Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity
Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity
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DOI：
10.1016/j.celrep.2019.10.007
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发表时间：
2019-11-05
期刊：
影响因子：
8.8
通讯作者：
Brockman, Mark A.
中科院分区：
文献类型：
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作者：
Jin, Steven W.;Alsahafi, Nirmin;Brockman, Mark A.
HIV-1 Nef通过抵消宿主限制因子SERINC 5增强病毒粒子的感染性;然而，天然Nef多态性对该功能的影响在很大程度上是未知的。我们描述了91个HIV-1亚型B nef等位基因的SERINC 5下调活性，包括45个精英控制者和46个慢性进展者的分离株。与进展者衍生的克隆（中值96%活性）相比，控制者衍生的Nef克隆显示出较低的下调SERINC 5的能力（中值80%活性）（p = 0.0005）。我们鉴定了18种与差异功能相关的Nef多态性，包括两种导致SERINC 5下调的CTL逃逸突变：由HLA-B*08驱动的K94 E和由保护性等位基因HLA-B*57驱动的H116 N。编码Nef K94 E和/或H116 N的HIV-1毒株在SERINC 5存在下显示出较低的感染性和复制能力。我们的研究结果表明，HIV-1 Nef的天然多态性可以损害其内化SERINC 5的能力，这表明最近描述的功能的变化可能有助于病毒发病机制的差异。
HIV-1 Nef enhances virion infectivity by counteracting host restriction factor SERINC5; however, the impact of natural Nef polymorphisms on this function is largely unknown. We characterize SERINC5 downregulation activity of 91 primary HIV-1 subtype B nef alleles, including isolates from 45 elite controllers and 46 chronic progressors. Controller-derived Nef clones display lower ability to downregulate SERINC5 (median 80% activity) compared with progressor-derived clones (median 96% activity) (p = 0.0005). We identify 18 Nef polymorphisms associated with differential function, including two CTL escape mutations that contribute to lower SERINC5 downregulation: K94E, driven by HLA-B*08, and H116N, driven by the protective allele HLA-B*57. HIV-1 strains encoding Nef K94E and/or H116N display lower infectivity and replication capacity in the presence of SERINC5. Our results demonstrate that natural polymorphisms in HIV-1 Nef can impair its ability to internalize SERINC5, indicating that variation in this recently described function may contribute to differences in viral pathogenesis.