Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ

We have previously shown that high human papillomavirus (HPV) 16 load in Papanicolaou smears negative for dysplasia is strongly associated with risk for carcinoma in situ (CIS) of the cervix. Here we study the amount of HPV DNA for some of the most frequent high-risk HPV types as determinants of progression to cervical CIS. Real-time PCR is used to estimate the normalized viral load of HPV 16, 18, 31, 33, 35, 39, 45, 52, 58 and 67 in 457 cases of cervical CIS and 552 matched population controls. A total of 2,747 archival Pap smears from gynecologic health examinations, collected over a period of up to 26 years, were analyzed to assess viral load during the infection history. Cervical smear samples differ widely in amount of DNA, underscoring the need for normalization of HPV load to number of cells in the sample. The risk of developing cervical CIS increases with higher viral load for most of the HPV types studied. The range of copy numbers per cell does not differ between HPV types but the odds ratio for CIS in the percentile with highest viral load is substantially higher for HPV 16 (OR = 36.9; 95% CI = 8.9-153.2) than for HPV 31 (OR = 3.2; 95% CI = 1.1-9.1) or HPV 18/45 (OR = 2.6; 95% CI = 1.0-6.4). Therefore, HPV viral load may be predictive of future risk of cervical CIS at a stage when smears are negative for squamous abnormalities, but differences between HPV types need closer attention.     

Clearance of human papillomavirus infection after successful conization in patients with cervical intraepithelial neoplasia

The natural history of high‐risk human papillomavirus (HRHPV) infection after successful treatment of cervical intraepithelial neoplasia (CIN) is not well known. This study was performed to evaluate the rate and pattern of HRHPV infection clearance after successful conization for CIN and to analyze factors associated with such clearance. A total of 287 patients who underwent loop electrosurgical excision procedures (LEEP) owing to HRHPV‐associated CIN were included. All patients had negative resection margins on LEEP specimens and underwent HPV testing with the hybrid capture II system at 3‐, 6‐, 9‐, 12‐, 18‐ and 24‐month follow‐up visits after LEEP. Persistent HPV infections were detected in 45.6%, 14.3%, 6.3%, 2.2%, 1.5% and 1.1% of patients at 3, 6, 9, 12, 18 and 24 months after LEEP, respectively. Clearance rates did not differ by age, parity or severity of cervical lesion. However, clearance rates were significantly slower in patients with HPV DNA loads >500 RLU/PC before LEEP (p = 0.040). During 2 years of follow‐up after LEEP, 24 patients had recurrent disease revealed by biopsy. The odds ratios for recurrent disease in patients with persistent HRHPV infection increased gradually from 5.17 at the 3‐month follow‐up visit to 12.54, 15.69 and 25.90 at 6‐, 9‐, 12‐ and 24‐month follow‐up visits, respectively. We conclude that HRHPV infection cleared gradually in most patients within 6 months of treatment. Clearance rates were significantly slower in patients with HPV DNA loads >500 RLU/PC. Persistent HPV infection was a significant positive predictor of recurrence.     

Experience with high-risk human papillomavirus testing on vaginal brush-based self-samples of non-attendees of the cervical screening program

We evaluated the effect of offering brush-based vaginal self-sampling for high-risk human papillomavirus (hrHPV) testing to non-attendees of the cervical screening program on response rate, compliance to follow-up and cervical intraepithelial neoplasia grade 2 or 3 (CIN2+/CIN3+) yield. In addition, concordance of hrHPV test results between physician-taken cervical scrapes and vaginal self-samples was determined. A total of 26,409 nonattending women were randomly assigned to receive a vaginal brush device for hrHPV testing by Hybrid Capture-2 method (i.e., self-sampling group, n = 26,145) or a reinvitation for regular cytology-based screening (i.e., recall control group, n = 264). hrHPV-positive self-sampling responders were invited for a physician-taken scrape for cytology and blinded hrHPV testing. If cytology was abnormal, women were referred for colposcopy. Response rate in the self-sampling group was significantly increased compared to the recall control group (30.8% versus 6.5%; p < 0.001). The concordance rate between hrHPV detection in self-samples and corresponding physician-taken cervical scrape samples was 68.8%. Amongst women with CIN3+ and CIN2+, the concordance rates in hrHPV positivity between both samples were 95.5% and 93.8%, respectively. Adherence at baseline to cytology triage of hrHPV-positive self-sampling women (89.1%) and colposcopy referral of those with abnormal cytology (95.8%) was high. The CIN2+/CIN3+/carcinoma yields were 1.5%, 1.0% and 0.1%, respectively, in self-sampling responders. In conclusion, offering hrHPV testing on self-sampled vaginal material with a brush device to non-attendees significantly increases the attendance to the regular screening program, yields hrHPV test results that are in very good concordance with those of physician-taken scrapes in women with CIN2+/CIN3+, and is effective in detecting CIN2+/CIN3+.     

