来自具有不同民族和来源的KSHV相关疾病患者的Kaposi肉瘤疱疹病毒（KSHV）基因组测序显示多重感染、新型多态性以及低的宿主内变异性

Sequencing of Kaposi's Sarcoma Herpesvirus (KSHV) genomes from persons of diverse ethnicities and provenances with KSHV-associated diseases demonstrate multiple infections, novel polymorphisms, and low intra-host variance

PLoS Pathogens

影响因子:4.9

分区:医学1区 Top / 微生物学1区寄生虫学1区病毒学1区

发表日期:2024 Jul

作者: Vickie A Marshall, Elena M Cornejo Castro, Charles A Goodman, Nazzarena Labo, Isabella Liu, Nicholas C Fisher, Kyle N Moore, Ananthakrishnan Nair, Taina Immonen, Brandon F Keele, Mark N Polizzotto, Thomas S Uldrick, Yunxiang Mu, Tanuja Saswat, Laurie T Krug, Kevin M McBride, Kathryn Lurain, Ramya Ramaswami, Robert Yarchoan, Denise Whitby

DOI: 10.1371/journal.ppat.1012338

摘要

最近发表的一份来自喀麦隆卡波西肉瘤病例对照研究的近全长KSHV基因组显示出病毒重组和混合感染的强烈证据，但未发现与疾病相关的序列变异。采用相同方法，还测序了来自76名KSHV相关疾病患者的102个额外的KSHV基因组。诊断涵盖所有KSHV相关疾病（KAD）：卡波西肉瘤（KS）、原发性渗出淋巴瘤（PEL）、KSHV相关的大细胞淋巴瘤（KSHV-LCL）、多中心Castleman病的一种类型（KSHV-MCD）以及KSHV炎性细胞因子综合征（KICS）。参与者来自22个不同国家，为获得多样化的KSHV基因组的近全长新序列提供了可能性。这些包括KSHV K1亚型A、B、C、F以及之前没有完整序列的E亚型的基因组。观察到高度重组的现象。14名个体（18%）显示出感染多种KSHV变异株的证据（从两个到四个独特的基因组）。对从不同采样部位（包括PBMC、组织活检、口腔液体和积液）获得的序列的26次比对发现不同生物空间中的基因组几乎完全保守。在编码区和非编码区中均发现多态性，包括在K3和K15基因中的插入/缺失（indels）以及首次报道的序列倒置。其中一个在KSHV ORF46中的多态性特异于KSHV K1亚型E2，编码一个突变，导致尿嘧啶DNA糖苷酶的亮氨酸环延长区发生变化，影响该蛋白的生化功能。这一发现证实了KSHV序列变异可能具有功能性后果，值得进一步研究。本研究是迄今为止在KAD患者中对KSHV基因组序列进行的最大、最具多样性的分析，为全球KSHV基因组学提供了重要的新信息。

Abstract

Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics.