Mutational pressure by host APOBEC3s more strongly affects genes expressed early in the lytic phase of herpes simplex virus-1 (HSV-1) and human polyomavirus (HPyV) infection.
Mutational pressure by host APOBEC3s more strongly affects genes expressed early in the lytic phase of herpes simplex virus-1 (HSV-1) and human polyomavirus (HPyV) infection.
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宿主 APOBEC3 的突变压力更强烈地影响单纯疱疹病毒 1 (HSV-1) 和人多瘤病毒 (HPyV) 感染裂解期早期表达的基因。
DOI：
10.1371/journal.ppat.1009560
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发表时间：
2021-04
期刊：
影响因子：
6.7
通讯作者：
MacCarthy T
中科院分区：
文献类型：
--
作者：
Shapiro M;Krug LT;MacCarthy T
单纯疱疹病毒1型（HSV-1）在年轻时感染大多数人，有时会造成致命后果。裂解性HSV-1感染后，基因表达按时间顺序发生：立即早期（IE）基因表达，然后是早期（E）基因，然后是晚期（L）基因。在这个感染周期中，HSV-1基因组有可能暴露于APOBEC 3（A3）蛋白，这是一个胞苷脱氨酶家族，可导致单链DNA（ssDNA）上的C>U突变，通常导致C>T转换。我们开发了一个计算模型的A3的裂解周期的HSV-1的突变压力，以确定病毒动力学基因类是最容易受到A3突变。使用计算机随机方法，我们模拟了不同强度的A3突变压力下的感染周期。我们发现IE和E基因比L基因更容易受到A3的攻击。我们通过分析25个HSV-1分离株的A3进化足迹来验证该模型。我们发现IE和E基因已经进化到比L基因更不代表A3热点基序，这与IE和E基因上更大的选择压力相一致。我们将该模型扩展到两步感染，例如多瘤病毒的感染，并发现相同的模式适用于超过25种人类多瘤病毒（HPyVs）基因组。在感染过程中较早表达的基因比较晚表达的基因更容易发生突变。胞苷脱氨酶的APOBEC家族是先天免疫的组分，其可以结合病毒DNA并引起突变。我们开发了一个计算模型的裂解生命周期的单纯疱疹病毒1（HSV-1），一个大的双链DNA病毒，评估的潜在影响APOBEC上的病毒及其演变。该模型考虑了三种类型的病毒基因：立即早期（IE），早期（E）和晚期（L）。我们发现，在裂解生命周期中最早表达的基因，E，特别是IE，最容易受到APOBEC介导的突变的影响，因为即使是低水平的突变也足以破坏感染过程。我们能够通过分析已发表的HSV-1基因组来验证计算模型的预测，特别是通过使用软件工具来量化每个基因组进化的程度，以减少APOBEC偏好突变的DNA基序（也称为“突变热点”）的数量。我们的分析表明，IE和E基因已经进化为避免APOBEC 3靶向。我们将我们的建模和基因组分析扩展到人类多瘤病毒，这是一种较小的双链DNA病毒，其生命周期比HSV-1更简单，并发现了类似的结果。这些研究强调了在病毒感染早期表达的基因对APOBEC的脆弱性，并可能建议将这些基因作为治疗靶点。
Herpes-Simplex Virus 1 (HSV-1) infects most humans when they are young, sometimes with fatal consequences. Gene expression occurs in a temporal order upon lytic HSV-1 infection: immediate early (IE) genes are expressed, then early (E) genes, followed by late (L) genes. During this infection cycle, the HSV-1 genome has the potential for exposure to APOBEC3 (A3) proteins, a family of cytidine deaminases that cause C>U mutations on single-stranded DNA (ssDNA), often resulting in a C>T transition. We developed a computational model for the mutational pressure of A3 on the lytic cycle of HSV-1 to determine which viral kinetic gene class is most vulnerable to A3 mutations. Using in silico stochastic methods, we simulated the infectious cycle under varying intensities of A3 mutational pressure. We found that the IE and E genes are more vulnerable to A3 than L genes. We validated this model by analyzing the A3 evolutionary footprints in 25 HSV-1 isolates. We find that IE and E genes have evolved to underrepresent A3 hotspot motifs more so than L genes, consistent with greater selection pressure on IE and E genes. We extend this model to two-step infections, such as those of polyomavirus, and find that the same pattern holds for over 25 human Polyomavirus (HPyVs) genomes. Genes expressed earlier during infection are more vulnerable to mutations than those expressed later. The APOBEC family of cytidine deaminases are a component of innate immunity that can bind to viral DNA and cause mutations. We developed a computational model of the lytic life cycle of herpes simplex virus 1 (HSV-1), a large double-stranded DNA virus, to evaluate the potential effects of APOBEC on the virus and its evolution. The model considered three types of viral genes: Immediate Early (IE), Early (E) and Late (L). We found that genes expressed earliest in the lytic life cycle, E and particularly IE, are the most vulnerable to APOBEC-mediated mutations, because even low levels of mutation were sufficient to disrupt the infection process. We were able to validate the predictions of the computational model by analyzing published HSV-1 genomes, in particular by using software tools that quantify the extent to which each genome has evolved to reduce the number of DNA motifs (also known as “mutational hotspots”) that are preferred by APOBEC for mutation. Our analysis suggested that the IE and E genes have evolved to avoid APOBEC3 targeting. We extended our modeling and genomic analysis to human Polyomaviruses, which are smaller double-stranded DNA viruses with a simpler life cycle than HSV-1 and found similar results. These studies highlight the vulnerability to APOBEC of genes expressed early during viral infection and may suggest these genes as therapeutic targets.
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影响因子：
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