RESUMO
Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.
Assuntos
Sobrevivência Celular , Produtos do Gene tax , Vírus Linfotrópico T Tipo 1 Humano , NF-kappa B , Paraparesia Espástica Tropical , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Humanos , Produtos do Gene tax/metabolismo , Produtos do Gene tax/genética , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , NF-kappa B/metabolismo , Paraparesia Espástica Tropical/virologia , Paraparesia Espástica Tropical/metabolismo , Apoptose , Infecções por HTLV-I/virologia , Infecções por HTLV-I/metabolismo , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T/metabolismo , Linfócitos T/virologia , Leucemia-Linfoma de Células T do Adulto/virologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma de Células T do Adulto/patologia , Fosforilação , Células HEK293RESUMO
This study investigates the neutralizing activity against the XBB1.5 variant and the ancestral strain in a population post-bivalent vaccination using a pseudo virus assay validated with authentic virus assay. While bivalent booster vaccination and past infections enhanced neutralization against the XBB 1.5 strain, individuals with comorbidities showed reduced responses. The study suggests the need for continuous vaccine updates to address emerging SARS-CoV-2 variants and highlights the importance of monitoring real-world immune responses.