山东青岛地区宫颈癌组织中ＨＰＶ１６型Ｅ６和Ｅ２基因突变分析

目的　通过分析山东青岛地区宫颈组织中ＨＰＶ１６型Ｅ６和Ｅ２基因突变情况,探讨其与该地区宫颈癌的关系。方法　从１０４例青岛地区宫颈疾病组织中提取ＤＮＡ作为模板,采用聚合酶链式反应（ＰＣＲ）技术筛选出高危型ＨＰＶ及ＨＰＶ１６阳性标本,扩增出ＨＰＶ１６型Ｅ６、Ｅ２全长基因,ＰＣＲ产物纯化后测序,与德国ＨＰＶ标准株进行比对分析。结果　宫颈组织中高危型ＨＰＶ阳性率为９３.２７％（９７／１０４）,ＨＰＶ１６阳性率为６９.２３％（７２／１０４）。ＨＰＶ１６阳性标本中扩增出Ｅ６基因３７例,有５例与标准株序列相同,３２例存在突变,其中２５例突变型别为Ｔ１７８Ｇ或Ｔ１７８Ａ（Ｄ２５Ｅ）。在Ｅ２基因全序列测序中,２３例均存在Ｃ３６８４Ａ（Ｔ-Ｋ）,１４例同时存在Ｔ３５２４Ｃ、Ｃ３６８４Ａ（Ｔ-Ｋ）和Ｃ３７８７Ａ（Ｄ-Ｅ）,９例同时存在Ａ２９２６Ｇ、Ｃ３１５９Ａ（Ｔ-Ｋ）、Ｇ３２４９Ａ（Ｒ-Ｑ）、Ｔ３３８４Ｃ（Ｉ-T）、Ｃ３４１０Ｔ（Ｐ-Ｓ）和Ｃ３６８４Ａ（Ｔ-Ｋ）。结论　山东青岛地区宫颈癌患者ＨＰＶ１６型Ｅ６、Ｅ２基因与德国标准株比较存在多处变异,Ｅ６与Ｅ２基因突变可能存在相关性。     

Etiologic role of human papillomavirus infection in bladder carcinoma

BACKGROUND:

The authors elucidated an etiologic role of human papillomavirus (HPV) infection in carcinoma of the bladder.

METHODS:

One hundred seventeen of 224 patients with bladder carcinoma who were treated between 1997 and 2009 were enrolled in this study. The presence of HPV DNA was tested on frozen carcinoma tissues that were obtained by transurethral resection using a polymerases chain reaction‐based method. Localization of HPV was observed on archival tissue specimens by in situ hybridization (ISH) for high‐risk HPV DNA. Cyclin‐dependent kinase (CDK) inhibitor 2A (inhibits CDK4) (p16‐INK4a) and minichromosome maintenance protein‐7 (mcm‐7)—surrogate markers for high‐risk HPV‐E7 oncoprotein—and HPV‐L1 (capsid) protein expression were evaluated by immunohistochemistry.

RESULTS:

HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6‐45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2‐17.0) were associated with HPV infection. ISH analysis indicated that high‐risk HPV DNA was localized in the nuclei of tumor cells of all HPV‐positive samples. p16‐INK4a and mcm‐7 were expressed in 94% and 89% of HPV‐positive carcinoma cells, respectively. HPV‐L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma.

