Human papillomavirus infection: Epidemiology, biology, host interactions, cancer development, prevention, and therapeutics.

Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. It is caused by the HPV, a DNA virus that infects epithelial cells in various mucous membranes and skin surfaces. HPV can be categorised into high-risk and low-risk types based on their association with the development of certain cancers. High-risk HPV types, such as HPV-16 and HPV-18, are known to be oncogenic and are strongly associated with the development of cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancers. These types of HPV can persist in the body for an extended period and, in some cases, lead to the formation of precancerous lesions that may progress to cancer if left untreated. Low-risk HPV types, such as HPV-6 and HPV-11, are not typically associated with cancer but can cause benign conditions like genital warts. Genital warts are characterised by the growth of small, cauliflower-like bumps on the genital and anal areas. Although not life-threatening, they can cause discomfort and psychological distress. HPV is primarily transmitted through sexual contact, including vaginal, anal, and oral sex. It can also be transmitted through non-penetrative sexual activities that involve skin-to-skin contact. In addition to sexual transmission, vertical transmission from mother to child during childbirth is possible but relatively rare. Prevention of HPV infection includes vaccination and safe sexual practices. HPV vaccines, such as Gardasil and Cervarix, are highly effective in preventing infection with the most common high-risk HPV types. These vaccines are typically administered to adolescents and young adults before they become sexually active. Safe sexual practices, such as consistent and correct condom use and limiting the number of sexual partners, can also reduce the risk of HPV transmission. Diagnosis of HPV infection can be challenging because the infection is often asymptomatic, especially in men. In women, HPV testing can be done through cervical screening programs, which involve the collection of cervical cells for analysis. Abnormal results may lead to further diagnostic procedures, such as colposcopy or biopsy, to detect precancerous or cancerous changes. Overall, HPV infection is a prevalent sexually transmitted infection with significant implications for public health. Vaccination, regular screening, and early treatment of precancerous lesions are key strategies to reduce the burden of HPV-related diseases and their associated complications. Education and awareness about HPV and its prevention are crucial in promoting optimal sexual health. This study aimed to carry out a literature review considering several aspects involving HPV infection: Global distribution, prevalence, biology, host interactions, cancer development, prevention, therapeutics, coinfection with other viruses, coinfection with bacteria, association with head and neck squamous cell carcinomas, and association with anal cancer.

hTERT and IGF-1R Proteins Expression in Response to Treatment in Patients with HPV Alpha 9-Positive Cervical Cancer.

Human papillomavirus (HPV) infection is strongly associated with cervical cancer (CC). Genomic alterations caused by viral infection and subsequent dysregulation of cellular metabolism under hypoxic conditions could influence the response to treatment. We studied a possible influence of IGF-1Rb, hTERT, HIF1a, GLUT1 protein expression, HPV species presence and relevant clinical parameters on the response to treatment. In 21 patients, HPV infection and protein expression were detected using GP5+/GP6+PCR-RLB and immunohistochemistry, respectively. The worse response was associated with radiotherapy alone compared with chemoradiotherapy (CTX-RT), anemia and HIF1a expression. HPV16 type was the most frequent (57.1%) followed by HPV-58 (14.2%) and HPV-56 (9.5%). The HPV alpha 9 species was the most frequent (76.1%) followed by alpha 6 and alpha 7. IGF-1Rb (85.7%), HIF1a (61.9%), GLUT1 (52.3%), and hTERT expression [cytoplasm and nucleus (90.4%)] were detected. The MCA factorial map showed different relationships, standing out, expression of hTERT and alpha 9 species HPV, expression of hTERT and IGF-1Rb expression [Fisher's exact test (P = 0.04)]. A slight trend of association was observed between, GLUT1 and HIF1 a expression, hTERT and GLUT1 expression. A noteworthy finding was the subcellular localization of hTERT in the nucleus and cytoplasm of CC cells and its possible interaction with IGF-1R in presence of HPV alpha 9 species. Our findings suggest that the expression of HIF1a, hTERT, IGF-1Rb and GLUT1 proteins that interact with some HPV species may contribute to cervical cancer development, and the modu lation of treatment response.

