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Exploring monitoring strategies for population surveillance of HPV vaccine impact using primary HPV screening 探索使用HPV初级筛查对HPV疫苗影响的人群监测策略
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200255
Louiza S. Velentzis , David Hawkes , Michael Caruana , Julia ML. Brotherton , Megan A. Smith , Lara Roeske , Khurram A. Karim , Suzanne M. Garland , C. David Wrede , Jeffery Tan , Cosette Wheeler , Philip E. Castle , Marion Saville , Karen Canfell

Australia's cervical screening program transitioned from cytology to HPV-testing with genotyping for HPV16/18 in Dec’2017. We investigated whether program data could be used to monitor HPV vaccination program impact (commenced in 2007) on HPV16/18 prevalence and compared estimates with pre-vaccination benchmark prevalence. Pre-vaccination samples (2005–2008) (n = 1933; WHINURS), from 25 to 64-year-old women had been previously analysed with Linear Array (LA). Post-vaccination samples (2013-2014) (n = 2989; Compass pilot), from 25 to 64-year-old women, were analysed by cobas 4800 (cobas), and by LA for historical comparability. Age standardised pre-vaccination HPV16/18 prevalence was 4.85% (95%CI:3.81–5.89) by LA; post-vaccination estimates were 1.67% (95%CI:1.21–2.13%) by LA, 1.49% (95%CI:1.05–1.93%) by cobas, and 1.63% (95%CI:1.17–2.08%) for cobas and LA testing of non-16/18 cobas positives (cobas/LA). Age-standardised pre-vaccination oncogenic HPV prevalence was 15.70% (95%CI:13.79–17.60%) by LA; post-vaccination estimates were 9.06% (95%CI:8.02–10.09%) by LA, 8.47% (95%CI:7.47–9.47%) by cobas and cobas/LA. Standardised rate ratios between post-vs. pre-vaccination rates were significantly different for HPV16/18, non-16/18 HPV and oncogenic HPV: 0.34 (95%CI:0.23–0.50), 0.68 (95%CI:0.55–0.84) and 0.58 (95%CI:0.48–0.69), respectively. Additional strategies (LA for all cobas positives; combined cobas and LA results on all samples) had similar results. If a single method is applied consistently, it will provide important data on relative changes in HPV prevalence following vaccination.

2017年12月,澳大利亚的宫颈筛查项目从细胞学转向HPV检测,并对HPV16/18进行基因分型。我们调查了计划数据是否可用于监测HPV疫苗接种计划(始于2007年)对HPV16/18流行率的影响,并将估计值与疫苗接种前的基准流行率进行了比较。疫苗接种前样本(2005-2008年)(n=1933;WHINURS),来自25至64岁女性,之前曾使用线性阵列(LA)进行过分析。通过cobas 4800(cobas)和LA对25至64岁女性的疫苗接种后样本(2013-2014)(n=2989;Compass试点)进行了历史可比性分析。LA的年龄标准化疫苗接种前HPV16/18患病率为4.85%(95%CI:3.81-5.89);LA的疫苗接种后估计值为1.67%(95%CI:1.21–2.13%),cobas的疫苗接种估计值为1.49%(95%CI:1.05–1.93%),cobas和LA检测非16/18 cobas阳性(cobas/LA)的疫苗接种预测值为1.63%(95%CI:1.17–2.08%)。LA的年龄标准化接种前致癌HPV患病率为15.70%(95%CI:13.79–17.60%);LA的疫苗接种后估计值为9.06%(95%CI:8.02–10.09%),cobas和cobas/LA的估计值为8.47%(95%CI:7.47–9.47%)。后与。HPV16/18、非16/18型HPV和致癌HPV的疫苗接种前率显著不同:分别为0.34(95%CI:0.23–0.50)、0.68(95%CI:0.55–0.84)和0.58(95%CI=0.48–0.69)。其他策略(所有cobas阳性的LA;所有样本的cobas和LA组合结果)具有相似的结果。如果持续应用单一方法,它将提供有关接种疫苗后HPV患病率相对变化的重要数据。
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引用次数: 0
Molecular dissection of the E6 PBM identifies essential residues regulating Chk1 phosphorylation and subsequent 14-3-3 recognition E6 PBM的分子解剖鉴定了调节Chk1磷酸化和随后的14-3-3识别的必要残基
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200257
Arushi Vats , Jayashree V. Thatte , Lawrence Banks

