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Identification and characterisation of novel potential phospho-acceptor sites in HPV-16 E7 hpv - 16e7新型潜在磷酸化受体位点的鉴定和表征
IF 4.3 Q1 VIROLOGY Pub Date : 2023-09-01 DOI: 10.1016/j.tvr.2023.200270
Oscar Trejo-Cerro , Justyna Broniarczyk , Nezka Kavcic , Michael Myers , Lawrence Banks

Several studies have described functional regulation of high-risk human papillomaviruses (HPVs), E6 and E7 oncoproteins via posttranslational modifications (PTMs). However, how these PTMs modulate the activity of E6 and E7, particularly in their targeting of cellular proteins, is not completely understood. In this study, we show that HPV16 E7 can be phosphorylated by casein kinase I (CKI) and glycogen synthase kinase 3 (GSK3). This principal phosphorylation occurs at threonine residues 5 and 7 with a more minor role for residues 19–20 in the N-terminal region of 16 E7. Intriguingly, whilst mutational analyses suggest that residues 5 and 7 may be dispensable for the transformation of primary baby rat kidney cells by E7, intact residues 19 and 20 are required. Furthermore, negative charges at these residues (TT19-20DD) enhance the pRb-E7 interaction and cells display increased proliferation and invasion capacities. Using a proteomic approach with a phosphorylated peptide spanning the TT19-20 region of HPV16 E7, we have identified a panel of new, phospho-specific E7 interacting partners. These results shed new light on the complexity of N-terminal phosphorylation of E7 and how this can contribute towards expanding the repertoire of E7 targeted pathways.

一些研究描述了通过翻译后修饰(PTM)对高危人乳头瘤病毒(HPV)、E6和E7癌蛋白的功能调节。然而,这些PTM如何调节E6和E7的活性,特别是在其靶向细胞蛋白方面,尚不完全清楚。在本研究中,我们发现HPV16E7可以被酪蛋白激酶I(CKI)和糖原合成酶激酶3(GSK3)磷酸化。这种主要的磷酸化发生在苏氨酸残基5和7,而在16E7的N-末端区域中,残基19-20的作用较小。有趣的是,虽然突变分析表明残基5和7对于E7转化原代幼鼠肾细胞可能是可有可无的,但需要完整的残基19和20。此外,这些残基上的负电荷(TT19-20DD)增强了pRb-E7的相互作用,细胞表现出增加的增殖和侵袭能力。使用跨越HPV16 E7 TT19-20区域的磷酸化肽的蛋白质组学方法,我们已经鉴定了一组新的磷酸特异性E7相互作用伴侣。这些结果为E7 N端磷酸化的复杂性以及这如何有助于扩大E7靶向途径的范围提供了新的线索。
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引用次数: 0
Association of two genomic variants with HPV type-specific risk of cervical cancer 两种基因组变异与宫颈癌症HPV类型特异性风险的相关性
IF 4.3 Q1 VIROLOGY Pub Date : 2023-07-25 DOI: 10.1016/j.tvr.2023.200269
Finja Seifert , Rieke Eisenblätter , Julia Beckmann , Peter Schürmann , Patricia Hanel , Matthias Jentschke , Gerd Böhmer , Hans-Georg Strauß , Christine Hirchenhain , Monika Schmidmayr , Florian Müller , Peter Fasching , Alexander Luyten , Norman Häfner , Matthias Dürst , Ingo B. Runnebaum , Peter Hillemanns , Thilo Dörk , Dhanya Ramachandran

Problem

Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18.

Methods

We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues.

Results

rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03–1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18–7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels.

Conclusions

We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.