Analysis of HPV Integrations in Mexican Pre-Tumoral Cervical Lesions Reveal Centromere-Enriched Breakpoints and Abundant Unspecific HPV Regions.

Human papillomavirus (HPV) DNA integration is a crucial event in cervical carcinogenesis. However, scarce studies have focused on studying HPV integration (HPVint) in early-stage cervical lesions. Using HPV capture followed by sequencing, we investigated HPVint in pre-tumor cervical lesions. Employing a novel pipeline, we analyzed reads containing direct evidence of the integration breakpoint. We observed multiple HPV infections in most of the samples (92%) with a median integration rate of 0.06% relative to HPV mapped reads corresponding to two or more sequence breakages. Unlike cancer studies, most integrations events were unique (supported by one read), consistent with the lack of clonal selection. Congruent to other studies, we found that breakpoints could occur, practically, in any part of the viral genome. We noted that L1 had a higher frequency of rupture integration (25%). Based on host genome integration frequencies, we found previously reported integration sites in cancer for genes like FHIT, CSMD1, and LRP1B and putatively many new ones such as those exemplified in CSMD3, ROBO2, and SETD3. Similar host integrations regions and genes were observed in diverse HPV types within many genes and even equivalent integration positions in different samples and HPV types. Interestingly, we noted an enrichment of integrations in most centromeres, suggesting a possible mechanism where HPV exploits this structural machinery to facilitate integration. Supported by previous findings, overall, our analysis provides novel information and insights about HPVint.

HPV Induces Changes in Innate Immune and Adhesion Molecule Markers in Cervical Mucosa With Potential Impact on HIV Infection.

While most HPV infections are asymptomatic and clear spontaneously, persistent infection with high-risk HPVs is associated with cervical cancer and with increased risk of HIV acquisition. Although several hypotheses have been proposed to explain this phenomenon, none has been confirmed. Our aim was to investigate the expression of host factors involved in the susceptibility to HIV infection among HPV-infected women. Cervical samples were collected to characterize the expression levels of HIV susceptibility markers in the mucosa of HPV-infected compared with HPV-uninfected women. No differences in the frequency of CCR5+, integrin α4ß7+, activated and memory CD4+ T-cell were detected between the groups. We additionally evaluated the expression levels of genes involved in innate immune responses and in cell adhesion. HPV infected patients expressed higher levels of TLR9 and lower levels of pattern recognition receptors that recognize RNA (TLR3, TLR7, and MDA5/IFIH1). We also detected an impaired IFN pathway, with an increased Type I IFN and a decreased IFNα2 receptor expression. HPV+ samples displayed reduced expression of genes for adherens and tight junctions. Taken together, these results suggest that although HPV infection does not result in the recruitment/activation of susceptible CD4+ T-cell in the female genital tract, it leads to changes in the innate antiviral immune responses and in cell adhesion that are likely to favor HIV infection.

Composite Analysis of the Virome and Bacteriome of HIV/HPV Co-Infected Women Reveals Proxies for Immunodeficiency.

The human cervical microbiome is complex, and its role in health and disease has just begun to be elucidated. In this study, 57 cervical swab samples from 19 HIV/HPV co-infected women were analyzed for both virome and bacteriome composition. Virome analysis focused on circular DNA viruses through rolling circle amplification followed by next-generation sequencing (NGS). Data were assigned to virus families and genera, and HPV types were identified. NGS data of bacterial 16S from a subset of 24 samples were assigned to operational taxonomic units and classified according to vaginal microbiome community state types (CSTs). Four viral families were found: Papillomaviridae, Anelloviridae, Genomoviridae, and Herpesviridae. Papillomavirus reads were more abundant in women with premalignant cervical lesions, which were also strongly associated with multiple (≥3) high-risk HPV infection. Anellovirus read abundance was negatively correlated with host CD4+ T-cell counts. The bacteriome revealed the presence of CST III and CST IV, and women with ≥1% frequency of genomovirus or herpesvirus reads displayed an increased risk of carrying CST IV. By characterizing the composition of the cervical circular DNA viruses and the bacteriome of HIV/HPV co-infected women, we identified putative interactions between these two microorganism communities and their associations with patients' clinical characteristics, notably immunodeficiency status.

