Human Papillomavirus infection in oral and anogenital sites: prevalence and rates of concordance / Infecção pelo Papilomavírus Humano em regiões orais e anogenitais: prevalência e taxa de concordância

Introduction: HPV infection causes cancer at several anatomical sites. However, the infection's natural history in non-cervical sites is understudied. Objective: To evaluate oral and anogenital HPV infections, correlating HPV prevalence rates and genotypes with site of infection and risk factors. Methods: In the present study, 351 samples from oral, genital, and anal sites of 117 patients were investigated by using PCR MY09/11 detection, followed by genotyping with RFLP. Results: HPV DNA prevalence was 89.7% (105/117) in genital lesions, 53.8% (63/117) in oral samples, and 58.9% (69/117) in anal samples. Regarding the risk factors associated with HPV in genital lesions, statistically significant rates for oral (p=0.039) and anal sex practices (p=0.0000012) were found. For oral samples, a relevant correlation concerning oral contraceptive use (p=0.039), tobacco smoking (p=0.036), and alcohol use (p=0.0075) were observed; whereas in anal samples, higher risk for HPV infection in patients who reported non-exclusive sexual partners (p=0.013) were found. The presence of viral DNA in all the three sites concurrently was observed in 36.8% of the cases (43/117). Among them, 18% (21/117) presented concordant HPV genotypes, diverging from the literature, and thus corroborating that there is still much to learn about HPV natural history, since different biological behaviors are expected within different populations. Differences in anatomy and physiology of the studied sites can determine different prevalence rates of infection by diverse genotypes. Conclusion: Due to the high prevalence of HPV DNA in extragenital sites, further studies are required to define aspects of HPV natural history among different human anatomical sites.

Introdução: As infecções causadas pelos papilomavírus humanos (HPV) são responsáveis pelo desenvolvimento de cânceres em diversos sítios anatômicos humanos. Entretanto, a história natural da infecção em sítios que não a cérvice uterina não é muito clara. Objetivo: Avaliar infecções orais, genitais e anais por HPV, correlacionando taxas de prevalência do vírus e seus genótipos aos sítios de infecção e a fatores de risco sócio-demográficos. Métodos: Em nosso estudo, investigamos 351 amostras coletadas dos sítios oral, genital e anal de 117 pacientes, por meio da técnica de PCR MY09/11, seguida de genotipagem por RFLP. Todos os pacientes apresentavam lesões genitais benignas. Resultados: A prevalência do HPV foi de 89,7% (105/117) nas lesões genitais, 53,8% (63/117) nas amostras orais e 58,9% (69/117) nas amostras anais. Em relação aos fatores de risco associados à infecção genital, encontramos diferenças estatísticas significativas para prática de sexo oral (p=0,039) e sexo anal (p=0,0000012). Já para as amostras orais, observamos importante correlação entre infecção e uso de contraceptivo oral (p=0,039), tabagismo (p=0,036) e uso de álcool (p=0,0075) enquanto nas amostras anais, alto risco de infecção pelo HPV foi associado a pacientes relatando parceiros sexuais não exclusivos (p=0,013). A presença do DNA viral simultaneamente nos três sítios estudados foi observada em 36,8% dos casos (43/117). Desses, 18% (21/117) apresentaram genótipos concordantes, diferindo da literatura, na qual há grande disparidade de descrições. Conclusão: Há a necessidade de novos estudos a fim de esclarecer a história natural do HPV em sítios extragenitais em diferentes populações, avaliando características anatômicas e fisiológicas com o intuito de esclarecer diferentes taxas de infecção por genótipos do HPV e diferentes processos de doença.

The Interplay of HIV-1 and Macrophages in Viral Persistence.

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.

A minor population of macrophage-tropic HIV-1 variants is identified in recrudescing viremia following analytic treatment interruption.

HIV-1 persists in cellular reservoirs that can reignite viremia if antiretroviral therapy (ART) is interrupted. Therefore, insight into the nature of those reservoirs may be revealed from the composition of recrudescing viremia following treatment cessation. A minor population of macrophage-tropic (M-tropic) viruses was identified in a library of recombinant viruses constructed with individual envelope genes that were obtained from plasma of six individuals undergoing analytic treatment interruption (ATI). M-tropic viruses could also be enriched from post-ATI plasma using macrophage-specific (CD14) but not CD4+ T cell-specific (CD3) antibodies, suggesting that M-tropic viruses had a macrophage origin. Molecular clock analysis indicated that the establishment of M-tropic HIV-1 variants predated ATI. Collectively, these data suggest that macrophages are a viral reservoir in HIV-1-infected individuals on effective ART and that M-tropic variants can appear in rebounding viremia when treatment is interrupted. These findings have implications for the design of curative strategies for HIV-1.

Human papillomavirus, Epstein-Barr virus, and methylation status of p16ink4a in penile cancer.