在大多数患者中,人乳头瘤病毒感染是发展侵袭性宫颈癌症不可或缺的因素。在最近的一项全基因组关联研究中,rs9357152和rs4243652分别与HPV16或HPV18的血清阳性有关。目前尚不清楚这些变异是否也与由HPV16或HPV18引发的癌症相关。方法在一项基因病例对照研究中,我们研究了这两种HPV易感性变异是否与类型特异性癌症相关,该研究分别以HPV16和HPV18为分层病例。我们进一步测试了rs9357152是否调节256个宫颈组织中人类白细胞抗原基因座36个基因中任何一个的基因表达。结果rs9357152与侵袭性HPV16阳性宫颈癌症相关(OR 1.33,95%CI 1.03-1.70,p=0.03),rs4243652与HPV18阳性腺癌相关(OR 2.96,95%CI 1.18-7.41,p=0.02)。rs9357152被发现是HPV阳性宫颈组织中HLA-DRB1的eQTL(pANOVA=0.00009),具有降低mRNA水平的风险等位基因。结论我们发现6号和14号染色体上的HPV血清阳性变异可能调节类型特异性宫颈癌症风险。rs9357152可能通过在存在HPV的情况下调节HLA-DRB1的诱导来发挥其作用。就多重测试而言,这些结果需要在更大规模的研究中得到证实。
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引用次数: 0
The human Papillomavirus twilight zone – Latency, immune control and subclinical infection 人乳头瘤病毒的潜伏期、免疫控制和亚临床感染
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-23 DOI: 10.1016/j.tvr.2023.200268
John Doorbar

The incorporation of HPV DNA testing into cervical screening programs has shown that many HPV-positive women are cytologically normal, with HPV-positivity fluctuating throughout life. Such results suggest that papillomaviruses may persist in a latent state after disease clearance, with sporadic recurrence. It appears that virus latency represents a narrow slot in a wider spectrum of subclinical and possibly productive infections. Clinical studies, and animal model infection studies, suggested a key role for host immune surveillance in maintaining such asymptomatic infections, and although infections may also be cleared, most studies have used the term ‘clearance’ to describe a situation where the presence of HPV DNA falls below the clinical detection level. Given our knowledge of papillomavirus immune evasion strategies and the restricted pattern of viral gene expression required for ‘basal cell’ persistence, the term ‘apparent clearance’ and ‘subclinical persistence’ of infection may better summarise our understanding. Subclinical infection also encompasses the lag phase, which occurs between infection and lesion development. This is dependent on infection titre, with multifocal infections developing more rapidly to disease. These concepts can usefully influence patient management where HPV-positivity occurs sometime after the onset of sexual activity, and where vertical transmission is suspected despite a lag period.

将HPV DNA检测纳入宫颈筛查计划表明,许多HPV阳性女性在细胞学上是正常的,HPV阳性在一生中都在波动。这些结果表明,乳头瘤病毒可能在疾病清除后以潜伏状态持续存在,并伴有散发性复发。病毒潜伏时间似乎代表了更广泛的亚临床和可能的生产性感染中的一个狭窄时段。临床研究和动物模型感染研究表明,宿主免疫监测在维持这种无症状感染方面发挥着关键作用,尽管感染也可能被清除,但大多数研究都使用“清除”一词来描述HPV DNA的存在低于临床检测水平的情况。鉴于我们对乳头瘤病毒免疫逃避策略的了解,以及“基础细胞”持续性所需的病毒基因表达的受限模式,感染的“明显清除”和“亚临床持续性”一词可能会更好地总结我们的理解。亚临床感染也包括滞后期,发生在感染和病变发展之间。这取决于感染滴度,多灶性感染发展得更快。这些概念可以有效地影响患者管理,其中HPV阳性发生在性活动开始后的某个时候,并且尽管有一段滞后期,但仍怀疑垂直传播。
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引用次数: 2
Is immunotherapy a potential game changer in managing human papillomavirus (HPV) infection and intraepithelial neoplasia? 免疫疗法是治疗人乳头瘤病毒(HPV)感染和上皮内瘤变的潜在改变者吗?
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-07 DOI: 10.1016/j.tvr.2023.200263
Peter L. Stern

The International Papillomavirus Conference was held in Washington DC in April 2023 and encompassed wide ranging basic, clinical and public health research relating to animal and human papillomaviruses. This editorial is a personal reflection, it does not attempt to be comprehensive and reports on some key aspects centred on the prospects for immune interventions in prevention and treatment of HPV infections and early precancers with a focus on cervical neoplasia. There is optimism for the future impact of immunotherapy in treating early HPV associated disease. This will depend on developing an appropriate design of vaccines and delivery vehicles which then need to be properly tested in clinical trials that are able to measure a useful clinical endpoint. Thereafter vaccines (prophylactic or therapeutic) still need global access and sufficient uptake to deliver impact and a key and necessary driver is education.