Human Papillomavirus and Genital Disease in Men: What We Have Learned from the HIM Study.

It is currently recognized that in addition to the major impact of human papillomavirus (HPV) infection in females, HPV causes considerable disease in men at the genitals, anal canal, and oropharynx. Specifically, genital HPV infections may progress to genital warts and penile carcinoma. Although studies concerning the natural history of HPV infections and associated neoplasias have mainly focused on women, during the last 2 decades considerable attention has been given in further understanding these infections in men. The HIM (HPV infection in men) Study, the only prospective multicenter study of male HPV natural history, consisted of a large prospective international cohort study in which men from Brazil, the United States, and Mexico were enrolled. The design and protocols of this study allowed unraveling crucial information regarding the relationship between HPV infection and clinical consequences in men, and associated risk factors at each of the anatomic sites where HPV is known to cause cancer in men.

HPV-Mediated Resistance to TNF and TRAIL Is Characterized by Global Alterations in Apoptosis Regulatory Factors, Dysregulation of Death Receptors, and Induction of ROS/RNS.

Persistent infection with high-risk human papilloma virus (HR-HPV) is the main risk factor for the development of invasive cervical cancer although is not sufficient to cause cervical cancer. Several host and environmental factors play a key role in cancer initiation/progression, including cytokines and other immune-response mediators. Here, we characterized the response to the individual and combined action of the pro-inflammatory cytokines tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) on HPV-transformed cells and human keratinocytes ectopically expressing E6 and E7 early proteins from different HPV types. We showed that keratinocytes expressing HPV early proteins exhibited global alterations in the expression of proteins involved in apoptosis regulation/execution, including TNF and TRAIL receptors. Besides, we provided evidence that TNF receptor 1 (TNFR1) was down-regulated and may be retained in the cytoplasm of keratinocytes expressing HPV16 oncoproteins. Finally, fluorescence analysis demonstrated that cytokine treatment induced the production and release of reactive oxygen and nitrogen species (ROS/RNS) in cells expressing HPV oncogenes. Alterations in ROS/RNS production and apoptosis regulatory factors expression in response to inflammatory mediators may favor the accumulation of genetic alterations in HPV-infected cells. Altogether, our results suggested that these events may contribute to lesion progression and cancer onset.

Association between Human Papillomavirus and Epstein-Barr Virus Infections and Cancer of the Uterine Cervix.

Cervical cancer screening was revolutionized in the early 1980s with the discovery of human papillomaviruses (HPVs) as the single causative agent of the disease. Viral infections contribute to ~12% of cancers worldwide, and two DNA viruses, Epstein-Barr virus and HPV, are associated with 38% of all virus-associated cancers. Most viral-associated cancers develop after a long latency period (15-40 yr).

Role of Epstein-Barr Virus and Human Papillomavirus Coinfection in Oral and Anogenital Carcinogenesis: Potential Tumorigenic Pathways.

Epstein-Barr virus (EBV) and human papillomavirus (HPV) have been implicated in 38% of all virus-related cancers. Over the past three decades, both have been detected in anogenital and head-and-neck squamous cell carcinomas (HNSCC), with evidence of involvement in tumor genesis and progression. Very little has been published on HPV/EBV coinfection. In this chapter, we review the literature on the role of these viruses in oral carcinoma and draw parallels with other HNSCCs and anogenital carcinomas, with emphasis on their interplay and potential signaling pathways. EBV infection seems to create an environment that favors HPV latency, supporting the claim that EBV is a cofactor in HPV-related carcinomas. In turn, under certain circumstances, HPV appears to be able to induce EBV to switch to the latent or replicative state. The main viral oncogenes expressed in these malignancies are EBNA1, EBNA2, LMP1, EBERs, and the high-risk HPV oncogenes E6 and E7. The most well-documented human proteins involved are p53, pRb, p16INK4a, p19ARF, Myc, E-cadherin, ß-catenin, EGFR, MLH1, and COX-2. These proteins are directly associated not only with viral products but also with one another in the development of malignancy. Knowledge of the molecular machinery behind carcinomas coinfected with HPV and EBV may help understand how these viruses trigger carcinogenesis and subsidize the development of new biomarkers of tumor aggressiveness and prognosis, alternative surrogate virus markers, and possible therapeutic targets.

