Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/13934
Título
Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection
Autor(es)
Vigon-Hernandez, Lorena ISCIII | Rodríguez-Mora, Sara ISCIII | Luna, Alejandro | Sandonis-Martin, Virginia ISCIII | Mateos, Elena ISCIII | Bautista, Guiomar | Steegmann, Juan Luis | Climent, Nuria | Plana, Montserrat | Perez-Romero, Pilar ISCIII | De Ory, Fernando de ISCIII | Alcamí, José ISCIII | García-Gutiérrez, Valentín | Planelles, Vicente | Lopez-Huertas, Maria Rosa ISCIII | Coiras, Mayte ISCIII
Fecha de publicación
2020-12
Cita
Biochem Pharmacol. 2020 Dec;182:114203.
Idioma
Inglés
Tipo de documento
journal article
Resumen
Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCRγδ and more than 18-fold increased production of IFNγ upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics.
Palabras clave
MESH
Adult | Aged | Aged, 80 and over | Antiviral Agents | CD4-Positive T-Lymphocytes | Cytoprotection | Female | HIV Infections | HIV-1 | Humans | Leukemia, Myelogenous, Chronic, BCR-ABL Positive | Male | Middle Aged | Protein Kinase Inhibitors
Descripción
Factor de impacto: 5,858 Q1
Versión en línea
DOI
Aparece en las colecciones
- Investigación > IIS > IDIBAPS - Instituto de Investigaciones Biomédicas August Pi i Sunyer (Cataluña)
- Eventos Científicos > ISCIII > Programa de Mentores del ISCIII > Publicaciones de los mentorizados
- Investigación > ISCIII > Centro Nacional de Microbiología (CNM)
- Investigación > IIS > IRYCIS - Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)