CONCLUSIONS:

The current results indicated that high‐risk HPV is likely to be a causative agent of some low‐grade bladder carcinomas that develop in younger patients. Cancer 2011. © 2010 American Cancer Society.     

Molecular alterations associated with cyclin D1 overexpression in endometrial cancer

Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification. In addition, Ras, PTEN and beta-catenin appear to modulate cyclin D1 levels. Since the causes of cyclin D1 overexpression are poorly understood in EC, we investigated whether or not this alteration is due to cyclin D1 gene amplification or to RAS, PTEN and beta-catenin mutation. We analyzed cyclin D1 expression in 18 AEHs, 65 EECs and 27 NEECs by immunohistochemistry as well as CCND1 gene amplification by FISH. In EECs, mutations in K-RAS, PTEN, beta-catenin and CCND1 were studied by PCR-SSCP and sequencing and MSI was evaluated by analyzing BAT-25 and BAT-26 microsatellites. Contingency tests were used to evaluate the relationships between variables. Cyclin D1 overexpression was not observed in AEHs but was present in 13.8% of EECs and 11.2% of NEECs (p = 0.031). CCND1 amplification was more frequent in NEECs (26.3%) than in EECs (2.1%) (p = 0.002). In EECs, cyclin D1 overexpression was not associated with mutations in K-RAS, PTEN or beta-catenin. However, in EECs with beta-catenin mutations, cyclin D1 was expressed mainly by cells expressing beta-catenin in the cytoplasm and nucleus but not in those with membranous expression. Finally, cyclin D1 overexpression was associated with MSI (p = 0.047). The molecular alterations associated with cyclin D1 overexpression differ in the 2 clinicopathologic types of EC. Cyclin D1 overexpression is associated with gene amplification in NEECs and with nucleocytoplasmic expression of beta-catenin and MSI in EECs.     

Incidence of cervical precancerous lesions and cervical cancer in Denmark from 2000 to 2019: Population impact of multi-cohort vaccination against human papillomavirus infection

In Denmark, vaccination against human papillomavirus (HPV) has been implemented in the children's vaccination program (January 2009) and in multiple catch-up cohorts (October 2008 in girls 13-15 years and in August 2012 in women up to 27 years). In the present study we estimate incidence of cervical intraepithelial neoplasia grade 3 (CIN3), adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma (AC) during 2000-2019. All cases of CIN3 and AIS were identified from the nationwide Pathology Data Bank, while SCC and AC were identified from the Danish Cancer Registry. We calculated age-standardized incidence rates and estimated annual percentage change (EAPC) with corresponding 95% confidence interval (CI) for the periods before vaccination implementation (2000-2005), early after implementation of childhood HPV vaccination and the first catch-up vaccination program (2006-2012), and after implementation of the second catch-up program (2013-2019). For CIN3 and AIS, age-specific incidence rates and EAPCs were calculated. An increasing age-standardized incidence was observed before introduction of HPV vaccination (2000-2005) for CIN3 [EAPC_CIN3: 3.0 (95% CI 1.7 to 4.3)] and AIS [EAPC_AIS: 3.5 (95% CI 0.7 to 6.4)]. In the most recent period (2013-2019), following implementation of the second catch-up program, a decrease was observed for both CIN3 [EAPC_CIN3: -6.5 (95% CI -8.3 to −4.8)], AIS [EAPC_AIS: -8.7 (95% CI -12.3 to −5.1)] and for SCC [EAPC_SCC: -3.9 (95% CI -7.5 to −0.2)]. In this study we document a decrease in the incidence of CIN3, AIS and SCC in the period after implementation of multi-cohort HPV vaccination in Denmark.     