Methylation of p16 ink4a promoter is independent of human papillomavirus DNA physical state: a comparison between cervical pre-neoplastic and neoplastic samples

BACKGROUND Epigenetic modifications in host cells, like p16 ink4a methylation, have been considered as putative complementary mechanisms for cancer development. Because only a small proportion of infected women develop cervical cancer, other factors might be involved in carcinogenesis, either independently or in association with high-risk human papillomavirus (HR-HPV) infections, including epigenetic factors. OBJECTIVES We hypothesised that p16 ink4a methylation might have a role in cancer development driven by HPV16, mainly in the presence of intact E1/E2 genes. Thus, our objectives were to assess the status of p16 ink4a methylation and the HPV16 E1/E2 integrity in samples in different stages of cervical diseases. METHODS Presence of HPV16 was determined by E6 type-specific polymerase chain reaction (PCR). Methylation status of the p16 ink4a promoter was assessed by methylation-specific PCR in 87 cervical specimens comprising 29 low-grade (LSIL), 41 high-grade (HSIL) lesions, and 17 cervical cancers (CC). Characterisation of E1 and E2 disruption (as an indirect indicator of the presence of episomal viral DNA) was performed by PCR amplifications. FINDINGS We observed a significantly increased trend (nptrend = 0.0320) in the proportion of methylated p16 ink4a in cervical samples during cancer development. Concomitant E1 and E2 disruptions were the most frequent pattern found in all groups: CC (76%), HSIL (54%), and LSIL (73%). No statistically significant differences between p16 ink4a methylation and E1/E2 integrity, in histological groups, was observed. MAIN CONCLUSIONS There was an increase in methylation of the p16 ink4a promoter from pre-neoplastic lesions to cancer. Additionally, a high frequency of E1/E2 disruptions in LSIL/HSIL suggested that viral DNA integration was an early event in cervical disease. Moreover, the methylation status was apparently independent of HPV16 integrity.

The relationship between anogenital HPV types and incident HIV infection among men who have sex with men and transgender women in Lima, Peru: Findings from a prospective cohort study.

Although it is known that individuals living with HIV have a higher HPV prevalence, the impact of individual HPV types on HIV acquisition is less clear. In this prospective cohort study we investigated the relationship between HPV types and incident HIV infection among men who have sex with men (MSM) and transgender women (TW) in Lima, Peru. Six hundred HIV-negative Peruvian MSM and TW participated in a 2-year study with biannual visits. At baseline, participants completed a computerized, self-administered questionnaire on sexual behavior and HPV knowledge and underwent a physical exam including anogenital swabs for HPV DNA (37 genotypes via linear array testing) and HIV testing; follow-up visits included the questionnaire and HIV testing. Participant mean age was 25 years (range = 18-40), with 48.9% self-identifying as gay and 86.5% reporting having sex exclusively with men. At baseline, 530 participants had HPV DNA present (61.1% with high-risk HPV, 84.9% with low-risk HPV). Among 571 participants who returned for any study visit, 73 (12.8%) became infected with HIV during the 2-year follow-up (6% HIV incidence). Compared to those without HIV, more participants with HIV had any HPV type present (97.3% vs. 87.6%, respectively, p = .01), more than one HPV type (79.5% vs. 58.2%, p < .01), or high-risk HPV (72.6% vs. 51.4%, p < .01). Some participants lost to follow-up could have been HIV-positive, which would have affected the relationship of HPV and HIV infection. Our prospective study showed that participants with any HPV type, more than one HPV type, or high-risk HPV were more likely to test positive for HIV. Although most studies have shown HPV-HIV coinfection, our findings illustrate the strong relationship between individual HPV types and HIV infection. This further illustrates the potential utility of HPV vaccine for MSM and TW, not only for HPV prevention but also possibly for HIV prevention.

