Infecção pelo papilomavírus humano: etiopatogenia, biologia molecular e manifestações clínicas / Human papillomavirus infection: etiopathogenesis, molecular biology and clinical manifestations

O papilomavírus humano (HPV) é um vírus DNA que apresenta tropismo por células epiteliais, causando infecções na pele e nas mucosas. A replicação do HPV ocorre no núcleo das células escamosas e o seu ciclo de vida é diretamente relacionado ao programa de diferenciação da célula hospedeira. Até o momento, foram completamente caracterizados cerca de 100 tipos diferentes de HPVs e há um grande número adicional de tipos ainda não sequenciados. Além de ser o responsável por lesões benignas de pele e mucosas, o HPV também está envolvido no desenvolvimento de diversos tumores cutaneomucosos: doença de Bowen, cânceres de pele não melanoma e carcinomas genitais. Esta revisão aborda as características do HPV, quadros cutâneos e mucosos benignos e malignos causados por ele e os principais métodos empregados em sua detecção e tipagem.

Human papillomavirus (HPV) is a DNA virus that presents tropism for epithelial cells, causing infections of the skin and mucous membranes. Replication of HPV occurs in the nuclei of squamous cells and its life cycle is directly related to the differentiation program of the host cell. To date, nearly 100 different types of HPV have been characterized and there is a large number of other types that have not been sequenced yet. Besides being responsible for benign lesions of the skin and mucous membranes, HPV is also involved in the development of various mucocutaneous tumors: Bowen's disease, non-melanoma skin cancers and genital carcinomas. This review discusses the characteristics of HPV, malignant and benign mucous and skin manifestations caused by HPV, besides the main methods of detection and typing of the virus.

Analysis of the p53 gene and papillomavirus detection in smears from cervical lesions

CONTEXT: Alterations of the p53 tumor suppressor gene are correlated with a critical step in the development of many human cancers.The tumor suppressor gene functions include regulation of the cell cycle and the cellular response to DNA damage, initiation of DNA repair and replication, induction of apoptosis and promotion of cell differentiation. CASE REPORT: Smears from ten cases of cervical lesions were analyzed for status of exons 5-8 of the p53 gene using PCR/SSCP. HPV infection was also screened by the PCR method using two PCR primer sets. Changes in the p53 gene were observed in a case of squamous carcinoma and a case of asymptomatic cervical intraepithelial neoplasia grade III (CIN III). High-risk HPV was detected in both cases showing that HPV infection and p53 mutation are not exclusive events

Prevention of carcinoma of cervix with human papillomavirus vaccine.

BACKGROUND: Carcinoma of cervix is the most common cancer found among the women of India. Though cervical cytology screening was effective in preventing carcinoma of cervix in developed nations, it is considered unsuitable in developing countries. Recent research has established an etiological link between human papillomavirus infection and carcinoma of cervix. In this review, an attempt is made to answer the question, 'whether carcinoma of cervix can be prevented with human papillomavirus vaccine?' METHODS: Literature search using Pubmed and Medline was carried out and relevant articles were reviewed. RESULTS: There is ample experimental evidence to show that DNA of human papillomavirus integrates with cervical cell genome. Viral genes E6 and E7 of HPV type 16 and 18 inactivate p53 function and Rb gene, thus immortalize the cervical epithelial cells. Recombinant vaccines blocked the function of E6 and E7 genes preventing development of papillomas in animals. Vaccination with HPV-VLPs encoding for genes of E6 and E7 neutralizes HPV integrated genome of malignant cells of uterine cervix. CONCLUSIONS: Based on experimental evidence, it is possible to prevent carcinoma of cervix with human papillomavirus vaccine, IMPLICATIONS: Further research is necessary to identify a effective and safe HPV vaccine, routes of administration and characteristics of potential beneficiaries.