Cyclin D1 amplification in chromosomal band 11q13 is associated with overrepresentation of 3q21-q29 in head and neck carcinomas

Eight cytogenetically characterized head and neck squamous cell carcinomas (HNSCCs) with CCND1 amplification in the form of a homogeneously staining region (hsr) in 11q13 were studied by COBRA FISH and FISH with specific probes to identify and characterize chromosomal segments added to the derivative chromosomes 11. In 4 of the tumors, it could be recognized that the material added was derived from the long arm of chromosome 3. The rearrangements were interpreted as der(11)hsr(11)(q13)t(3;11)(q21;q13) in 3 cases and as der(11)hsr(11)(q13)t(3;11)(q14;q13) in 1 case. In the other 4 cases, material from chromosomes 1, 16, or 19 was added to the derivative chromosomes 11. By further FISH analysis with 14 YAC clones spanning 3q13-q21 in the 4 tumors with der(11)hsr(11)t(3;11), it could be shown that they had different breakpoints at the molecular level, excluding the possibility that a particular gene was rearranged by the translocations. More surprisingly, gain of the 3q21-q29 segment was found in all 8 tumors with hsr in 11q13 and loss of 3p was seen in 7 of the tumors. These findings strongly indicate a synergistic effect of CCND1 amplification, loss of distal 11q, 3q gain and 3p deletion in HNSCC development and also suggests a mechanistic link between intrachromosomal amplification at 11q13 and recombination with distal 3q.     

宫颈癌患者人乳头瘤病毒感染分布特点

目的:探讨人乳头瘤病毒(HPV)各亚型在广西沿海地区宫颈癌患者中的分布情况,HPV感染与宫颈癌患者的年龄、临床分期、病理类型、分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发的关系。方法:通过凯普导流杂交HPV DNA检测法,对76例宫颈癌患者宫颈脱落细胞进行21种HPV亚型的检测。结果:宫颈癌HPV总阳性率为90.8%。宫颈癌患者HPV阳性各亚型出现的频率排序为:HPV16(56.5%),HPV18、33、58各(7.2%),HPV52、53各(5.8%),HPV31(4.3%),HPV45(2.9%),HPV35、51、56、66、68各(1.4%)。HPV6(5.8%),HPV11、44、43各(1.4%)均合并在高危感染中。HPV感染与临床分期、肿瘤分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发关联无显著性(P>0.05),与年龄密切相关,鳞癌HPV阳性率明显高于腺癌及其它癌,差异有统计学意义(P<0.05)。结论:广西沿海地区妇女宫颈癌患者中以HPV16、18、33、58感染为主要型别。HPV感染与宫颈癌的临床分期、肿瘤分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发无明显相关性,与发病年龄、病理类型有关。     

宫颈癌患者人乳头瘤病毒感染分布特点

目的：探讨人乳头瘤病毒（HPV）各亚型在广西沿海地区宫颈癌患者中的分布情况,HPV感染与宫颈癌患者的年龄、临床分期、病理类型、分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发的关系。方法：通过凯普导流杂交HPV DNA检测法,对76例宫颈癌患者宫颈脱落细胞进行21种HPV亚型的检测。结果：宫颈癌HPV总阳性率为90.8%。宫颈癌患者HPV阳性各亚型出现的频率排序为：HPV16（56.5%）,HPV18、33、58各（7.2%）,HPV52、53各（5.8%）,HPV31（4.3%）,HPV45（2.9%）,HPV35、51、56、66、68各（1.4%）。HPV6（5.8%）,HPV11、44、43各（1.4%）均合并在高危感染中。HPV感染与临床分期、肿瘤分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发关联无显著性（P〉0.05）,与年龄密切相关,鳞癌HPV阳性率明显高于腺癌及其它癌,差异有统计学意义（P〈0.05）。结论：广西沿海地区妇女宫颈癌患者中以HPV16、18、33、58感染为主要型别。HPV感染与宫颈癌的临床分期、肿瘤分化程度、肿瘤盆腔淋巴结转移及肿瘤的复发无明显相关性,与发病年龄、病理类型有关。     

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk

BACKGROUND:

Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community‐based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia.

METHODS:

Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real‐time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations.

RESULTS:

There was a significant association between HLA‐DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0‐25.2). After adjustment for age and viral load at study entry, haplotype HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7‐105.9). HLA‐DRB1*0403 allele was also associated with a significantly increased risk of high‐grade squamous intraepithelial lesion or cancer, showing a multivariate‐adjusted hazard ratio (95% CI) of 18.1 (2.6‐128.5).