Regulation of HPV transcription.

Human papillomavirus infection is associated with the development of malignant and benign neoplasms. Approximately 40 viral types can infect the anogenital mucosa and are categorized into high- and low-risk oncogenic human papillomavirus, depending on their association with the development of cervical carcinoma. High-risk human papillomavirus 16 and 18 are detected in 55% and 15% of all invasive cervical squamous cell carcinomas worldwide, respectively. Low-risk human papillomavirus 6 and 11 are responsible for 90% of genital warts and are also associated with the development of recurrent respiratory papillomatosis. Human papillomavirus preferentially infects mitotic active cells of the basal layer from both mucosal and cutaneous epithelium through microabrasions. The viral life cycle synchronizes with the epithelial differentiation program, which may be due, in part, to the binding of differentially expressed cellular transcription factors to the long control region throughout the various epithelial layers. This review aimed to summarize the current knowledge regarding the mechanisms by which viral gene expression is regulated and the influence of human papillomavirus heterogeneity upon this phenomenon. A better understanding of the regulatory mechanisms may elucidate the particularities of human papillomavirus-associated pathogenesis and may provide new tools for antiviral therapy.

Genetic variant in CXCL12 gene raises susceptibility to HPV infection and squamous intraepithelial lesions development: a case-control study.

BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted virus in women worldwide. The persistence of the virus may cause warts that are considered benign lesions and low or high grade intraepithelial lesions (LSIL/HSIL). Immunological system plays an important role in the resolution of infections. In this context, we highlight the chemokines, which are important regulators in the development of viral infections and inflammation. Among which CXCL12 stands out, due to its pro-inflammatory features, acting as chemoattractant recruiting immune cells. Several polymorphisms were identified in CXCL12 gene including rs1801157 in the 3'-untranslated region, which is characterized by a substitution of a guanine for an adenine. METHODS: In this study, 195 women were classified as HPV non-infected and 169 as HPV-infected. HPV-DNA was detected by polymerase chain reaction (PCR) and the polymorphism was assessed in blood cells through restriction fragment length polymorphism analysis. RESULTS: HPV infection was more incident in women who had more than 4 sexual partners during lifetime (p = 0.007), among those who presented lower number of pregnancies (p = 0.017). HPV was more prevalent among allele A carriers confirmed by logistic regression analysis adjusted for several confounding factors [ORADJ = 4.985; CI95% (2.85-8.72), p < 0.001]. An association between allele A carriers and HSIL development (p = 0.003) was also observed. CONCLUSIONS: In the present study, we demonstrated that CXCL12 rs1801157 is independently associated with HPV infection and exerts influence in HSIL development, suggesting it as a promising susceptibility biomarker for HPV infection and lesions development.

Human papillomavirus and genome instability: from productive infection to cancer.

Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.

Activities of stromal and immune cells in HPV-related cancers.

The immune system is composed of immune as well as non-immune cells. As this system is a well-established component of human papillomavirus- (HPV)-related carcinogenesis, high risk human papillomavirus (hrHPV) prevents its routes and mechanisms in order to cause the persistence of infection. Among these mechanisms are those originated from stromal cells, which include the cancer-associated fibroblasts (CAFs), the myeloid-derived suppressor cells (MDSCs) and the host infected cells themselves, i.e. the keratinocytes. These types of cells play central role since they modulate immune cells activities to create a prosperous milieu for cancer development, and the knowledge how such interactions occur are essential for prognostic assessment and development of preventive and therapeutic approaches. Nevertheless, the precise mechanisms are not completely understood, and this lack of knowledge precluded the development of entirely efficient immunotherapeutic strategies for HPV-associated tumors. As a result, an intense work for attaining how host immune response works, and developing of effective therapies has been applied in the last decade. Based on this, this review aims to discuss the major mechanisms of immune and non-immune cells modulated by hrHPV and the potential and existing immunotherapies involving such mechanisms in HPV-related cancers. It is noticed that the combination of immunotherapies has been demonstrated to be essential for obtaining better results, especially because the possibility of increasing the modulating capacity of the HPV-tumor microenvironment has been shown to be central in strengthening the host immune system.