Previous studies have shown that the high-risk HPV E6 oncoprotein PDZ binding motifs (PBMs) can interact with PDZ proteins or members of the 14-3-3 family, depending upon the E6 phosphorylation status. However, different HPV E6 oncoproteins are subjected to phosphorylation by different cellular kinases. We have therefore been interested in determining whether we can dissect E6's PDZ and 14-3-3 interactions at the molecular level. Using HPV-18 E6, we have found that its Chk1 phosphorylation requires residues both upstream and downstream of the phospho-acceptor site, in addition to the Chk1 consensus recognition motif. Furthermore, we demonstrate that different high-risk HPV E6 types are differentially phosphorylated by Chk1 kinases, potentially due to the differences in their carboxy-terminal residues, as they are critical for kinase recognition. Moreover, differences in the E6 phosphorylation levels of different HR HPV types directly link to their ability to interact with different 14-3-3 isoforms, based on their phospho-status. Interestingly, 14-3-3 recognition appears to be less dependent upon the precise sequence constraints of the E6 carboxy terminal region, whilst minor amino acid variations have a major impact upon PDZ recognition. These results demonstrate that changes in E6 phospho-status during the life cycle or during malignant progression will modulate E6 interactions and, potentially, inversely regulate the levels of PDZ and 14-3-3 proteins.

先前的研究表明,高危HPV E6癌蛋白PDZ结合基序(PBMs)可以与PDZ蛋白或14-3-3家族成员相互作用,这取决于E6磷酸化状态。然而,不同的HPV E6癌蛋白被不同的细胞激酶磷酸化。因此,我们一直有兴趣确定我们是否可以在分子水平上剖析E6的PDZ和14-3-3相互作用。使用HPV-18 E6,我们发现其Chk1磷酸化除了Chk1共有识别基序外,还需要磷酸化受体位点上游和下游的残基。此外,我们证明了不同的高危HPV E6类型被Chk1激酶不同地磷酸化,这可能是由于其羧基末端残基的差异,因为它们对激酶识别至关重要。此外,不同HR HPV类型E6磷酸化水平的差异直接与它们基于磷酸化状态与不同14-3-3亚型相互作用的能力有关。有趣的是,14-3-3的识别似乎较少依赖于E6羧基末端区域的精确序列限制,而微小的氨基酸变异对PDZ的识别有重大影响。这些结果表明,E6磷酸化状态在生命周期或恶性进展过程中的变化将调节E6相互作用,并可能反向调节PDZ和14-3-3蛋白的水平。
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引用次数: 0
Characterization of HPV subtypes in invasive cervical cancer in Botswana patients using a pan-pathogen microarray technology 使用泛病原体微阵列技术表征博茨瓦纳患者侵袭性宫颈癌的HPV亚型
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200262
Surbhi Grover , Tyler Seckar , Le Gao , Rohini Bhatia , Xiang Lin , Nicola Zetola , Doreen Ramogola-Masire , Erle Robertson

Human papillomavirus (HPV) plays a significant role in the development of cervical cancers in the setting of co-infection with HIV. Botswana has a high prevalence of HIV and cervical cancer. In this study, we investigated the distribution of HPV subtypes in cervical cancer biopsy samples from patients in Botswana using a highly sensitive pan-pathogen microarray technology, PathoChip, to detect both high- (HR-HPV) and low-risk HPV (LR-HPV) subtypes in women living with HIV (WLWH) and women living without HIV. We analyzed samples from 168 patients, of which 73% (n = 123) were WLWH with a median CD4 count of 479.5 cells/μL. Five HR-HPV subtypes were detected in the cohort: HPV 16, 18, 26, 34, and 53. The most prevalent subtypes were HPV 26 (96%) and HPV 34 (92%); 86% of WLWH (n = 106) had co-infection with four or more HR-HPV subtypes compared to 67% (n = 30) of women without HIV (p < 0.01). We detected 66 LR-HPV subtypes among all cervical cancer patients, with HPV 6b and 48 being most prevalent. Notably, signatures for LR-HPV subtypes 10, 41, 90, and 129 were only detected in WLWH. Signal intensity for HPV 18 was significantly weaker in WLWH with CD4 levels ≤200 cells/μL as compared to patients with >200 cells/μL and HIV-negative patients. Although the majority of cervical cancer specimens in this cohort were determined to have multiple HPV infections, the most prevalent HR-HPV subtypes (HPV 26 and HPV34) found in these cervical cancer samples are not covered in the current HPV vaccines. Though no conclusions can be made on the direct carcinogenicity of these subtypes the results do underlie the need for continued screening for prevention of cervical cancer.

