Immunonutrition in cervical cancer: immune response modulation by diet

ABSTRACT In the development of cervical cancer (CC), the immune response plays an essential role, from the elimination of human papillomavirus (HPV) infection to the response against the tumor. For optimal function of the immune response, various factors are required, one of the most important being an adequate nutrition. The complex interaction between nutrients and microbiota maintains the immune system in homeostasis and in case of infection, it provides the ability to fight against pathogen invasion, as occurs in HPV infection. The purpose of this article is to describe the role of diet, food, and specific nutrients in the immune response from the onset of infection to progression to precancerous lesions and CC, as well as the role of diet and nutrition during oncological treatment. The immunomodulatory role of microbiota is also discussed. A detailed analysis of the evidence leads us to recommend a nutritional pattern very similar to the Mediterranean diet or the prudent diet for an optimal immune response. Moreover, pre- and probiotics favorably modulate the microbiota and induce preventive and therapeutic effects against cancer.

Discrepancies in the evaluation of the safety of the human papillomavirus vaccine

Despite being more than ten years since its introduction, global acceptance to the human papillomavirus (HPV) vaccine is still low. The immunogenetic background of the host, and HPV antigen recognition, are important in natural HPV infection, and should be taken into account in the understanding of adverse autoimmune reactions by the HPV vaccine in certain groups. There is no doubt of the benefit of vaccines in the reduction of the incidence of infectious diseases, and in the case of HPV, the prevention of persistent infection that would lead to cervical cancer. Side-effects, however, should be closely monitored and reported without any bias, to ensure that the benefits of vaccines outweigh the risks of adverse reactions. In this article we bring the attention on certain adverse effects of the vaccine against HPV that have not been well studied as they are not well defined. We also compare the different approaches on HPV vaccine policies regarding its adverse reactions in countries like Japan and Colombia, vs. the recommendations issued by the WHO.

Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quantitative review

Recently, many studies have evaluated HPV vaccine safety and adverse effects. Two vaccine shave been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co., Inc., Whitehouse Station, NJ). We have performed a systematic review of all randomized controlled trials in which HPV vaccines were compared with placebo regarding safety, tolerability and adverse effects. Studies were searched up to March 2013 in the databases: Pubmed, Embase, Scielo and Cancerlit. Odds Ratios (OR) of most incident adverse effects were obtained. Twelve reports, involving 29,540 subjects, were included. In the HPV 16/18 group, the most frequently reported events related to the vaccine were pain (OR 3.29; 95% CI: 3.00–3.60), swelling (OR 3.14; 95% CI: 2.79–3.53) and redness (OR 2.41; 95% CI: 2.17–2.68). For the HPV 6/11/16/18 group the events were pain (OR 2.88; 95% CI: 2.42–3.43) and swelling (OR 2.65; 95% CI: 2.0–3.44). Concerning the HPV 16/18 vaccine, pain was the most common outcome detected. These effects can be due to a possible VLP-related inflammation process. Fatigue was the most relevant general effect observed followed by fever, gastrointestinal symptoms, and headache. In the HPV 6/11/16/18 group, only general symptoms, pain and swelling were observed. Pain and swelling were the most frequent. Comparing HPV 16/18 to HPV 6/11/16/18 vaccines, the former presented more adverse effects, perhaps because there are many more trials evaluating the bivalent vaccine. Other studies are needed to clarify this issue.

Prevalence of human papillomavirus infection, distribution of viral types and risk factors in cervical samples from human immunodeficiency virus-positive women attending three human immunodeficiency virus-acquired immune deficiency syndrome reference centres in northeastern Brazil

Human immunodeficiency virus (HIV)-positive patients have a greater prevalence of coinfection with human papillomavirus (HPV) is of high oncogenic risk. Indeed, the presence of the virus favours intraepithelial squamous cell lesion progression and may induce cancer. The aim of this study was to evaluate the prevalence of HPV infection, distribution of HPV types and risk factors among HIV-positive patients. Cervical samples from 450 HIV-positive patients were analysed with regard to oncotic cytology, colposcopy and HPV presence and type by means of polymerase chain reaction and sequencing. The results were analysed by comparing demographic data and data relating to HPV and HIV infection. The prevalence of HPV was 47.5%. Among the HPV-positive samples, 59% included viral types of high oncogenic risk. Multivariate analysis showed an association between HPV infection and the presence of cytological alterations (p = 0.003), age greater than or equal to 35 years (p = 0.002), number of partners greater than three (p = 0.002), CD4+ lymphocyte count < 200/mm3 (p = 0.041) and alcohol abuse (p = 0.004). Although high-risk HPV was present in the majority of the lesions studied, the low frequency of HPV 16 (3.3%), low occurrence of cervical lesions and preserved immunological state in most of the HIV-positive patients were factors that may explain the low occurrence of precancerous cervical lesions in this population.

Interleukin-12 gene adjuvant increases the immunogenicity of virus-like particles of human papillomavirus type 16 regional variant strain

Objectives: To analyze the immunogenicity of virus-like particles (VLP) of human papillomavirus type 16 (HPV16) isolated in East China and the adjuvant potential of interleukin-12 (IL-12). Methods: The variant HPV16 L1VLP expressed in sf9 insect cells were purified with cesium chloride gradient centrifugation. BALB/c mice were vaccinated with VLP (L1N), VLP with Freund's adjuvant (L1A) or VLP with IL-12 recombinant plasmid (L1P). HPV16 VLP specific IgG and IFN-γ level in the serum were detected by ELISA, and the percentage of CD4+ and CD8+ in spleen cells was detected with flow cytometry. Results: The titers of serum IgG antibodies in vaccinated groups were higher than in negative control and the serum antibodies mainly recognized conformation-dependent HPV16 VLP epitopes. Splenic CD4+ and CD8+ T cell subsets increased after vaccination in every experimental group, and CD8+ increased obviously in L1P group. The ratio of CD4+/CD8+ decreased in L1P group and increased in the other two groups, compared to control group. Vaccination induced specific secretion of IFN-γ in the serum of vaccinated group (p < 0.05), especially in the L1P group. Conclusions: VLP of HPV16 variant strain isolated in East China could induce humoral immunity and cellular immunity in mice, and IL-12 recombinant plasmid can enhance cellular immunity. .

Acquired epidermodysplasia verruciformis in a renal transplant recipient - Case report

A 24-year-old male patient, who underwent kidney transplant six years ago due to Lupus nephritis, for the last two years presented asymptomatic erythematous scaly plaques on the abdomen and areas exposed to light. Post-transplantation immunosuppressive medications included prednisone, mycophenolate sodium and sirolimus. The histopathologic features were typical for epidermodysplasia verruciformis. Epidermodysplasia verruciformis is a rare autosomal recessive genodermatosis with increased susceptibility to specific strains of cutaneous human papilloma virus. The term ''acquired epidermodysplasia verruciformis'' was recently introduced to the literature and describes epidermodysplasia verruciformis occurring in patients with impaired cell-mediated immunity. We report an additional case associated to immunosuppression after kidney transplantation.

Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection

Introduction The progression of human papillomavirus (HPV) infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. Methods We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. Results We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8%) was predominant in samples with ≥1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL) samples (p = 0.16). CD25 was present in great quantities in all samples. Conclusions The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker. .

Metilação genética, neoplasia intraepitelial cervical e câncer do colo uterino / Genetics methylation, cervical intraepithelial neoplasia and cervical cancer

O câncer de colo uterino é uma importante causa de morte entre as mulheres em países subdesenvolvidos. A infecção persistente pelo papilomavírus humano (HPV) oncogênico e o comprometimento da resposta imune são fatores de risco para o desenvolvimento da neoplasia intraepitelial cervical (NIC) e sua progressão para o câncer cervical invasivo. O diagnóstico precoce e o tratamento das lesões precursoras do câncer são de grande importância. Estudos epigenéticos estão sendo realizados com o objetivo de avaliar sua influencia nos processos de oncogênese, visto que alterações epigenéticas estão presentes em quase todos os tumores. A metilação de DNA e a acetilação de histonas são as duas mudanças epigenéticas mais estudadas. O melhor entendimento do perfil epigenético na neoplasia intraepitelial cervical e no câncer cervical invasor pode ser utilizado no diagnóstico e prognóstico deste câncer. O objetivo desta revisão consistiu em entender as mudanças epigenéticas encontradas até o momento nas pacientes com NIC e câncer de colo uterino. Foi realizada revisão da literatura de estudos indexados em banco de dados, como PubMed e LILACS. Verificou-se que, até o presente momento, não há um marcador de metilação que tenha o desempenho adequado para servir como indicador para as lesões precursoras do câncer, ou mesmo para o carcinoma cervical.

The cervical cancer is a major cause of death among women in developing countries. Persistent infection by human papillomavirus (HPV) and oncogenic involvement of the immune response are risk factors for the development of cervical intraepithelial neoplasia (CIN) and its progression to invasive cervical cancer. Early diagnosis and treatment of cancer precursor lesions are of great importance. Epigenetic studies are being conducted to evaluate its influence in the process of oncogenesis, since epigenetic alterations are present in almost all tumors. DNA methylation and histone acetylation are the two most studied epigenetic changes. An improved understanding of the epigenetic profile in CIN and invasive cervical cancer can be used in the diagnosis and prognosis of this cancer. The aim of this review was to understand the epigenetic changes found to date in patients with CIN and cervical cancer. We performed a literature review of studies indexed in databases such as PubMed and LILACS. It was found that, to our knowledge, there is no methylation marker with an adequate performance to serve as an indicator for cancer precursor lesions, or even for cervical carcinoma.

S100, CD68, and MHC class II molecule expression in cervical high- and low-grade HPV-induced lesions / Expressão de S100, CD68 e moléculas de MHC classe II em lesões cervicais de alto e baixo grau induzidas por HPV

INTRODUCTION: Some human papillomavirus (HPV) types are involved in malignant processes in the cervical epithelium, with 99 percent of cases attributed to oncogenic HPV infection. This study aimed to detect S100, CD68, and major histocompatibility complex class II (MHC-II) molecules in cervical uterine epithelial samples in patients with high- and low-grade lesions induced by HPV. METHODS: Fifty-eight samples from patients who were confirmed positive or negative for high-risk oncogenic HPV DNA, had histopathological diagnosis of cervical intraepithelial neoplasia (CIN) of grades I, II, or III, or were negative for intraepithelial lesion or malignancy were subjected to immunohistochemistry reaction to S100 protein, CD68, and MHC-II (HLA-DR alpha chain). RESULTS: The presence of MHC-II predominated in samples exhibiting histopathological alterations (p < 0.05). S100 detection was more numerous in carcinoma samples (CIN III) (75 percent). Presence of this protein correlated significantly (p < 0.05) with histopathological findings and viral load. CONCLUSIONS: A small expression of CD68 was observed, which may be explained by the observation in our study having been made on random microscopic fields and not on specific areas. The findings, such as the presence of S100 protein and MHC-II expression in samples with histological alterations, could suggest that the immune system fails to control HPV replication at the early stages of infection. Further studies with larger prospective data are necessary to confirm this result.

INTRODUÇÃO: Alguns tipos de papilomavirus humano (HPV) estão envolvidos em processos malignos no epitélio cervical, com 99 por cento dos casos atribuídos à infecção por HPV oncogênico. O objetivo deste estudo foi detectar a proteína S100, CD68 e moléculas de MHC-II (complexo principal de histocompatibilidade classe II) em amostras de epitélio cervical uterino, de pacientes com lesões de alto e baixo grau induzidas pelo HPV. MÉTODOS: Cinquenta e oito amostras de pacientes positivos ou negativos, confirmados, para DNA de HPV de alto ou baixo risco oncogênico, e que tiveram diagnóstico histopatológico de neoplasia intraepithelial cervical (NIC) de graus I, II ou III ou foram negativas para lesão intraepithelial e malignidade (NILM), foram submetidas à reação de imunohistoquímica (IHQ) para proteína S100, CD68 e MHC-II (HLA-DR cadeia alfa). RESULTADOS: A presença da molécula MHC-II predominou em amostras exibindo alterações histopatológicas (p < 0,05). A detecção de S100+ foi mais numerosa em amostras com carcinoma (NIC III) (75 por cento). A presença dessa proteína correlacionou-se significantemente (p < 0,05) com achados histopatológicos e a carga viral. CONCLUSÕES: Pequena expressão CD68+ foi observada, uma possível explicação seria que em nosso estudo as observações foram feitas em campo microscópicos aleatórios e não em áreas específicas. Os achados como a presença de S100 e a expressão de MHC-II, em amostras com alterações histológicas, podem sugerir que o sistema imune falha em controlar a replicação do HPV nas fases iniciais da infecção. Maiores estudos, com mais dados prospectivos, são necessários para confirmar esses resultados.

Morphometric analysis of dendritic cells from anal mucosa of HIV-positive patients and the relation to intraepithelial lesions and cancer seen at a tertiary health institution in Brazil / Análise morfométrica das células dendríticas da mucosa anal de pacientes HIV-positivos e relação com as lesões intraepiteliais e o câncer numa instituição de saúde terciária no Brasil

PURPOSE: To morphometrically quantify CD1a+ dentritic cells and DC-SIGN+ dendritic cells in HIV-positive patients with anal squamous intraepithelial neoplasia and to evaluate the effects of HIV infection, antiretroviral therapy and HPV infection on epithelial and subepithelial dendritic cells. METHODS: A prospective study was performed to morphometrically analyze the relative volume of the dendritic cells and the relationship between anal intraepithelial neoplasia and cancer in HIV-positive patients from the Tropical Medicine Foundation of Amazonas, Brazil. All patients were submitted to biopsies of anorectal mucosa to perform a classic histopathological and immunohistochemical analysis, employing antibodies against CD1a and DC-SIGN for the morphometric quantification of dendritic cells. RESULTS: HIV-negative patients displayed a CD1a DC density significantly higher than that of HIV-positives patients (3.75 versus 2.54) (p=0.018), and in patients with severe anal intraepithelial neoplasia had correlated between DC CD1a density with levels of CD4 + cells (p: 0.04) as well as the viral load of HIV-1 (p: 0.035). A not significant rise in the median density of CD1a+ DC was observed in the HIV positive/ HAART positive subgroup compared to the HIV positive/ HAART negative subgroup. The CD1a+ DC were also significantly increased in HIV-negative patients with anorectal condyloma (2.33 to 3.53; p=0.05), with an opposite effect in HIV-positive patients. CONCLUSIONS: Our data support an enhancement of the synergistic action caused by HIV-HPV co-infection on the anal epithelium, weakening the DC for its major role in immune surveillance. Notoriously in patients with severe anal intraepithelial neoplasia, the density of CD1a+ epithelial dendritic cells was influenced by the viral load of HIV-1. Our study describes for the first time the density of subepithelial DC-SIGN+ dendritic cells in patients with anal severe anal intraepithelial neoplasia and points to the possibility that a specific therapy for HIV induces the recovery of the density of epithelial DC.

OBJETIVO: Quantificar morfometricamente as células dendríticas DC CD1a+ e DC DC-SIGN+ em pacientes HIV positivos portadores de neoplasia escamosa intraepitelial anal e avaliar os efeitos da infecção pelo HIV, da terapia antirretroviral e da infecção pelo HPV sobre as células dendríticas epiteliais e subepiteliais. MÉTODOS: Um estudo prospectivo foi realizado para analisar morfometricamente o volume relativo das células dendríticas e as relações entre neoplasia intraepitelial anal e o câncer em pacientes HIV positivos da Fundação de Medicina Tropical do Amazonas, Brasil.Todos os pacientes foram submetidos a biópsia da mucosa retal para realizar uma análise clássica histopatológica e imunohistoquímica utilizando anticorpos contra anti-CD1a e anti-DC-SIGN, para a quantificação morfométrica das células dendríticas. RESULTADOS: Os pacientes HIV negativos apresentaram densidade das DC CD1a+ significativamente maior do que a dos pacientes HIV positivos (3,75 versus 2,54) (p:0,018), e os pacientes com severa apresentaram correlação das DC CD1a com os níveis de células TCD4(p:0,04) assim como a carga viral do HIV-1 (p:0,035). Observamos no subgrupo HIV-positivo/HAART positivo elevação não significativa na mediana da densidade das DC CD1a+ em relação ao grupo HIV-positivo/HAART negativo. As DC CD1a+ também se elevaram nos pacientes HIV negativo portadores de condiloma anorretal(2,33 para 3,53; p:0,05), com efeito inverso nos pacientes HIV positivos. CONCLUSÕES: Nossos dados confirmam a potencialização da ação sinérgica representada pela coinfecção HIV-HPV sobre o epitélio anal, fragilizando as DC em sua função primordial de vigilância imune. Notoriamente nos pacientes com neoplasia intraepithelial anal grave, a densidade das DC CD1a+ epiteliais sofreu influência da carga viral do HIV-1. Nosso estudo descreveu pela primeira vez a densidade das DC subepiteliais DC-SIGN+ em pacientes com neoplasia intraepithelial anal severa e apontamos para a possibilidade de que a terapia específica para o HIV induza a recuperação da densidade das DC epiteliais.

Resposta imune ao HPV e as neoplasias intra-epiteliais cervicais em mulheres infectadas e não infectadas pelo HIV: perfil de citocinas / Immune response to HPV and cervical intraepithelial neoplasia among HIV infected and non-infected women: Cytokines profile

A infecção pelo papilomavirus humano (HPV) está relacionada com o desenvolvimento do carcinoma cervical. A prevalência da infecção pelo HPV em pacientes portadoras do vírus da Imunodeficiência Humana (HIV) é maior que na população geral. Vários mecanismos são sugeridos para explicar essa prevalência aumentada em pacientes portadoras do HIV, sendo que a modulação da resposta imune parece desempenhar papel importante. O sistema imune é dividido didaticamente em dois tipos: imunidade inata e imunidade adquirida. Essa, por sua vez, é dividida em imunidade humoral e celular. As células TCD4 possuem papel crucial na resposta celular e são dividas em padrões. Os principais e mais conhecidos são em Th1 e Th2 de acordo com o perfil de citocinas sintetizadas. Em pacientes portadoras do HPV existe tendência de mudança do perfil Th1 para o perfil Th 2 à medida que a lesão agrava. Em pacientes co-infectadas HPV/HIV a taxa de clareamento da infecção pelo HPV é menor que em pacientes não infectadas pelo HIV. O melhor entendimento da resposta imune local poderia ajudar a compreender qual paciente tem maior risco de progressão da doença

The human papillomavirus (HPV) is related to the development of cervical cancer. The prevalence of HPV infection in patients infected with human immunodeficiency virus (HIV) is higher than in the general population. Several mechanisms are suggested to explain this increased prevalence in patients with HIV, and the modulation of the immune response seems to play an important role. The immune system is didactically divided into two types: innate and acquired immunity. The latter is further divided into humoral and cell mediated immunity. CD4 T cells, which have a crucial role in cell mediated response, are functionally being divided into patterns, the main and best known are Th1 and Th2 according to the cytokine profile that is produced. In patients with HPV there is a tendency to shift from th1 to th2 cytokine as the lesion gets worse. Among HPV/HIV coinfected patients, the clearence rate of HPV infection is lower than in patients not infected with HIV. It is argued that a better understanding of the local immune response could assist in the detection of patients who are at a greater risk of disease progression

Resposta imune celular ao papilomavírus humano em mulheres infectadas e não infectadas pelo vírus da imunodeficiência humana / Cellular immune response to human papillomavirus among women infected and noninfected with human immunodeficiency virus

Em razão da alta prevalência da infecção pelo papilomavírus humano (HPV) entre as mulheres, particularmente entre as jovens sexualmente ativas, podendo causar a neoplasia intraepitelial cervical (NIC) e o câncer cervical, é importante abordar os vários fatores associados a essa interação vírus-hospedeiro, e um dos fatores mais importantes é a resposta imune do hospedeiro. Esta, tanto sistêmica quanto local, tem papel crucial para determinar o curso da infecção. Nos casos de infecção persistente, há maior probabilidade de progressão para as NICs e/ou câncer invasor. Esta revisão tem como objetivo avaliar o papel da resposta imune local, em especial a resposta do tipo celular, no curso da infecção pelo HPV e na evolução ou regressão das lesões cervicais, na tentativa de melhor compreensão das diferentes formas de comportamento dessas lesões HPV induzidas, inclusive na associação com o vírus da imunodeficiência humana (HIV).

Given the high prevalence of human papillomavirus infection among women, particularly young sexually active women, and its role in the cause of cervical intraepithelial neoplasia and cervical cancer, it is important to address the several factors associated with this viral-host interaction. Among these factors, the most important is the host immune response. Both systemic and local response have crucial roles in determining the course of infection. In cases of persistent infection, there is a greater likelihood of progression to intraepithelial neoplasia and/or invasive cancer. The objective of this review is to evaluate the role of local immune response, particularly the response of cell type in the course of HPV infection as well as in the progression or regression of cervical lesions in order to better understand the behavior of different forms of HPV induced lesions, including its association with the human immunodeficiency virus.

Linfócitos CD4, CD8 e células NK no estroma da cérvice uterina de mulheres infectadas pelo papilomavírus humano / CD4 and CD8 T lymphocytes and NK cells in the stroma of the uterine cervix of women infected with human papillomavirus

INTRODUÇÃO: A resposta imune pode ser um elemento chave para a progressão ou remissão da infecção pelo papilomavírus humano (HPV) no estroma da cérvice uterina. Este estudo objetivou quantificar no estroma cervical a presença de linfócitos T CD4, CD8 e células NK, por imunohistoquímica, em lesões de alto e baixo grau em pacientes infectadas por HPV MÉTODOS: Utilizou-se 56 amostras de biópsia da estroma cervical, sendo 43 amostras positivas para DNA de HPV de alto risco oncogênico e com diagnóstico histopatológico de neoplasia intraepitelial cervical (NIC) de alto e baixo grau, ou negativa para lesão intraepitelial e malignidade (NILM), e 13 amostras de pacientes negativas para DNA de HPV com diagnóstico histopatológico NILM RESULTADOS: Maior quantidade de linfócitos T CD4 foi observada em amostras NIC II/III, carcinoma e NILM (p=0,04) e naquelas cuja carga viral esteve entre 10 e 1,000 RLU/PCB. O predomínio de linfócitos T CD8 ocorreu em maior proporção nas amostras NIC II/III (p=0,02) e em amostras com carga viral entre 100 e 1.000 RLU/PCB. As células NK prevaleceram nas amostras com lesões de baixo grau e com baixa carga viral CONCLUSÕES: Este estudo comprovou que nas fases iniciais da infecção, onde não há ainda alterações celulares de alto grau, não temos a presença de células que possam desencadear a fase efetora da resposta imune.

INTRODUCTION: Immune response might be a key element regarding the progression or regression of human papillomavirus (HPV) infection in the stroma of the uterine cervix. This study aimed to quantify the presence of CD4 and CD8 T lymphocytes and NK cells in the cervical stroma, by means of immunohistochemistry, in high and low grade lesions in patients infected by HPV METHODS: Fifty-six biopsy samples from the uterine cervix were used. Forty-three samples were positive for oncogenic high-risk HPV DNA and had a histopathological diagnosis of high and low-grade cervical intraepithelial neoplasia (CIN) or negative for intraepithelial lesion and malignancy (NILM); while the other 13 samples were negative for HPV DNA with a histopathological diagnosis of NILM RESULTS: Higher quantities of CD4 T lymphocytes were observed in CIN II/III, carcinoma and NILM samples (p = 0.04) and in those in which the viral load was between 10 and 1.000 RLU/PCB. CD8 T lymphocytes were predominant in CIN II/III samples (p = 0.02) and also in samples with viral loads between 100 and 1,000 RLU/PCB. NK cells predominated in samples with low-grade lesions and low viral load CONCLUSIONS: This study proved that in the initial stages of the infection, in which no high-grade cell abnormalities have yet occurred, no cells that might trigger the effector phase of the immune response.

Frequência de Papilomavírus humano (HPV) e Chlamydia trachomatis em gestantes / Frequency of Human Papillomavirus (HPV) and Chlamydia trachomatis in Pregnant Women

Este estudo transversal de caráter analítico teve por objetivo avaliar a frequência da infecção pelo Papilomavírus humano (HPV) e Chlamydia trachomatis, bem como de alterações citopatológicas e colposcópicas em um grupo de 96 gestantes (51 HIV soropositivas e 45 HIV soronegativas) no período de abril de 2006 a maio de 2007. Todas responderam a questionário padrão seguido de atendimento ginecológico. Foram coletadas amostras da cérvice uterina para pesquisa de HPV e C. trachomatis pela técnica de Captura de Híbrido (CH II®) para a colpocitologia oncótica e, por fim, realizou-se o exame colposcópico. Os dados foram armazenados e analisados no Epi Info, versão 6.04 e SPSS versão 9.0. Utilizou-se o teste do Qui-quadrado considerando o valor de 5 por cento (p<0,05) como limiar de significância para análise estatística. Das gestantes HIV positivas, 62,7 por cento foram positivas para HPV e 17,6 por cento para C. trachomatis. Entre as gestantes HIV negativas, 17,8 por cento e 4,4 por cento foram positivas para o HPV e para a C. trachomatis, respectivamente. A colpocitologia oncótica identificou maior frequência de lesões intraepiteliais escamosas cervicais de baixo grau em ambos os grupos, sendo 21,6 por cento entre as gestantes HIV positivas e 13,3 por cento no grupo HIV negativo. O epitélio acetobranco foi o achado colposcópico mais reiterado nos dois grupos. Concluiu-se que a infecção pelo HPV e por C. trachomatis é mais freqüente em gestantes infectadas pelo HIV caracterizando, desta forma, à luz de conhecimentos atuais, uma população de maior risco de desenvolver câncer cervical.

A cross-sectional analytical study was conducted in order to identify the frequency of the Human Papillomavirus (HPV) infection, Chlamydia trachomatis, colposcopic and cytological findings in a group of 96 pregnant women (51 HIV positive and 45 HIV negative) from April 2006 to May 2007. All patients went through a standard questionnaire, followed by gynecological examination. Samples were collected for HPV survey and C. trachomatis by the Hybrid Capture II technique for oncotic colpocytology (Papanicolaou), followed by colposcopy. Data were stored and analyzed using Epi Info, version 6.04 and SPSS version 9.0. For statistical analysis the chi-square test were used with level of significance set at 5 percent. Among the HIV positive pregnant women 62.7 percent were positive for HPV and 17.6 percent were positive for C. trachomatis. In contrast, for HIV negative pregnant women 17.8 percent and 4.4 percent were positive for HPV and C. trachomatis, respectively. The Pap smear identified a larger amount of low grade squamous intraepithelial lesions in both groups, 21.6 percent in HIV positive pregnant women and 13.3 percent in HIV negative pregnant women. The aceto white epithelium was the most frequent colposcopy abnormality. In conclusion, the infection by HPV and C. trachomatis is more common in pregnant women infected with HIV, characterizing, thus, based on current knowledge, a population that is more susceptible to cervical cancer.

