Molecular mechanisms of HPV mediated neoplastic progression

Abstract Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets

Screening of novel inhibitors targeting Human Papillomavirus 16 E6/AP/P53 ternary complex towards development of therapeutic strategies against HPV-mediated oncogenesis

Cervical cancer is the fourth most common cancer in women worldwide. It is well known that high-risk HPV is the main etiological agent for this infectious viral carcinoma. Human papillomaviruses are small (50 nm) double-stranded DNA viruses composed of a genome of 8 kilobase pair, enclosed inside a non-enveloped capsid protein. The genome includes three portions: (a) early genes (E1, E2, E4, E5, E6, E7) those regulate the vegetative and productive phase of viral life cycle; (b) late genes (L1, L2) which encode the capsid protein and (c) a noncoding regulatory region called long control region (LCR) involved in the regulation of viral replication and transcription. The HPV oncoproteins E6 and E7 recognize numerous host proteins, in large part by hijacking cellular domain-motif interaction networks. E6 and E7 oncoproteins disrupt cell cycle checkpoint control by inhibiting CDKs inhibitors (P21, P27) and degrading P53. In the process of E6 mediated degradation, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP3. Subsequently, the E6/E6AP heterodimer recruits and degrades p53. The LxxLL peptide of E6AP is sufficient to render E6 liable to interact with p53 ‘core’ (DNA binding) domain of p53 required for the interaction with E6/E6AP9–11. In the present study, we explored specific novel inhibitors targeting three different druggable pocket i.e., E6-binding cleft, LxxLL pocket of AP and the p53-binding cleft of E6/E6AP/p53 ternary complex using AutoDock tool. A total of five novel compounds with higher binding energy were identified as potential competitive inhibitors against HPV16 E6/AP/P53 ternary complex. The combinatorial strategies targeting these druggable pockets are expected to open up better avenues for the development of therapeutic strategies against HPV-mediated oncogenesis in near future

HPV Genotypes distribution in Indian women with and without cervical carcinoma: Implication for HPV vaccination program in Odisha, Eastern India

Abstract Background Considering the limited cross protection offered by the current HPV vaccines, understanding the HPV genotype distribution among the different population is essential in predicting the efficacy of current vaccine and devising new vaccine strategy. The present work aimed at investigating the HPV genotypes distribution among women with and without cervical carcinoma in Odisha, Eastern India. Methods A total of 607 participants have been enrolled between January 2014 and June 2016. L1-PCR, sequencing, and E6/E7 nested multiplex type- specific PCR were performed for HPV detection and genotyping. Cytological distribution of 440 cases includes invasive cervical carcinoma or ICC ( n \u2009=\u2009210), inflammatory smear ( n \u2009=\u2009162), normal cytology ( n \u2009=\u200968). Statistical analyses were performed by using SPSS version 20.0 software and MediCal version 14.10.2(7). A p -value of\u2009\u2264\u20090.05 was considered statistically significant. Results The overall prevalence of HPV infection was (359/595) 60.33%. Prevalence of HPV infection was 93.80% (197/210) in invasive cervical cancer (ICC) cases, 54.32% (88/162) in inflammatory smear and 19.11% (13/68) in normal cervical cytology. The most prevalent genotype was HPV16 (87.28%) followed by HPV18 (24.56%) and HPV 51(3.46%). The overall prevalence of single type was 76.58% and highest (78.9%) among ICC cases. The most frequent genotype combination after HPV16\u2009+\u200918(9.4%) was HPV16\u2009+\u200966\u2009+\u200968(2.7%) which was frequently observed in inflammatory cytology. Age\u2009>\u200945years, parity \u22653, low socio-economic condition, rural residential area and post menopause state were significantly associated with HPV infection. Multiple infections did not have a significant association with any of the clinicopathological variables (stage, LN metastasis, cell type) except tumor size\u2009\u2265\u20092cm in ICC cases. The impact of 2v, 4v, and 9v vaccines in preventing cervical cancer in Odisha were 89.99, 91.65, and 92.16% respectively. Conclusion This data would help planning an appropriate strategy for disease monitoring and provides baseline data for post-vaccination surveillance in the region. The nonavalent vaccine would be significant in preventing cervical carcinoma in Odisha. Hence an effective vaccination program based on regional HPV epidemiological profile along with the cervical cancer screening is necessary to reduce the cervical cancer burden in India

HPV genotypes co-infections associated with cervical carcinoma: Special focus on phylogenetically related and non-vaccine targeted genotypes.

HPV is the major causative agent for cervical cancer. Study on the risk of cervical cancer associated with different hr-HPV genotypes would be useful for disease management and new vaccine strategy. With limited reports available, the present study aimed to investigate the pattern of HPV genotypes coinfections and risk of cervical carcinoma associated with them in Indian population. 15 HPV genotypes were detected by E6/E7 multiplex nested type-specific PCR in the HPV-positive cervical samples of 172 cervical cancer cases and 174 subjects with normal cytology. Association between the genotypes and cervical cancer was estimated by calculating the Odds ratio and 95% confidence interval. Risk of cervical carcinoma was associated with multiple genotypes excluding HPV16 (OR:5.87; 95% CI-1.28-26-29; p = .02), multiple genotypes excluding HPV18 (OR = 2.5; 95% CI = 1.09-6.05; p = .03), multiple genotypes of α9 species(OR = 5.3 95% CI = 1.14-24.03; p = .007), and multiple genotypes of α7 species (OR = 2.5; 95% CI = .49-13.45; p = .2). Genotypes not targeted by quadrivalent vaccine types (OR = 2.94 95% CI = 1.48-5.80; p = .001) conferred 2.94 fold higher risk of cervical carcinoma. Cases those coinfected with phylogenetically related genotypes (OR = 2.29; 95% CI(.69-7.59) p = .17) were at 2.9 fold higher risk of invasive cervical carcinoma than those infected with other genotypes although it is not statistically significant. Whereas phylogenetically unrelated genotypes coinfection is negatively associated with cervical carcinoma (OR = .44 95% CI (.244-.8) p = .007) and it is statistically significant.Genotypes not targeted by 9-valent vaccines (OR = .40; 95% CI = .19-.85; p = .017) associated with lesser risk of cervical carcinoma as compared to other genotypes. Subjects infected with any HPV genotype/genotypes excluding HPV16 in association with HPV 18 (OR = 4.1; 95% CI = 1.81-9.25 P = < .001) were at 4.1 fold higher risk of developing invasive cervical carcinoma.In conclusion, the risk of development of cervical cancer is genotype specific and might be associated with type-specific interactions between the genotypes in multiple infections

Distribution of cases infected with different species of HPV genotypes.

<p>Distribution of cases infected with different species of HPV genotypes.</p

Enrollment of cases and outcomes.

<p>Enrollment of cases and outcomes.</p

Association of multiple infections with the risk of cervical cancer.

<p>Association of multiple infections with the risk of cervical cancer.</p

Distribution of HPV genotypes as single and coinfection in different phylogenetic groups.

<p>Distribution of HPV genotypes as single and coinfection in different phylogenetic groups.</p

Demographic factors associated with cervical carcinoma.

<p>Demographic factors associated with cervical carcinoma.</p