Molecular variability of human papillomaviruses and susceptibility to cervical neoplasia

Genetic variability in the genome of human papillomaviruses (HPV) has been described, particularly in the high-risk types 16 and 18. Based on extensive DNA sequencing analyses of HPV isolates from clinical specimens, a number of variants have been described whose nucleotide sequence does not vary more than 2 percent in coding and 5 percent in noncoding regions of the viral genome. Nucleotide sequence variation has being used as a tool for epidemiological studies of viral transmission and persistence. In the ongoing cohort study being performed in Brazil, we are abalyzing the risk of persistent infection and development of cervical lesions regarding geographical relatedness of variants. Infections with HPV types 16 and 18 were more likely to persist than those with other oncogenic types, with no significant differences between European and non-European variants regarding their tendency to persist. On the other hand, non-European HPV 16 and 18 variants were more strongly associated with risk of cervical neoplasia during follow-up than European variants, as compared with other oncogenic HPVs and low oncogenic risk HPVs. Epitope variability mays also have important implications in the immune response elicited against these viruses as well as in the design of vaccines directed against HPVs. Since these viruses are the etiologic agents of cervical cancer, those studies may provide useful information for the control of these common infections, leading ultimately to a reduction in the morbidity and mortality rates associated with this cancer.

Genetic susceptibility to HPV infection and cervical cancer

Squamous cell carcinoma of the cervix (SCCC) is one of the leading causes of death in developing countries. Infection with high-risk human papillomavirus (HPV) is the major risk factor to develop malignant lesions in the cervix. Polymorphisms of the MHC and p53 genes seem to influence the outcome of HPV infection and progression to SCCC, although controversial data have been reported. MHC are highly polymorphic genes that encode molecules involved in antigen presentation, playing a key role in immune regulation, while p53 is a tumor suppressor gene that regulates cell proliferation. The HPV E6 protein from high-risk types binds p53 and mediates its degradation by the ubiquitin pathway. The role of these polymorphisms in genetic susceptibility to HPV infection and to SCCC remains under investigation

En busca de secuencias retrovirales relacionadas con el cáncer de mama humano / Searching for retroviral sequences related to human breast cancer

The participation of viruses in mammary carcinogenesis has been largely studied in animals. A model similar to the mouse mammary tumor virus (MMTV) was previously proposed. Several lines of research supported the participation of MMTV in human breast cancer, but these evidences were contradicted when further research was performed. One major issue was the presence of human endogenous retroviral sequences that confounded results reporting MMTV-like sequences in human breast cancer. To overcome this problem we selected a 660 bp sequence of the MMTV env gene with low homology to endogenous sequences and search for a sequence to it using the polymerase chain reaction (PCR). The sequence was found in 38 of the human breast cancers and in 2 of the normal breasts studied. The sequence was not present in tumors from other organs. It was 90-98 homologous to MMTV and only 18 to human endogenous retrovirus (HERV) K-10. It was also detected in some of the positive tumors by Southern blot hybridization using one of the cloned 660 bp as a probe. Using reverse transcriptase PCR, it was possible to demonstrate that the 660 bp sequence is expressed in the majority of the tumors. Also, preliminary experiments revealed that sequences related to the LTR and gag genes of MMTV were present in the DNA of breast tumors. The origin of the MMTV-like sequences in tumor DNA could be the result of integrated MMTV-like sequences derived from a human mammary virus or may represent unknown endogenous sequences that can only be detected in breast tumors.

Mouse mammary tumor virus (MMTV), a retrovirus that exploits the immune system. Genetics of susceptibility to MMTV infection

All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in inbred mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms that determine genetic susceptibility to MMTV-induced mammary tumors, the regulation of virus gene expression in vivo and how the virus is transmitted between different cell types. We have found that some endogenous MMTVs are only expressed in lymphoid tissue and that a single base pair change in the long terminal repeat of MMTV determines whether the virus is expressed in mammary gland. This expression in lymphoid cells is necessary for the infectious cycle of MMTV, and both T and B cells express and shed MMTV. Infected lymphocytes are required not only for the initial introduction of MMTV to the mammary gland, but also for virus spread at later times. Without this virus spread, mammary tumorigenesis is dramatically reduced. Mammary tumor incidence is also affected by the genetic background of the mouse and at least one gene that affects infection of both lymphocytes and mammary cells has not yet been identified. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms that viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.