人乳头瘤病毒(HPV)在与HIV共同感染的情况下,在宫颈癌的发展中起着重要作用。博茨瓦纳艾滋病毒和癌症的发病率很高。在这项研究中,我们使用高度敏感的全抗原微阵列技术PathoChip,对博茨瓦纳癌症宫颈活检样本中HPV亚型的分布进行了调查,以检测艾滋病毒感染者(WLWH)和无艾滋病毒感染者中的高风险(HR-HPV)和低风险HPV(LR-HPV)亚型。我们分析了168名患者的样本,其中73%(n=123)为WLWH,CD4计数中位数为479.5个细胞/μL。在队列中检测到五种HR-HPV亚型:HPV 16、18、26、34和53。最常见的亚型是HPV 26(96%)和HPV 34(92%);86%的WLWH(n=106)与四种或四种以上的HR-HPV亚型共感染,相比之下,67%(n=30)的无HIV的妇女(p<0.01)。值得注意的是,LR-HPV亚型10、41、90和129的特征仅在WLWH中检测到。CD4水平≤200个细胞/μ;μL和HIV阴性患者。尽管该队列中的大多数癌症标本被确定为具有多种HPV感染,但在这些癌症宫颈样本中发现的最流行的HR-HPV亚型(HPV 26和HPV34)不包括在当前的HPV疫苗中。虽然还不能对这些亚型的直接致癌性做出结论,但这些结果确实是继续筛查预防宫颈癌症的必要性的基础。
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引用次数: 0
Elevated iNOS and 3′-nitrotyrosine in Kaposi's Sarcoma tumors and mouse model 卡波西肉瘤肿瘤及小鼠模型中iNOS和3′-硝基酪氨酸升高
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200259
Olga Vladimirova , Samantha Soldan , Chenhe Su , Andrew Kossenkov , Owen Ngalamika , For Yue Tso , John T. West , Charles Wood , Paul M. Lieberman

Kaposi's Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi's Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3/mSLK tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3/mSLK tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. L-NMMA treatment reduced KSHV gene expression and perturbed cellular gene pathways relating to oxidative phosphorylation and mitochondrial dysfunction. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.

卡波西肉瘤(KS)是一种由人类疱疹病毒8型(HHV8)引起的异质性多灶性血管恶性肿瘤,也称为卡波西氏肉瘤相关疱疹病毒(KSHV)。在这里,我们发现KS病变在整个KS病变中广泛表达iNOS/NOS2,在LANA阳性梭形细胞中富集。iNOS副产物3-硝基酪氨酸也在LANA阳性肿瘤细胞中富集,并与一部分LANA核体共定位。我们发现iNOS在KS的L1T3/mSLK肿瘤模型中高度表达。iNOS表达与KSHV裂解周期基因表达相关,后者在晚期肿瘤(>4周)中升高,但在早期(1周)异种移植物中升高程度较低。此外,我们发现L1T3/mSLK肿瘤生长对一氧化氮抑制剂L-NMMA敏感。L-NMMA治疗降低了KSHV基因表达,并干扰了与氧化磷酸化和线粒体功能障碍有关的细胞基因通路。这些发现表明,iNOS在KS中KSHV感染的内皮转化的肿瘤细胞中表达,iNOS的表达取决于肿瘤微环境应激条件,并且iNOS酶活性有助于KS肿瘤生长。
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引用次数: 4
Human papillomavirus genomics: Understanding carcinogenicity 人类乳头瘤病毒基因组学:了解致癌性
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200258
Chase W. Nelson , Lisa Mirabello

