且相应地，未检测到 APOBEC3G 归因的超突变。相比之下，猪唯一的内源性 APOBEC3 蛋白的过表达未能显著干扰 PERV 的传播。总之，这些数据首次证明 APOBEC3 蛋白可用于增强细胞的先天抗病毒防御能力，以防止内源性逆转录病毒的人畜共患病传播。这些研究表明，人 APOBEC3G 转基因猪将提供更安全、无 PERV 的异种移植资源，并且类似的跨物种 APOBEC3 依赖性限制策略可能对阻止其他内源性和外源性逆转录病毒感染有用。