Regulation of Cellular Metabolism by High-Risk Human Papillomaviruses.

The alteration of glucose metabolism is one of the first biochemical characteristics associated with cancer cells since most of these cells increase glucose consumption and glycolytic rates even in the presence of oxygen, which has been called “aerobic glycolysis" or the Warburg effect. Human papillomavirus (HPV) is associated with approximately 5% of all human cancers worldwide, principally to cervical cancer. E6 and E7 are the main viral oncoproteins which are required to preserve the malignant phenotype. These viral proteins regulate the cell cycle through their interaction with tumor suppressor proteins p53 and pRB, respectively. Together with the viral proteins E5 and E2, E6 and E7 can favor the Warburg effect and contribute to radio- and chemoresistance through the increase in the activity of glycolytic enzymes, as well as the inhibition of the Krebs cycle and the respiratory chain. These processes lead to a fast production of ATP obtained by Warburg, which could help satisfy the high energy demands of cancer cells during proliferation. In this way HPV proteins could promote cancer hallmarks. However, it is also possible that during an early HPV infection, the Warburg effect could help in the achievement of an efficient viral replication.

Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers.

The modulation of the host innate immune system is a well-established carcinogenesis feature of several tumors, including human papillomavirus- (HPV-) related cancers. This virus is able to interrupt the initial events of the immune response, including the expression of Toll-like receptors (TLRs), cytokines, and inflammation. Both TLRs and cytokines play a central role in HPV recognition, cell maturation and differentiation as well as immune signalling. Therefore, the imbalance of this sensitive control of the immune response is a key factor for developing immunotherapies, which strengthen the host immune system to accomplish an efficient defence against HPV and HPV-infected cells. Based on this, the review is aimed at exposing the HPV immune evasion mechanisms involving TLRs and cytokines and at discussing existing and potential immunotherapeutic TLR- and cytokine-related tools.

Prevalence of human papillomavirus types in North and Central regions of Mexico.

Human papillomavirus (HPV) is a DNA virus linked to mucosal and cutaneous carcinogenesis. More than 200 different HPV types exist. We carried out a transversal study to investigate the prevalence of HPV types in two regions of Mexico. A total of 724 genital and non-genital samples from women (F) and men (M) were studied; 241 (33%) from North-Eastern (NE) and 483 (66%) from South-Central (SC) Mexico. The overall prevalence was 87%. In genital lesions from females, the NE group showed a prevalence of HPV types 16 (37%), 6 (13%), 59 (6%), 11, 18 and 66 (5.4% each); and the SC group showed types 6 (17%), 16 (15%), 11 (14.5%), 18 (12%) and 53 (6%). In the genital lesions from males, NE group showed types 16 (38%), 6 (21%), 11 (13%) and 59 plus 31 (7.5%) and the SC group showed types 6 (25%), 11 (22%), 18 (17%) and 16 (11.5%). When the two regions were compared, a higher prevalence of low-risk HPV 6 and 11 was found in the SC region and of high-risk HPV 59, 31 and 66 (the latter can also be present in benign lesions) in the NE region. Our findings complement efforts to understand HPV demographics as a prerequisite to guide and assess the impact of preventive interventions.

Tipificación viral en el seguimiento de conización: rol pronóstico de la persistencia del HPV post cono con asa / Viral typing in conization monitoring: prognostic role of HPV persistence post cone with loop

RESUMEN Fundamento: La persistencia del virus papiloma posterior a la conización del cuello uterino, se ha considerado un factor de riesgo para la persistencia de lesiones intra epiteliales (LIE) causadas por virus papiloma. Para determinar la asociación entre persistencia de lesión cervical y la presencia del virus papiloma posterior a la conización del cuello uterino, se realizó un estudio observacional prospectivo en un grupo de 123 pacientes portadoras de lesiones intraepiteliales de alto grado (LIEAG) tratadas con conización. Material y métodos: Se siguieron a 123 pacientes portadoras de LIEAG, ingresadas a la Unidad de Patología Cervical entre Abril de 2013 y Abril de 2014, las que fueron seguidas por 2 años hasta Abril de 2016. Se realizó genotipificación antes, y entre 4 a 6 meses posterior a la conización. Los datos se tabularon considerando la edad, paridad, tipo de virus, persistencia de LIE, reconización o requerimiento de histerectomía posterior. Resultados: La mediana de la edad fue de 37 años, el 91% fueron multíparas, y solo el 9% fueron nulíparas. El 56% ingresó por NIE III y el 44% por NIE II. Los virus más frecuentes fueron el 16, 31,58, 52 y 56. La persistencia de virus papiloma se constató en el 37% de las pacientes conizadas. La persistencia de LIE se observó en el 27% de las pacientes que fueron positivas para virus papiloma posterior a la conización, en comparación a sólo el 5% en las que fueron negativas. Del total de pacientes positivas para virus papiloma posterior a la conización, 12 de ellas presentaron persistencia de lesión confirmadas histológicamente por biopsia cervical, 8 pacientes requirieron recono por LIE de alto grado, 2 pacientes fueron a histerectomía y en 2 casos se realizó seguimiento estricto por NIE I. Cuando la tipificación post cono fue negativa solamente 3 pacientes requirieron conización y en sólo una se realizó seguimiento estricto por NIE I. Conclusión: La persistencia del virus papiloma posterior a la conización se asocia a mayor persistencia de LIEAG, mayor frecuencia de reconización o histerectomía posterior.

ABSTRACT Backgroud: The persistence of papilloma virus after conization of the cervix has been considered a risk factor for the persistence of cervical intra epithelial lesion (CIN) caused by papilloma virus. Aim: In order to determine the association between cervical lesion persistence and the presence of papilloma virus after conization, a prospective observational study was performed in a group of 123 patients with intraepithelial lesions treated with conization. Material and methods: We followed 123 patients with high grade CIN who were admitted to the Cervical Pathology Unit, between April 2013 and April 2014; they were followed for 2 years until April 2016. Viral genotyping was done before, and among the 4 to 6 months after the LEEP. Data were tabulated considering age, parity, type of virus, persistence of CIN, reconization or requirement of posterior hysterectomy. Results: The median age was 37 years, 91% were multiparous, and only 9% were nulliparous. 56% had NIE III and 44% NIE II. The most frequent viruses were 16, 31, 58, 52 and 56. The persistence of papillomavirus was present in 37% of patients. The persistence of CIN was observed in 27% of patients who were positive for papilloma virus after conization, compared to only 5% in those who were negative. Of the total number of patients positive for papilloma virus, in 12 of them had intra epitelial lesions were confirmed by cervical biopsy, 8 patients required recone for high grade CIN, 2 patients underwent hysterectomy, and 2 patients underwent follows up strictly by CIN I. When post cone typing was negative only 3 patients required conization and only one was followed strictly by CIN I.

Regulation of HPV transcription

Human papillomavirus infection is associated with the development of malignant and benign neoplasms. Approximately 40 viral types can infect the anogenital mucosa and are categorized into high- and low-risk oncogenic human papillomavirus, depending on their association with the development of cervical carcinoma. High-risk human papillomavirus 16 and 18 are detected in 55% and 15% of all invasive cervical squamous cell carcinomas worldwide, respectively. Low-risk human papillomavirus 6 and 11 are responsible for 90% of genital warts and are also associated with the development of recurrent respiratory papillomatosis. Human papillomavirus preferentially infects mitotic active cells of the basal layer from both mucosal and cutaneous epithelium through microabrasions. The viral life cycle synchronizes with the epithelial differentiation program, which may be due, in part, to the binding of differentially expressed cellular transcription factors to the long control region throughout the various epithelial layers. This review aimed to summarize the current knowledge regarding the mechanisms by which viral gene expression is regulated and the influence of human papillomavirus heterogeneity upon this phenomenon. A better understanding of the regulatory mechanisms may elucidate the particularities of human papillomavirus-associated pathogenesis and may provide new tools for antiviral therapy.