Superantígenos y retrovirus del tumor mamario murino / Superantigens and murine mammary tumor retrovirus

Hosts and their pathogens have co-evolved for millions of years, developing multiple and intimate interactions. Vertebrates have evolved a very complex immune system which pathogens have often been able to circumvent, in some cases even managing to appropriate some of its components for their own purpose. Among the pathogens which do use components of the immune system to survive and propagate, those coding for the expression of superantigens (SAgs) are now under intense scrutiny. Investigations concerning one of these pathogens, the mouse mammary tumor virus (MMTV), led to the understanding of how the expression of such components is a critical step in their life cycle. A number of milk-borne exogenous MMTV infect mice shortly after birth and, when expressed, produce superantigens. Herein, we describe the biological effects of new variants of MMTV. Two of these, BALB14 and BALB2 encoding SAgs with V beta 14+ and V beta 2+ specificities, respectively, were present in BALB/c mice of our colony (BALB/cT); a third variant, termed MMTV LA, originated in (BALB/cTxAKR)F1 mice from recombination between BALB 14 and Mtv-7 endogenous provirus. The recombinant LA virus induces the deletion of V beta 6+ and V beta 8.1+ T cells as a consequence of the acquisition of SAg hypervariable coding region of Mtv-7. The SAg encoded by MMTV LA strongly stimulates cognate T cells in vivo leading to a very effective amplification of lymphoid cells in BALB/c mice, correlating with a high incidence of mammary tumors. These results suggest that the presence of non-productive endogenous proviruses--generally considered to confer a selective advantage to the host by protecting it from infection with exogenous MMTVs encoding cross-reactive SAgs--could also be advantageous for the pathogen by increasing its variability, thus broadening the host range and allowing the expansion of highly tumorigenic variants.

Mouse mammary tumor virus (MMTV), a retrovirus that exploits the immune system. Genetics of susceptibility to MMTV infection

All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in inbred mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms that determine genetic susceptibility to MMTV-induced mammary tumors, the regulation of virus gene expression in vivo and how the virus is transmitted between different cell types. We have found that some endogenous MMTVs are only expressed in lymphoid tissue and that a single base pair change in the long terminal repeat of MMTV determines whether the virus is expressed in mammary gland. This expression in lymphoid cells is necessary for the infectious cycle of MMTV, and both T and B cells express and shed MMTV. Infected lymphocytes are required not only for the initial introduction of MMTV to the mammary gland, but also for virus spread at later times. Without this virus spread, mammary tumorigenesis is dramatically reduced. Mammary tumor incidence is also affected by the genetic background of the mouse and at least one gene that affects infection of both lymphocytes and mammary cells has not yet been identified. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms that viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.

Visión retrospectiva de la relación entre los retrovirus y el cáncer / Retrovirus and cancer revisited