Human papillomavirus (HPV) causes virtually all cervical cancers and many cancers at other anatomical sites in both men and women. However, only 12 of 448 known HPV types are currently classified as carcinogens, and even the most carcinogenic type — HPV16 — only rarely leads to cancer. HPV is therefore necessary but insufficient for cervical cancer, with other contributing factors including host and viral genetics. Over the last decade, HPV whole genome sequencing has established that even fine-scale within-type HPV variation influences precancer/cancer risks, and that these risks vary by histology and host race/ethnicity. In this review, we place these findings in the context of the HPV life cycle and evolution at various levels of viral diversity: between-type, within-type, and within-host. We also discuss key concepts necessary for interpreting HPV genomic data, including features of the viral genome; events leading to carcinogenesis; the role of APOBEC3 in HPV infection and evolution; and methodologies that use deep (high-coverage) sequencing to characterize within-host variation, as opposed to relying on a single representative (consensus) sequence. Given the continued high burden of HPV-associated cancers, understanding HPV carcinogenicity remains important for better understanding, preventing, and treating cancers attributable to infection.

人乳头瘤病毒(HPV)几乎会导致男性和女性的所有宫颈癌和许多其他解剖部位的癌症。然而,在448种已知的HPV类型中,目前只有12种被归类为致癌物,即使是最致癌的类型——HPV16——也很少导致癌症。因此,HPV对于宫颈癌症是必要的,但不充分,其他因素包括宿主和病毒遗传。在过去的十年中,HPV全基因组测序已经证实,即使是n型HPV变异中的细微规模也会影响癌前/癌症风险,并且这些风险因组织学和宿主种族/民族而异。在这篇综述中,我们将这些发现放在HPV生命周期和不同病毒多样性水平的进化背景下:类型之间、类型内和宿主内。我们还讨论了解释HPV基因组数据所必需的关键概念,包括病毒基因组的特征;导致致癌的事件;APOBEC3在HPV感染和进化中的作用;以及使用深度(高覆盖率)测序来表征宿主内变异的方法,而不是依赖于单一的代表性(一致性)序列。鉴于HPV相关癌症的持续高负担,了解HPV的致癌性对于更好地理解、预防和治疗可归因于感染的癌症仍然很重要。
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引用次数: 4
Tegument proteins of Epstein-Barr virus: Diverse functions, complex networks, and oncogenesis eb病毒被膜蛋白:多种功能、复杂网络与肿瘤发生
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200260
Takayuki Murata

The tegument is the structure between the envelope and nucleocapsid of herpesvirus particles. Viral (and cellular) proteins accumulate to create the layers of the tegument. Some Epstein-Barr virus (EBV) tegument proteins are conserved widely in Herpesviridae, but others are shared only by members of the gamma-herpesvirus subfamily. As the interface to envelope and nucleocapsid, the tegument functions in virion morphogenesis and budding of the nucleocapsid during progeny production. When a virus particle enters a cell, enzymes such as kinase and deubiquitinase, and transcriptional activators are released from the virion to promote virus infection. Moreover, some EBV tegument proteins are involved in oncogenesis. Here, we summarize the roles of EBV tegument proteins, in comparison to those of other herpesviruses.

外壳是疱疹病毒颗粒的外壳和核衣壳之间的结构。病毒(和细胞)蛋白质积累形成被盖层。一些EB病毒(Epstein-Barr virus,EBV)盖蛋白在疱疹病毒科中广泛保守,但另一些仅由γ疱疹病毒亚家族成员共享。作为包膜和核衣壳的界面,盖层在子代生产过程中起到病毒粒子形态发生和核衣衣壳出芽的作用。当病毒颗粒进入细胞时,激酶和去泛素酶等酶以及转录激活剂会从病毒颗粒中释放出来,以促进病毒感染。此外,一些EB病毒外壳蛋白参与了肿瘤的发生。在这里,我们总结了EBV盖蛋白与其他疱疹病毒的作用。
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引用次数: 0
Unresolved issues in the management of human papillomavirus-associated mucosal high-grade pre-cancers 人乳头瘤病毒相关的粘膜高级别癌前病变治疗中尚未解决的问题
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2022.200250
Charles JN. Lacey

This article reviews human papillomavirus-associated mucosal high-grade pre-cancers and their management. It examines pre-cancer classification systems, the natural history of HPV-associated pre-cancers, the various types of management and treatment for HPV pre-cancers, the various mucosal site-specific considerations, and then some of the unresolved issues. Different conclusions are reached for each of the relevant mucosal sites, which are cervix, vagina, vulva, anus, penis and oro-pharynx, and indeed there are differing volumes of evidence relating to each of these sites, and thus differing degrees of certainty/uncertainty in the recommendations.