Little is known about penile carcinogenesis. The aim of this study was to evaluate the prevalence of HPV and EBV, and the methylation status of p16ink4a in penile cancer samples, and to contribute to the understanding of the mechanisms responsible for penile cancer development. HPV DNA was detected in 63.6% of 122 cases, with HPV16 being the most prevalent type. EBV DNA was detected in 47.7%, with EBV-1 being the most prevalent type. HPV/EBV co-infections were found in 27.3% of the cases. Hypermethylation in p16ink4a was detected in 64.5% of 110 tested cases. An association between the absence of HPV absence and p16ink4a hypermethylation was also found. Death and/or progressive disease was associated with grade (P = 0.001), T stage (P < 0.0001), and N stage (P < 0.0001). In the multivariable model, grade and N stage were independent risk factors for disease-free survival (P = 0.008 and P < 0.001, respectively). Patients without viral infection had a median age significantly lower than that of the HPV-infected patients. We suggest at least two pathways for penile carcinogenesis, one HPV-independent linked to epigenetic events, probably via p16ink4a inactivation; and another, dependent on HPV infection.

High Risk Human Papillomavirus Infection of the Foreskin in Asymptomatic Men and Patients with Phimosis.

PURPOSE: There has been increasing interest in understanding the natural history of HPV and the diseases that it causes in men. HPV infection is strongly associated with penile cancer, lack of neonatal circumcision and phimosis. We investigated the incidence of HPV infection in asymptomatic men and patients with phimosis. MATERIALS AND METHODS: We assessed 110 asymptomatic men and 30 patients who underwent circumcision due to phimosis. DNA was extracted from swabbed samples collected from asymptomatic men and from foreskin samples collected at circumcision. Polymerase chain reaction using consensus primers for detecting HPV-MY09/11 was performed to detect generic HPV DNA. HPV genotyping was done by polymerase chain reaction amplification with primers for the E6 gene DNA sequences HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV35, HPV45 and HPV58. RESULTS: HPV was present in 46.66% of patients with phimosis, of whom 50% had high risk HPV genotypes. Of asymptomatic cases 16.36% were HPV positive but only 1 sample showed high risk HPV. We detected a significantly high rate of HPV genital infection in patients presenting with phimosis compared with asymptomatic men (p = 0.00167). The prevalence of high risk HPV genotypes in patients with phimosis was also statistically significant (p = 0.0004). CONCLUSIONS: We found a robust association between phimosis and the genital HPV prevalence in men and a significant frequency of high risk HPV. Other studies are needed to investigate the occurrence of factors that can increase the incidence of penile carcinoma and determine its impact on female genital infection in cervical cancer.

Human papillomavirus infection inhealthy men from Rio de Janeiro, Brazil / Infecções por papilomavírus humanos em homens saudáveis do Rio de Janeiro, Brasil

Genital infections by human papillomavirus (HPV) are the most prevalent sexually transmitted viral diseases worldwide. Although the naturalhistory of cervical cancer is better understood, there are still scarce information regarding the etiology of penile cancer, and the natural history of HPV infection in men is not yet fully elucidated. Objective: This study aimed to determine the prevalence of HPV infection in penile samples, from a clinicall yasymptomatic male population. Methods: A total of 550 samples were collected between January 2011 and July 2014 in different institutions in the Stateof Rio de Janeiro, including a dermatology clinic and a metallurgical company. The samples were collected from the anatomical regions of the glans andbalanopreputial sulcus. HPV identification was made through the generic and type-specific Polymerase Chain Reaction (PCR), and Restriction FragmentLength Polymorphism (RFLP) techniques. Results: An overall prevalence of HPV infection was observed in 21.8% (120 subjects). The most prevalent HPV type was HPV 6 (35%), followed by HPV 16 (20.8%), HPV 11 (19.1%), HPV 31 (6.7%), HPV 33 (6.7%), HPV 45 (8.3%) and HPV 58 (3.3%). Hence,infection was associated with low-risk oncogenic types in 54.1% of the studied individuals, while high-risk oncogenic types were detected in 45.9% ofthem. The age of the studied subjects ranged from 18 to 65 years with a mean age of 28.4 years. Conclusion: According to our findings, we can infer thatthe prevalence of HPV infection among asymptomatic male population was considerably lower than the described in the literature, although in agreementwith results reported in some recently published studies. We believe that the results may contribute to understand the features of circulation of HPV in malepopulation, in order to evaluate risk-benefits and strategies of disease prevention.

