University of Saskatchewan, Biochemistry, Microbiology, and Immunology, College of Medicine, Saskatoon, Saskatchewan, Canada.
University of Saskatchewan, Department of Medicine, College of Medicine, Saskatoon, Saskatchewan Canada; Saskatchewan Infectious Disease Care Network, Saskatoon, Saskatchewan, Canada; Saskatchewan HIV/AIDS Research Endeavour, Saskatoon, Saskatchewan, Canada.
Virology. 2019 Jan 15;527:21-31. doi: 10.1016/j.virol.2018.11.004. Epub 2018 Nov 15.
The APOBEC3 enzyme family are host restriction factors that induce mutagenesis of HIV-1 proviral genomes through the deamination of cytosine to form uracil in nascent single-stranded (-)DNA. HIV-1 suppresses APOBEC3 activity through the HIV-1 protein Vif that induces APOBEC3 degradation. Here we compared two common polymorphisms of APOBEC3F. We found that although both polymorphisms have HIV-1 restriction activity, APOBEC3F 108 A/231V can restrict HIV-1 ΔVif up to 4-fold more than APOBEC3F 108 S/231I and is partially protected from Vif-mediated degradation. This resulted from higher levels of steady state expression of APOBEC3F 108 A/231 V. Individuals are commonly heterozygous for the APOBEC3F polymorphisms and these polymorphisms formed in cells, independent of RNA, hetero-oligomers between each other and with APOBEC3G. Hetero-oligomerization with APOBEC3F 108 A/231V resulted in partial stabilization of APOBEC3F 108 S/231I and APOBEC3G in the presence of Vif. These data demonstrate functional outcomes of APOBEC3 polymorphisms and hetero-oligomerization that affect HIV-1 restriction.
APOBEC3 酶家族是宿主限制因子，通过将胞嘧啶脱氨形成新生单链 (-)DNA 中的尿嘧啶，诱导 HIV-1 前病毒基因组的突变。HIV-1 通过 HIV-1 蛋白 Vif 抑制 APOBEC3 活性，诱导 APOBEC3 降解。在这里，我们比较了 APOBEC3F 的两种常见多态性。我们发现，尽管这两种多态性都具有 HIV-1 限制活性，但 APOBEC3F 108A/231V 可以将 HIV-1 ΔVif 限制多达 4 倍，比 APOBEC3F 108S/231I 更有效，并且部分免受 Vif 介导的降解。这是由于 APOBEC3F 108A/231V 的稳定状态表达水平更高。个体通常对 APOBEC3F 多态性呈杂合状态，这些多态性在细胞中形成，彼此之间以及与 APOBEC3G 之间无需 RNA 即可形成异源寡聚体。与 APOBEC3F 108A/231V 的异源寡聚化导致 Vif 存在时 APOBEC3F 108S/231I 和 APOBEC3G 的部分稳定。这些数据表明 APOBEC3 多态性和异源寡聚化的功能后果影响 HIV-1 的限制。
