RESUMO
Infection by human papillomavirus (HPV) alters the microenvironment of keratinocytes as a mechanism to evade the immune system. A-to-I editing by ADAR1 has been reported to regulate innate immunity in response to viral infections. Here, we evaluated the role of ADAR1 in HPV infection in vitro and in vivo. Innate immune activation was characterized in human keratinocyte cell lines constitutively infected or not with HPV. ADAR1 knockdown induced an innate immune response through enhanced expression of RIG-I-like receptors (RLR) signaling cascade, over-production of type-I IFNs and pro-inflammatory cytokines. ADAR1 knockdown enhanced expression of HPV proteins, a process dependent on innate immune function as no A-to-I editing could be identified in HPV transcripts. A genetic association study was performed in a cohort of HPV/HIV infected individuals followed for a median of 6 years (range 0.1-24). We identified the low frequency haplotype AACCAT significantly associated with recurrent HPV dysplasia, suggesting a role of ADAR1 in the outcome of HPV infection in HIV+ individuals. In summary, our results suggest that ADAR1-mediated innate immune activation may influence HPV disease outcome, therefore indicating that modification of innate immune effectors regulated by ADAR1 could be a therapeutic strategy against HPV infection.
Assuntos
Adenosina Desaminase/genética , Coinfecção/fisiopatologia , Infecções por HIV/fisiopatologia , Infecções por Papillomavirus/fisiopatologia , Proteínas de Ligação a RNA/genética , Adenosina Desaminase/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Coinfecção/genética , Coinfecção/virologia , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/virologia , Queratinócitos/metabolismo , Queratinócitos/virologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Papillomaviridae/fisiologia , Infecções por Papillomavirus/virologia , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/fisiopatologia , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/genética , Adulto JovemRESUMO
BACKGROUND: High-grade endometrial stromal sarcoma (HGES) is an aggressive disease with dismal prognosis. Surgery is the standard treatment, and radiotherapy seems to reduce local relapse. No other treatment has proved to be useful in the case of non-resectable diseases. CASE: A 41-year-old woman suffering HGES, with positive staining for CD117 (c-kit) and large abdominal and retroperitoneal mass progressing after chemotherapy, was treated with Imatinib Mesylate. After 3 months, objective response was documented and radical surgery performed. Two years after surgical intervention, she is currently free of the disease. CONCLUSION: The response seen with Imatinib should be further investigated in a larger number of cases.