As infecções genitais pelo Papilomavírus humano (HPV) são hoje as mais prevalentes viroses de transmissão sexual em todo o mundo. Embora a história natural do câncer cervical seja melhor compreendida, pouco se sabe sobre a etiologia do câncer de pênis e a história natural do HPV no homem não está completamente elucidada. Objetivo: Este estudo teve como objetivo, determinar a prevalência do HPV em amostras penianas de uma população masculina assintomática. Métodos: Foram coletadas 550 amostras entre janeiro de 2011 e julho de 2014 em diferentes instituições do Estado do Rio de Janeiro, dentre elas:uma clínica de dermatologia e uma indústria metalúrgica. As amostras foram coletadas de sítios anatômicos como sulco balanoprepucional. A identificação do HPV foi feita pela Reação em Cadeia da Polimerase (PCR) genérica e tipo-específica, bem como pelo Polimorfismo do padrão de comprimento de fragmentos de restrição (RFLP). Resultados: A prevalência total da infecção pelo HPV foi de 21,8% (120 indivíduos). O tipo viral de maior prevalência foi o HPV 6 (35%),seguido pelo HPV 16 (20,8%), HPV 11 (19,1%), HPV 31 (6,7%), HPV 33 (6,7%), HPV 45 (8,3%) e HPV 58 (3,3%). A infecção foi majoritariamente associada a tipos de baixo risco oncogênico (54,1%), enquanto os genótipos oncogênicos foram detectados em 45,9% dos pacientes. A idade dos pacientes variou de 18 a 65 anos com média de 28,4. Conclusão: De acordo com nossos achados, podemos sugerir que a prevalência do HPV na população masculina assintomática foi consideravelmente menor do que a descrita em alguns estudos da literatura, mas em acordo com o reportado recentemente por vários autores. Acreditamos que estes resultados podem contribuir para a compreensão dos aspectos epidemiológicos associados à infecção no trato genital masculino, a fim de avaliar estratégias de prevenção de doenças associadas e avaliar o risco-benefício das diferentes abordagens aplicadas em Saúde-Pública.

Human papillomavirus infection in multiple sites / Infecção por papilomavírus humano em múltiplos sítios

Studies concerning human papillomavirus natural history have been focused on cervical infection and disease, but have scarcely describedanal infections, especially in clinically health population. Hence, knowledge on HPV natural history is recently being investigated although viral maintenance in hosts is poorly understood. Detection on diverse, extragenital sites may add in the elucidation of infection-dissemination-reinfection cycle reported onthe human genital tract. Besides that, it is evident the importance of an adequate screening of the viruses for appropriate diagnosis, mainly in the first steps of the neoplasia in order to provide a better prognosis. Our results pointed out HPV prevalence rates in genital lesions of 87% (80/92) and of 47.8%(44/92) for anal samples. We pointed out that this high prevalence is due to clinically detected lesions, that contributes to the risk of extragenital infections,mainly by host auto-inoculation. Despite the difference in samples size, we did not find statistical relevant differences related with genera (men 85.1% and women 92%; p>0.05), corroborating the idea of no tropism differences by sex. Never heless, for anal samples, statistically significant differences werefound between men and women (68% of anal HPV infection in women against 40.3% in men (p=0.038). These results reveal that female anal infections are more frequent than in men, suggesting that infection by auto inoculation occurs and can render this site as an HPV reservoir, occasionally becoming clinical lesions. Hormonal profile, sexual behavior and differences among body sites can explain these differences here described. Our study is a preliminaryevaluation of HPV infection in human multiple sites.

Muitos estudos sobre a história natural do papilomavírus humano (HPV) têm focado nas infecções cervicais, mas pouco tem se falado sobre infecções anais em pacientes assintomáticos. Assim, a história natural do HPV ainda está em construção e os mecanismos de manutenção dele no organismo hospedeiro são pouco compreendidos. Entendemos que a detecção do vírus em sítios extragenitais poderá ajudar na compreensão da cadeia de infecção disseminação-reinfecção pelo HPV no trato genital humano. Além disso, é evidente a importância de um rastreio adequado do vírus diante de diagnósticos clínicos, principalmente no período inicial da lesão, provendo, assim, um melhor prognóstico. Nossos resultados apontaram uma prevalência da infecção por HPV em lesões genitais de 87% (80/92) e nas amostras anais tal prevalência foi de 47,8% (44/92). Ressaltamos que nossa prevalência foi alta, mas estudamos indivíduos com lesões genitais clinicamente detectadas, aumentando, assim, o risco de infecção em outros sítios e confirmando a ocorrência da presença do HPV no hospedeiro, provavelmente decorrente de autoinoculação. Apesar da diferença entre o número de indivíduos dos sexos feminino e masculino em nosso estudo, não encontramos diferenças estatísticas relacionadas à presença do HPV em lesões genitais (H: 85,1% e M: 92%; p>0.05),corroborando que não há diferenças entre o tropismo por gênero referente às infecções genitais. Entretanto, no caso das infecções anais, a porcentagem foi estatisticamente diferente: 68% de HPV anal em mulheres e 40,3% em homens (p=0,038). Estes resultados apontam que a aquisição da infecção anal em mulheres, apesar de assintomática, é mais frequente do que em homens, sugerindo que esta mucosa possa ser infectada por autoinoculação e funcionar como um reservatório feminino, o que eventualmente poderá resultar em lesões. Tais discrepâncias da prevalência entre homens e mulheres poderiam se explicadas pelo comportamento sexual, por efeitos hormonais e por diferenças entre sítios. Nosso estudo se trata de um levantamento preliminar da infecção por HPV em múltiplos sítios.