国际乳头瘤病毒大会于2023年4月在华盛顿特区举行,涵盖了与动物和人乳头瘤病毒相关的广泛基础、临床和公共卫生研究。这篇社论是个人的反思,并不试图全面,它报道了一些关键方面,重点是免疫干预在预防和治疗HPV感染和早期癌前病变方面的前景,重点是宫颈肿瘤。人们对免疫疗法在治疗早期HPV相关疾病方面的未来影响持乐观态度。这将取决于开发合适的疫苗和递送载体设计,然后需要在能够测量有用临床终点的临床试验中对其进行适当测试。此后,疫苗(预防性或治疗性)仍然需要全球获得和足够的吸收才能产生影响,教育是一个关键和必要的驱动因素。
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引用次数: 0
Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus zeste同源物2增强子不依赖甲基转移酶的功能维持人致癌乳头瘤病毒和多瘤病毒诱导的致瘤性
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-07 DOI: 10.1016/j.tvr.2023.200264
Michelle Khattri , Yutaka Amako , Julia R. Gibbs , Joseph L. Collura , Reety Arora , Alexis Harold , Meng Yen Li , Paul W. Harms , Elena Ezhkova , Masahiro Shuda

Merkel cell polyomavirus (MCV) and high-risk human papillomavirus (HPV) are human tumor viruses that cause Merkel cell carcinoma (MCC) and oropharyngeal squamous cell carcinoma (OSCC), respectively. HPV E7 and MCV large T (LT) oncoproteins target the retinoblastoma tumor suppressor protein (pRb) through the conserved LxCxE motif. We identified enhancer of zeste homolog 2 (EZH2) as a common host oncoprotein activated by both viral oncoproteins through the pRb binding motif. EZH2 is a catalytic subunit of the polycomb 2 (PRC2) complex that trimethylates histone H3 at lysine 27 (H3K27me3). In MCC tissues EZH2 was highly expressed, irrespective of MCV status. Loss-of-function studies revealed that viral HPV E6/E7 and T antigen expression are required for Ezh2 mRNA expression and that EZH2 is essential for HPV(+)OSCC and MCV(+)MCC cell growth. Furthermore, EZH2 protein degraders reduced cell viability efficiently and rapidly in HPV(+)OSCC and MCV(+)MCC cells, whereas EZH2 histone methyltransferase inhibitors did not affect cell proliferation or viability within the same treatment period. These results suggest that a methyltransferase-independent function of EZH2 contributes to tumorigenesis downstream of two viral oncoproteins, and that direct targeting of EZH2 protein expression could be a promising strategy for the inhibition of tumor growth in HPV(+)OSCC and MCV(+)MCC patients.

Merkel细胞多瘤病毒(MCV)和高危型人乳头瘤病毒(HPV)是分别导致Merkel细胞癌(MCC)和口咽鳞状细胞癌(OSCC)的人类肿瘤病毒。HPV E7和MCV大T(LT)癌蛋白通过保守的LxCxE基序靶向视网膜母细胞瘤肿瘤抑制蛋白(pRb)。我们鉴定了皮同源物2增强子(EZH2)是一种常见的宿主癌蛋白,通过pRb结合基序被两种病毒癌蛋白激活。EZH2是多梳2(PRC2)复合物的催化亚基,其在赖氨酸27(H3K27me3)处对组蛋白H3进行三甲基化。在MCC组织中,EZH2高度表达,与MCV状态无关。功能丧失研究表明,病毒性HPV E6/E7和T抗原表达是Ezh2mRNA表达所必需的,并且Ezh2对HPV(+)OSCC和MCV(+)MCC细胞生长是必需的。此外,在HPV(+)OSCC和MCV(+)MCC细胞中,EZH2蛋白降解物有效且快速地降低了细胞活力,而EZH2组蛋白甲基转移酶抑制剂在同一治疗期内不影响细胞增殖或活力。这些结果表明,EZH2的甲基转移酶非依赖性功能有助于两种病毒癌蛋白下游的肿瘤发生,并且直接靶向EZH2蛋白表达可能是抑制HPV(+)OSCC和MCV(+)MCC患者肿瘤生长的一种有前途的策略。
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引用次数: 1
Diversity of cervicovaginal human papillomavirus (HPV) genotypes and naturally occurring E6/E7 DNA polymorphisms of HPV-16 in Ghana 加纳宫颈阴道人乳头瘤病毒(HPV)基因型的多样性和自然发生的HPV-16 E6/E7 DNA多态性
IF 4.3 Q1 VIROLOGY Pub Date : 2023-06-01 DOI: 10.1016/j.tvr.2023.200261
Gladys Kaba , Andrew Stevenson , Samuel Asamoah Sakyi , Thomas Okpoti Konney , Ramya Bhatia , Nicholas A. Titiloye , Samuel A. Oppong , Francis Agyemang-Yeboah , Kate Cuschieri , Sheila V. Graham

Human papillomavirus (HPV) E6 and E7 oncogene expression is essential for cervical carcinogenesis. Evidence exists that E6/E7 variants may have different transforming activities while the risk of HPV-16 variants (A/D) differs by race/ethnicity. We determined the type-specific diversity of HPV infection in women with high grade cervical disease or cervical cancer in Ghana and investigated naturally occurring E6/E7 DNA variants in this population. HPV genotyping was carried out on 207 cervical swab samples collected from women referred to a gynaecology clinic at two teaching hospitals in Ghana. HPV-16, HPV-18 and HPV-45 were detected in 41.9%, 23.3% and 16.3% of cases respectively. HPV-16 E6/E7 DNA sequencing was performed in 36 samples. Thirty samples contained E6/E7 variants of the HPV-16-B/C lineage. 21/36 samples were of the HPV-16C1 sublineage variant and all contained the E7 A647G(N29S) single nucleotide polymorphism (SNP). This study reveals the diversity of E6/E7 DNA and the dominance of HPV16 B/C variants in cervicovaginal HPV infection in Ghana. Type-specific HPV diversity analysis indicates that most Ghanaian cervical disease cases are vaccine preventable. The study provides an important baseline from which for the impact of vaccine and antivirals on clinically relevant HPV infection and associated disease can be measured.

人乳头瘤病毒E6和E7癌基因的表达对宫颈癌的发生至关重要。有证据表明,E6/E7变体可能具有不同的转化活性,而HPV-16变体(A/D)的风险因种族/民族而异。我们确定了加纳患有高级别宫颈病或癌症的女性HPV感染的类型特异性多样性,并调查了该人群中自然发生的E6/E7 DNA变异。对加纳两家教学医院妇科诊所的207名女性的宫颈拭子样本进行了HPV基因分型。HPV-16、HPV-18和HPV-45的检出率分别为41.9%、23.3%和16.3%。对36个样本进行了HPV-16 E6/E7 DNA测序。30个样本含有HPV-16-B/C谱系的E6/E7变体。21/36份样本为HPV-16C1亚系变异株,均含有E7 A647G(N29S)单核苷酸多态性(SNP)。本研究揭示了E6/E7 DNA的多样性和HPV16 B/C变体在加纳宫颈阴道HPV感染中的优势。类型特异性HPV多样性分析表明,大多数加纳宫颈疾病病例都可以通过疫苗预防。该研究为疫苗和抗病毒药物对临床相关HPV感染和相关疾病的影响提供了一个重要的基线。
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引用次数: 0
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
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Tumour Virus Research
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