Impacto y mecanismo de acción del tratamiento de inhibidores de Tirosina Kinasas en la infección por el Virus de la Inmunodeficiencia Humana

Resumo

The latent viral reservoir formed by HIV-1, mainly in CD4 + T cells, is responsible for the failure of antiretroviral therapy (ART) to achieve a complete elimination of the virus in infected individuals. 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 restriction 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). Our first objective was to analyze the susceptibility to HIV-1 infection of CD4+ T lymphocytes from patients with LMC treated with TKIs. 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. 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 when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to was associated with enhanced NK-dependent cytotoxic activity. Enhanced cytotoxic activity was also observed in CD8 + T TCRγδ cells. Additionally, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIVinfected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML, three male individuals were recruited in Spain and Germany. Reservoir size and composition in peripheral blood lymphocytes from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells, the reactivation of proviruses from these cells and SAMHD1 phosphorylation were reduced. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with viral replication and HIV-1 reservoir dynamics. Moreover, treatment of HIV-infected individuals with dasatinib as adjuvant of ART could disturb the reservoir reactivation and reseeding, which might have a beneficial impact to reduce its size.