Cervical cancer prevention & the role of human papillomavirus vaccines in India.

Human papillomavirus (HPV) is a necessary cause of cervical cancer, the leading cause of cancer deaths among Indian women. Current screening and prevention programs based on cytology have not been effective in reducing the disease burden. Two vaccines are now available for primary prevention. They generate neutralizing antibodies to HPV capsid protein. The vaccines have been shown to confer nearly 100 per cent protection against cervical pre-cancers and genital warts caused by HPV types 16/18 in HPV naïve population with few or no side effects. Though there is some cross-protection, around 30 per cent of cervical cancers will not be prevented by the vaccine. Vaccination and screening, which are complementary and synergistic, now constitute the new paradigm for prevention of this disease.

HPV vaccination: the promise & problems.

Four-fifths of the cervical cancer burden in the world is experienced in developing countries. HPV genotypes 16 and 18 account for 70 per cent of cervical cancers and currently available vaccines targeting these two types confer a high degree of protection against HPV 16/18 infection and related cervical precancerous lesions. However, widespread implementation of HPV vaccination programs are challenged by the unaffordable high costs of the vaccines and the lack of effective vaccine delivery platforms for sexually naïve girls. Other unresolved issues include long-term protection, cross-protection against HPV types not included in the vaccine and whether booster doses will be needed. Sensitivities associated with a vaccine preventing a sexually transmitted infection in girls, lack of awareness, public demand and political will, lack of coordination between cancer control, sexual and reproductive health and vaccine delivery services are additional challenges. Reduced costs, simple vaccine regimes and strengthening vaccine delivery platforms for adolescents should eventually facilitate HPV vaccine introduction in developing countries.

Immune responses to human papilloma viruses.

HPV infection in the genital tract is common in young sexually active individuals, the majority of whom clear the infection without overt clinical disease. However most of those who develop benign lesions eventually mount an effective cell mediated immune response and the lesions regress. Regression of ano-genital warts is accompanied histologically by a CD4+ T cell dominated Th1 response; animal models support this and provide evidence that the response is modulated by CD4+ T cell dependent mechanisms. Failure to develop effective CMI to clear or control infection results in persistent infection and, in the case of the oncogenic HPVs, an increased probability of progression to CIN3 and invasive carcinoma. The central importance of the CD4+ T cell population in the control of HPV infection is shown by the increased prevalence of HPV infections and HGSIL in individuals immunosuppressed as a consequence of HIV infection. The prolonged duration of infection associated with HPV seems to be associated with effective evasion of innate immunity as reflected in the absence of inflammation during virus replication, assembly and release, and down regulation of interferon secretion and response thus delaying the activation of adaptive immunity. Serum neutralising antibody to the major capsid protein L1 usually develops after the induction of successful cell mediated immunity and these antibody and cell mediated responses are protective against subsequent viral challenge in natural infections in animals. Prophylactic vaccines consisting of HPV L1 VLPs generate high anti L1 serum neutralizing antibody concentrations and in clinical trials have shown greater than 95 per cent efficacy against both benign and neoplastic genital HPV associated disease. These vaccines are delivered intramuscularly and therefore circumvent the immune evasion strategies of the virus.

Papilomavírus humano: fatores de risco, carcinogênese, resposta imune e tratamento / Human papillomavirus: risk factors, carcinogenesis, imune response and treatment

O papilomavírus humano (HPV) é reconhecido como agente etiológico principal e essencial no desenvolvimento da maioria dos cânceres de colo do útero. Este artigo é uma revisão bibliográfica que aborda os diversos fatores de risco que influenciam os processos de infecção e carcinogênese, as vacinas contra o HPV recentemente desenvolvidas, o tratamento das infecções já instaladas e as possíveis futuras ferramentas de prevenção e terapêutica.

HPV is recognized as the main and essential etiologic agent in the development of most cervical cancers. This article is a review of the literature that explores the various risk factors influencing the processes of infection and carcinogenesis, the recently developed vaccines, treatment of already established infections, and the possible future tools for prevention and therapeutics.