The discovery of RNA oncoviruses dates back to 1911 when Rous isolated the avian virus which is the cause of the sarcoma which bears his name and to 1936 when Bittner related the "milk factor" to the development of murine mammary cancer. During the 50s, the successive descriptions of virus-induced sarcoma-leukemias in mice led to the oncogene theory and gradually to the postulation of a viral origin of cancer. The discovery of the reverse transcriptase in 1970 led to the establishment of the Retroviridae family including both onco and lentiviruses. The decade of the 80s was marked by three fundamental discoveries which altered the concept of oncovirus: 1) oncogenes became established as part of the cellular genome converting retroviruses into occasional vectors of the oncogene; 2) as the T cell growth factor, interleukin-2, became available, the first human oncovirus, HTLV-I, was isolated and proved to be the cause of adult T cell leukemia; 3) HIV was isolated and classified as a lentivirus and as the cause of AIDS. A few years later the antioncogenes were discovered. Both oncogenes and anti-oncogenes were found to collaborate in the cell cycle, maintaining an equilibrium between proliferation and apoptosis. Today the viral theory has been replaced by the gene theory of cancer which postulates that neoplastic transformation is the result of a cascade of events which include uncorrected DNA errors, blocking of apoptosis, activation of oncogenes and deletion of antioncogenes. At the present time, the intriguing question for retrovirologists is the role played by endogenous retroviruses which in man occupy up to 0.1 of the cellular genome.

Microsatellite instability in Epstein-Barr virus associated with nasopharyngeal carcinoma.

The result reported here represents the first human genomic screen for MSI in Epstein-Barr-Virus associated NPC. The analysis revealed the incidence of MSI only 1 of 23 cases (4%) which indicates that MSI is less common in NPC development.

Loss of heterozygosity for chromosome 11 in Epstein-Barr-virus associated nasopharyngeal carcinoma.

In order to demonstrate and define possible tumor suppressor gene loci on chromosome 11 associated with NPC, we used 7 STR to test for LOH on 25 NPC samples. LOH was detected in 46 per cent of cases. Most LOH loci were clustered on the long arm. Further study demonstrated 22 per cent and 45.5 per cent of cases with LOH on 11q13 and 11q23 respectively.

Altered p53 expression in Epstein Barr virus positive T cell lymphomas

Recent studies have suggested a probable association between Epstein-Barr virus (EBV) and nasal/nasopharyngeal T cell lymphomas but the role of oncogenes or tumor suppressor genes is poorly understood. We have studied the frequency of p53 expression and its relation to the EBV infection in 33 Korean patients with head and neck (H&N) lymphomas. All cases (23 B cell & 10 T cell) were immunostained for p53 protein using the mAb D07 (Novocastra) and the avidin biotin peroxidase method. EBER in situ hybridization was performed using a fluorescein conjugated EBV oligonucleotide probe (Dako). Among 33 lymphomas, 16 cases stained positively for p53 protein. P53 expression was frequent both in higher grade lymphomas and in advanced stage. Nine cases were EBER positive, EBER was more commonly found in T cell lymphomas than in B cell lymphomas (70% vs 8.7%). EBER positive lymphomas showed a higher frequency of p53 positivity than EBER negative lymphomas (78% vs 38%), although the difference was not statistically significant (p = 0.095). These findings indicate altered expression of p53 protein occurs in H&N lymphomas, especially in late event lymphoma progression and appears to play a role in the development of EBER positive T cell lymphomas.

Aspectos moleculares de los papilomavirus humanos y su relación con el cáncer cérvico-uterino / Molecular aspects of human papillomaviruses and their relationship to uterine-cervix carcinoma

Los papilomavirus son responsables del desarrollo de lesiones epiteliales benignas y malignas en mamíferos. Más de 60 tipos diferentes de papilomavirus humanos (HPVs) han sido aislados hasta ahora: algunos de ellos participan de manera importante en el desarrollo del cáncer cervical. El DNA de los tipos de 90 por ciento de los carcinomas genitales. La integración del DNA viral en el genoma celular puede ser un paso importante en el desarrollo de la enfermedad. Dos genes tempranos de los HPVs (E6 y E7) están involucrados en la inmortalización celular. Otro gen temprano (E2) participa en el control de la expresión de los oncogenes, al unirse directamente a regiones conservadas del genoma viral como celular, interactúan con la región regulatoria de los HPVs, y participan en la regulación de la transcripción de los oncogenes E6 y E7. Factores celulares, tales como el sistema inmune, oncogenes o antioncogenes, parecen jugar un papel importante en la carcinogénesis asociada con los HPVs.