本文综述了人乳头瘤病毒相关的粘膜高级癌前病变及其治疗。它检查了癌前分类系统、与HPV相关的癌前自然史、HPV癌前的各种管理和治疗类型、各种粘膜特定部位的考虑因素,以及一些尚未解决的问题。对于每个相关的粘膜部位,即宫颈、阴道、外阴、肛门、阴茎和口咽,都得出了不同的结论,事实上,这些部位的证据量不同,因此建议的确定性/不确定性程度也不同。
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引用次数: 0
Association of PNPLA3 (rs738409) & TM6SF2 (rs58542926) and ATG16L1 (rs2241880) genetic variants with susceptibility to hepatocellular carcinoma in a group of Egyptian patients with HCV-induced liver cirrhosis PNPLA3 (rs738409)、TM6SF2 (rss58542926)和ATG16L1 (rs2241880)基因变异与埃及hcv诱导的肝硬化患者肝细胞癌易感性的关联
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200256
Asmaa Mohamed Fteah , Ali Abdel Rahim , Afaf Ahmed AbdelHady , Hanan Shawky , Mohamed A Elrefaiy , Doaa Mamdouh Aly
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引用次数: 0
The adenoviral E4orf3/4 is a regulatory polypeptide with cell transforming properties in vitro 腺病毒E4orf3/4是一种在体外具有细胞转化特性的调节多肽
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200254
Wing-Hang Ip, Luca D. Bertzbach, Thomas Speiseder, Thomas Dobner

The human adenovirus species C type 5 (HAdV-C5) early region 4 (E4) encodes several distinct polypeptides, defined as E4orf1 to E4orf6/7 according to the order and arrangement of the corresponding open reading frames (ORFs). All E4 gene products operate through a complex network of interactions with key viral and cellular regulatory proteins involved in transcription, apoptosis, cell cycle control, and DNA repair. Here, we generated a set of virus mutants carrying point mutations in the individual E4 genes. The phenotypic characterizations of these mutants revealed that mutations of these ORFs had no or only moderate effects on virus replication. Even a triple mutant that fails to produce E4orf3, E4orf4, and the yet uncharacterized alternatively spliced E4orf3/4 fusion protein, was replicating to wild type levels. The E4orf3/4 protein consists of the N-terminal 33 amino acid residues from E4orf3 and the C-terminal 28 amino acid residues from E4orf4. Intriguingly, we found that, similar to E4orf3, E4orf3/4 possesses properties that support the E1A/E1B-induced transformation of primary rodent cells. These results identify and functionally characterize E4orf3/4 and conclude that E4orf3/4 is another E4 region protein that is dispensable for virus replication but promotes the E1A/E1B-induced transformation of primary rodent cells.

人类腺病毒C型5(HAdV-C5)早期区4(E4)编码几种不同的多肽,根据相应开放阅读框(ORF)的顺序和排列,定义为E4orf1至E4orf6/7。所有E4基因产物都通过与关键病毒和细胞调节蛋白的复杂相互作用网络运作,这些蛋白涉及转录、细胞凋亡、细胞周期控制和DNA修复。在这里,我们产生了一组在单个E4基因中携带点突变的病毒突变体。这些突变体的表型特征表明,这些ORF的突变对病毒复制没有或只有中等影响。即使是一个不能产生E4orf3、E4orf4和尚未表征的选择性剪接E4orf3/4融合蛋白的三重突变体,也在复制到野生型水平。E4orf3/4蛋白由E4orf3的N端33个氨基酸残基和E4orf4的C端28个氨基酸残基组成。有趣的是,我们发现,与E4orf3类似,E4orf3/4具有支持E1A/E1B诱导的原代啮齿动物细胞转化的特性。这些结果鉴定了E4orf3/4并对其进行了功能表征,并得出结论,E4orf3%4是另一种对病毒复制可有可无的E4区蛋白,但促进了E1A/E1B诱导的原代啮齿动物细胞的转化。
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引用次数: 0
Editorial board member 编委会成员
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/S2666-6790(23)00012-5
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引用次数: 0
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Tumour Virus Research
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