CONCLUSIONS:

HLA‐DRB1*0403 allele and HLA‐DRB1*0405‐DQA1*0301‐DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk. Cancer 2012;. © 2011 American Cancer Society.     

Prevalence of genotype‐specific human papillomavirus infection and cervical neoplasia in Taiwan: A community‐based survey of 10,602 women

Human papillomavirus (HPV) causes cervical neoplasia; but limited data are available from Asia. We conducted a large‐scale community‐based cohort study in Taiwan to estimate prevalence of genotype‐specific HPV infection and cervical neoplasia. Following written informed consent, cervical cells for cytology and HPV testing were collected from 11,923 participants (aged 30–65 years old, mean 46.3) in 1991–1992. Genotyping was performed using MY11/GP6+ PCR‐based HPV Blot (EasyChip) for 39 HPV types. The overall HPV prevalence was 16.2% for 10,602 eligible participants, and 13.8% for 10,190 cytologically normal participants. The most common carcinogenic types were HPV52 (2.5%), HPV16 (2.0%), HPV56 (1.8%), HPV18 (1.6%), HPV33 (1.2%), HPV58 (1.3%) and HPV39 (1.0%). Among the 56 prevalent invasive and in situ cases, HPV16 (48.2%) was most common, followed by HPV58 (25.0%), HPV52 (19.6%), HPV31 (8.9%), HPV33 (8.9%) and HPV18 (3.6%). HPV16 and HPV58 caused cytological HSIL+ at younger ages than HPV52. Approximately half of the cervical cancer cases and high‐grade precursors in Taiwan could be prevented by prophylactic vaccines against HPV16 and HPV18 infection. Up to 40% more could be prevented by targeting HPV58, HPV52, HPV33 and HPV31, arguing for the introduction of vaccines including more types.     

Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women

To test the reliability of the Hybrid Capture II (HC-II) assay detecting 13 high-risk human papillomavirus (HR-HPV) types for the screening of cervical lesions, we monitored by cytology, HR-HPV testing, colposcopy and biopsy, 3,091 women with normal smears at the first entry. Our primary endpoint was clinical progression defined as the presence of a high-grade lesion (HGSIL) at the biopsy. In our population of 659 HR-HPV-infected women, 241 (36.6%) had a positive HR-HPV test at 2 to 4 examinations with a final histological diagnosis of HGSIL in 51 cases (21.2%) within 4 to 36 months, while women with regressive HPV infection did not develop any lesion during the same period. In the cohort of 2,432 women testing negative for HR-HPV infection, only 2 women (0.08%) developed a HGSIL. Both were HR-HPV positive 18 and 24 months after the first entry, at the time of diagnosis of disease. The RR of incident HGSIL when a HR-HPV was detected at enrollment in women with normal smears was 96.7 (95% CI, 95.8-97.7). The RR increased to 237.3 (95% CI, 222.8-251.8) when the HR-HPV test remained positive at 2 controls, and to 314.3 (95% CI, 260.7-367.9) when the HR-HPV test was positive at 3 controls. The evaluation of the viral load of HR-HPV by the HC-II did not represent a sensitive approach to predict the recurrence of HR-HPV infection and/or the apparition of HGSIL. Nevertheless, a recurrent HR-HPV infection detected with HC-II represents a reliable tool to select populations at risk for the development of HGSIL.     

Effects of exposure to polycyclic aromatic hydrocarbons combined with high-risk human papillomavirus infection on cervical intraepithelial neoplasia: A population study in Shanxi Province,China

High-risk human papillomavirus (HR-HPV) infection is a major etiological agent in the progression of cervical intraepithelial neoplasia (CIN) and cervical cancer. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic pollutants that exist widely in the environment. We hypothesized that PAHs exposure was related to the progression of cervical cancer, and could increase the effect of HR-HPV on CIN. We investigated the effects of PAHs exposure combined with HR-HPV infection on CIN in community population in Shanxi Province, China. A total of 2,285 women were enrolled into the study. HR-HPV genotypes were detected by flow-through hybridization technology. 1-hydroxypyrene (1-OHP) was detected by high-performance liquid chromatography. The top three HR-HPV genotypes were 16, 58 and 52 in turn. With unconditional logistic regression analysis, we found that HR-HPV infection (adjusted odds ratio [aOR] = 4.08, 95% confidence interval [CI]: 3.00–5.54), HPV16 infection (aOR = 4.71, 95% CI: 3.39–6.53), HPV58 infection (aOR = 2.29, 95% CI: 1.41–3.73) and PAHs high exposure (aOR = 2.57, 95% CI: 1.82–3.62) increased the risk of CIN2/3, showing an increasing trend (p < 0.001) with the severity of cervical lesions. Compared to Q1 (<0.06 μmol/molCr) levels of 1-OHP, women with Q4 (>0.11 μmol/molCr) had a higher risk for CIN2/3 (aOR = 7.68, 95% CI: 4.83–12.22). Additionally, we observed that there was a synergic effect between high exposure to PAHs and HR-HPV infection in CIN2/3. Furthermore, the results from the generalized multifactor dimensionality reduction model showed that there were joint interactions of PAHs, HPV16, HPV58 and HPV52 on the risk of CIN2/3. Our study revealed that high exposure to PAHs could increase the risk for CIN, and it posed stronger risk when combined with HR-HPV infection.     

Circulating human papillomavirus type 16 specific T-cells are associated with HLA Class I expression on tumor cells, but not related to the amount of viral oncogene transcripts

Human papillomavirus (HPV) is a necessary factor in the pathogenesis of cervical cancer. Circulating HPV-specific T-cells responding to the E6 and E7 HPV proteins can be detected only in half of cervical cancer patients. Potential explanations for the absence of this response are lack of sufficient amounts of antigen to activate the immune response or local immune escape mechanisms. We studied the relationship between HPV 16 E6/E7 oncogene mRNA expression, human leukocyte antigen (HLA) expression on tumor cells and the presence of circulating E6- and E7-specific T-cell responses in cervical cancer patients. The amount of antigen was assessed by HPV E6/E7 mRNA expression levels measured by quantitative polymerase chain reaction. HLA Class I and Class II expression on tumor cells was analyzed by immunohistochemistry. A proliferative HPV-specific T-cell response was detected in 15/29 patients. The amount of HPV E6/E7 mRNA was not related to the presence of immune response. HLA Class I expression was downregulated in 19 patients and completely lost in 7 patients. HLA Class II expression was upregulated in 18 patients. HLA Class I expression on tumor cells showed a strong correlation with immunity (p = 0.001). Explicitly, all patients with complete HLA loss lacked HPV specific T-cell responses. The presence of circulating HPV-specific T-cells might reflect ongoing antitumor response that is sustained by CD8+ T-cells killing HLA Class I positive cancer cells. We hypothesize that HLA Class I expression status on tumor cells might as well influence the response to HPV E6/E7 directed immunotherapy.     

Selective suppression of monocyte chemoattractant protein-1 expression by human papillomavirus E6 and E7 oncoproteins in human cervical epithelial and epidermal cells

Infection of cervical keratinocytes by high-risk HPV is involved in the etiology of cervical carcinoma. Since viral products are immunogenic, development of cancer may require suppression of immune responses directed against infected epithelial cells. Many markers of host immune effector responses decrease as cervical intraepithelial neoplasia progresses. Among these is epithelial cell expression of the chemokine MCP-1, though the mechanism for its suppression is unclear. Here, we show that the E6 and E7 viral oncogenes from high-risk HPV, individually and together, suppress MCP-1 expression in primary epithelial cells derived from the female genital tract. This is not a consequence of global suppression of chemokine expression since other chemokines, including IP-10, IL-8 and RANTES, were less affected. Furthermore, 4 of 6 HPV-positive cervical carcinoma cell lines did not express MCP-1. Our data indicate that suppression of MCP-1 expression is part of the program of high-risk HPV E6/E7-induced transformation of primary epithelial cells. These observations are consistent with a model in which MCP-1 expression by infected keratinocytes, which would stimulate an immune attack on HPV-transformed cells, is suppressed for invasive cervical cancer to appear.