Human polyomaviruses and cancer: an overview

The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers

Progressive multifocal leukoencephalopathy: a challenging diagnosis established at autopsy

Progressive multifocal leukoencephalopathy (PML) is a feared entity that occurs most frequently in conditions of extreme immunodeficiency. The diagnosis is often made long after the onset of symptoms due to the physicians’ unfamiliarity, and the unavailability of diagnostic tests in some medical centers. Although the incidence of PML is decreasing among HIV patients with the advent of highly active antiretroviral therapy (HAART), in Brazil this entity is the fourth highest neurological complication among these patients. The authors present the case of a middle-aged man who tested positive for HIV concomitantly with the presentation of hyposensitivity in the face and the right side of the body, accompanied by mild weakness in the left upper limb. The clinical features worsened rapidly within a couple of weeks. The diagnostic work-up pointed to the working diagnosis of PML after brain magnetic resonance imaging; however, the detection of the John Cunningham virus (JCV) in the cerebral spinal fluid was negative. HAART was started but the patient died after 7 weeks of hospitalization. The autopsy revealed extensive multifocal patchy areas of demyelination in the white matter where the microscopy depicted demyelination, oligodendrocytes alterations, bizarre atypical astrocytes, and perivascular lymphocytic infiltration. The immunohistochemistry was positive for anti-SV40, and the polymerase chain reaction of the brain paraffin-embedded tissue was positive for JCV. The authors highlight the challenges for diagnosing PML, as well as the devastating outcome of PML among HIV patients

Detection and molecular characterization of Merkel cell Polyomavirus in Merkel cell carcinoma carcinomas de células de Merkel.

O carcinoma de células de Merkel (CCM) é uma neoplasia rara, muito agressiva que afeta principalmente indivíduos maiores de 50 anos e com o sistema imunológico comprometido. A associação do Poliomavírus humanos 5 (MCPyV) ao CCM foi estabelecida e é aceita até o momento como a única associação positiva entre um Poliomavírus e uma neoplasia em humanos. No entanto, dados como prevalência viral e presença de possíveis variantes moleculares específicas de uma determinada região geográfica não têm sido analisados em amostras do Brasil. No presente estudo, analisamos 84 amostras de 57 pacientes diagnosticados com CCM obtidas do AC Camargo Cancer Center, visando determinar: i) a prevalência de MCPyV; ii) as caracteristicas filogenéticas das sequências virais identificadas por sequenciamento; iii) a prevalência de co-infecção com HPV e iv) avaliar o padrão de expressão de proteínas relacionadas a perda de polaridade celular. Através dessa análise determinamos que a prevalência viral nas amostras estudadas é de 94,8%. Na caracterização das sequências geradas, analisarmos os fragmentos virais LT3 e VP1 e identificamos quatro variantes moleculares correspondentes a três variantes e a sequência protótipo em cada um destes. As variantes identificadas foram comparadas às descritas em banco de dados e suas sequências foram utilizadas para construir árvores filogenéticas. Dessa maneira, verificamos uma distribuição ampla e aleatória das variantes identificados nos ramos destas árvores. Finalmente, analisamos o padrão de expressão de proteínas relacionadas ao evento de perda de polaridade. De maneira geral, não observamos diferenças significates entre os padrões de marcação para as proteínas analisadas individualmente entre amostras positivas em negativas para o vírus.Merkel cell carcinoma (MCC) is a rare, very aggressive neoplasm that mainly affects individuals older than 50 years and with compromised immune systems. The association of human Polyomavirus 5 (MCPyV) with CCM has been established and is accepted to date as the only positive association between a Polyomavirus and a neoplasm in humans. However, data such as viral prevalence and the presence of possible molecular variants specific to a given geographical region have not been analyzed in samples from Brazil. In the present study, we analyzed 84 samples from 57 patients diagnosed with CCM obtained from the AC Camargo Cancer Center, in order to determine: i) the prevalence of MCPyV; ii) the phylogenetic characteristics of the viral sequences identified by sequencing; iii) the prevalence of HPV co-infection and iv) to evaluate the expression pattern of proteins related to loss of cellular polarity. Through this analysis we determined that the viral prevalence in the samples studied was 94.8%. In the characterization of the generated sequences, we analyzed the viral fragments LT3 and VP1 and identified four molecular variants corresponding to three variants and the prototype sequence in each of these. The identified variants were compared to those described in the database and their sequences were used to construct phylogenetic trees. In this way, we verified a wide and random distribution of the variants identified in the branches of these trees. Finally, we analyzed the expression pattern of proteins related to the loss of polarity event. In general, we did not observe significant differences between the marking patterns for the proteins analyzed individually between positive samples in negative for the virus

Human polyomaviruses and cancer: an overview

The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers