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INTRODUCTION: Protein p16 has been extensively studied as a potential biomarker for precursor lesions to distinguish cervical Intraepithelial neoplasia (CIN) from their mimics. However, the use of p16 as prognostic biomarker for diagnosis of cervical cancer and precancer is controversial. This study focuses on the assessment of peer-reviewed scientific data related to the use of p16 to predict disease severity and its controversies. METHODS: We reviewed publications in MEDLINE/PubMed assessing the clinical, diagnostic and prognostic significance of p16 in CIN and cervical cancer; we included publications from 2009 to June 2017. RESULTS: The use of p16 as a prognostic marker is still unreliable, although it could be a useful tool for diagnosis of Cervical Intraepithelial Neoplasia lesions with undetermined morphology. Moreover, p16 appears to be a specific marker of high-risk oncogenic HPV infection. CONCLUSION: This review shows the potential utility and drawbacks of p16 for clinical practice and the diagnosis of cervical cancer. Further studies are required to substantiate the role of p16 in conjunction with other more sensitive and specific biomarkers for diagnosing CIN and predicting its progression.

INTRODUÇÃO: A proteína p16 tem sido estudada como um biomarcador potencialmente específico de lesões cervicais precursoras e como uma forma de diferenciar as lesões parecidas com Neoplasia intra-epitelial cervical (NIC). Contudo existem várias controvérsias sobre a utilização de p16 como um biomarcador prognóstico e como uma ferramenta para o diagnóstico de câncer cervical e de lesões pré-câncer. O objetivo deste estudo foi a revisão de dados científicos por pares de bases, relacionados com a utilização da p16 e suas controvérsias. MÉTODOS: O estudo foi projetado como uma revisão da literatura das publicações do Medline/PubMed que avaliam o significado clínico, diagnóstico ou prognóstico do p16 em lesões de NIC e no câncer cervical no período de janeiro de 2009 a junho de 2017. RESULTADOS: o uso do p16 como um marcador prognóstico ainda não é confiável, apesar de que a p16 poderia ser uma ferramenta útil para o diagnóstico em lesões de NIC com morfologia indeterminada. Além disso, a p16 parece ser um marcador específico de infecção por HPV de alto risco oncogênico. CONCLUSÃO: A presente revisão mostra a potencial utilidade da proteína p16, bem como os inconvenientes para uso clínico-patológico e diagnóstico no câncer cervical. Contudo são necessários mais estudos para fundamentar o papel da p16 em conjunto com os outros biomarcadores mais sensíveis e específicos para diagnosticar NIC e prever a sua progressão.

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This manuscript focuses on the detection of viral nucleic acids by in situ based methodologies. The optimal protocol depends on the virus. We will describe protocols for viral RNA detection by reverse transcriptase (RT) in situ PCR. We will also directly compare this method to the detection of viral RNA using standard in situ hybridization with locked nucleic acid (LNA) probes. Most DNA viruses are associated with high viral copy number and, thus, can be detected by standard in situ hybridization. Retroviral provirus is an exception as the single integrated DNA is best detected by PCR in situ hybridization. We will also describe protocols for the co-localization of viral DNA and RNA with host cytokines. Our protocol typically has the protein immunohistochemistry as the second step, with the key features being pretreatment step, antibody concentration, co-labeling analyses with a computer-based system, and co-analyzes with serial sections.

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Human immunodeficiency virus (HIV-1) has become an important risk factor for human papillomavirus (HPV) infection and the development of HPV associated lesions in the female genital tract. HIV-1 may also increase the oncogenicity of high risk HPV types and the activation of low risk types. The Center for Disease Control and Prevention declared invasive cervical cancer an acquired immunodeficiency virus (AIDS) defining illness in HIV positive women. Furthermore, cervical cancer happens to be the second most common female cancer worldwide. The host's local immune response plays a critical factor in controlling these conditions, as well as in changes in the number of professional antigen-presenting cells, cytokine, and MHC molecules expression. Also, the production of cytokines may determine which arm of the immune response will be stimulated and may influence the magnitude of immune protection. Although there are many studies describing the inflammatory response in HPV infection, few data are available to demonstrate the influence of the HIV infection and several questions regarding the cervical immune response are still unknown. In this review we present a brief account of the current understanding of HIV/HPV co-infection, emphasizing cervical immune response.

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The aim of this study was to characterize the immune system profile in the uterine cervix of 17 human papillomavirus (HPV)-infected women, compared with 17 whom were coinfected with HIV-1. Five histologically normal cervices in immunocompetent women were used as controls. HPV infection was associated with a marked increase in cells expressing interleukin (IL)-6, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Coinfection by HPV and HIV-1 led to decreased expression of IL-6, TNF-alpha, and IFN-gamma. However, coinfection led to increased numbers of cells expressing IL-4, IL-10, and IL-8. Compared with the histologically normal cervices, increased numbers of macrophages (CD68, RFD7) and T lymphocytes (CD4, CD8) were seen in HPV-infected cervices; coinfection with HIV-1 was associated with a higher number of CD8 cells and lower number of CD68 cells. HPV DNA localized exclusively to the dysplastic squamous cells, whereas HIV-1 RNA was detected mainly in CD68-positive stromal cells. In conclusion, this study shows differential expression of various cytokines and classes of inflammatory cells, relative to HIV-1 infection and HPV coinfection, which may relate to the risk of transmission of HIV-1 and increased risk of cervical cancer in these women.

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Human immunodeficiency virus (HIV-1) has become an important risk factor for human papillomavirus (HPV) infection and the development of HPV associated lesions in the female genital tract. HIV-1 may also increase the oncogenicity of high risk HPV types and the activation of low risk types. The Center for Disease Control and Prevention declared invasive cervical cancer an acquired immunodeficience virus (AIDS) defining illness in HIV positive women. Furthermore, cervical cancer happens to be the second most common female cancer worldwide. The host's local immune response plays a critical factor in controlling these conditions, as well as in changes in the number of professional antigen-presenting cells, cytokine, and MHC molecules expression. Also, the production of cytokines may determine which arm of the immune response will be stimulated and may influence the magnitude of immune protection. Although there are many studies describing the inflammatory response in HPV infection, few data are available to demonstrate the influence of the HIV infection and several questions regarding the cervical immune response are still unknown. In this review we present a brief account of the current understanding of HIV/HPV co-infection, emphasizing cervical immune response.

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Pouco se conhece sobre a imunopatogenia da infecção pelo HPV e sua influência na replicação viral do HIV-1. A resposta imune cervical desempenha um papel preponderante no controle da infecção, contudo quais mecanismos específicos, estariam envolvidos, ainda permanece em grande parte, obscuro. Este estudo teve como objetivo caracterizar o processo inflamatório na cérvix uterina de mulheres co-infectadas pelo HIV/HPV. Trinta e quatro fragmentos de lesão cervical foram analizadas. Foi observado grande número de células inflamatórias, principalmente macrófagos, linfócitos T CD4 e T CD8 em ambos os grupos estudados, contudo um aumento significativo (P < 0,05) de CD8 foi observado nas amostras das pacientes co-infectadas, comparadas às somente infectadas pelo HPV. Não observamos, porém, atividade citotóxica putativa nestas células com comprovada pela ausência de grânulos de perforina e Fas-L. Observamos ainda, alteração do perfil de citocinas, do tipo 2 nestas pacientes. 91por cento, apresentavam HPV de alto risco oncogênico, sugerindo que estas mulheres, têm grandes chances de desenvolverem o câncer cervical. Detectamos também, grande quantidade de células infectadas pelo HIV-1, principalmente macrófagos endocervicais, com distribuição peri-vascular, onde havia simultaneamente a expressão de citocinas pro-inflamatórias (TNF-a e IL-6). No entanto, expressão rara de SSI/SOCS, um modulador negativo da expressão de citocinas, foi identificado nas áreas onde o HIV-1 estava presente; sugerindo desta forma que o HIV-1 possa ter mecanismos que inibem a regulação de citocinas, causando um desequilíbrio e favorecimento da replicação viral mais acentuada do HIV-1. Este estudo, é o primeiro a caracterizar o processo inflamatório na lesão uterina de pacientes co-infectadas por HIV/HPV, de uma forma tão ampla; caracterizando a expressão de citocinas, o fenótipo das células inflamatórias, a detecção de células alvo do HIV-1 e a presença de moléculas reguladoras negativas de citocinas.

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