Provirus reactivation is impaired in HIV-1 infected individuals on treatment with dasatinib and antiretroviral therapy

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. We previously determined that CD4 + T cells from individuals with chronic myeloid leukemia (CML) on treatment with dasatinib are resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral effect is the preservation of SAMHD1 activity. In this study, we aimed to evaluate the impact of dasatinib on the viral reservoir of HIV-infected individuals with CML who were on simultaneous treatment with ART and dasatinib. Due to the low estimated incidence of HIV-1 infection and CML (1:65,000), three male individuals were recruited in Spain and Germany. These individuals had been on treatment with standard ART and dasatinib for median 1.3 years (IQR 1.3-5.3 years). Reservoir size and composition in PBMCs from these individuals was analyzed in comparison with HIV-infected individuals on triple ART regimen and undetectable viremia. The frequency of latently infected cells was reduced more than 5-fold in these individuals. The reactivation of proviruses from these cells was reduced more than 4-fold and, upon activation, SAMHD1 phosphorylation was reduced 40-fold. Plasma levels of the homeostatic cytokine IL-7 and CD4 effector subpopulations TEM and TEMRA in peripheral blood were also reduced. Therefore, 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

Ahora / Ara

La cinquena edició del microrelatari per l’eradicació de la violència contra les dones de l’Institut Universitari d’Estudis Feministes i de Gènere «Purificación Escribano» de la Universitat Jaume I vol ser una declaració d’esperança. Aquest és el moment en el qual les dones (i els homes) hem de fer un pas endavant i eliminar la violència sistèmica contra les dones. Ara és el moment de denunciar el masclisme i els micromasclismes començant a construir una societat més igualitària. Cadascun dels relats del llibre és una denúncia i una declaració que ens encamina cap a un món millor

Vittorio f. Guidano, en homenaje.

We have gathered here to pay tribute to Vittorio F. Guidano. Give up Tribute is to give testimony of someone who maintained a way of being a person and who leave a job. Taking the floor today is a very special moment, because by talking about our experience of him, we update the figure of him, which no longer belongs to life, but he has not yet entered history. Death is the element of history, while time is the element of life, as Ortega y Zambrano they knew how to see.Nos hemos reunido aquí para rendir homenaje a Vittorio F.Guidano. Rendir homenaje es dar testimonio de alguien que mantuvo un modo de ser persona y que deja una obra. Tomar la palabra hoy constituye un momento muy especial, porque al hablar de nuestra experiencia de él, actualizamos su figura, que ya no pertenece a la vida, pero todavía no ha entrado en la historia. La muerte es el elemento de la historia, mientras que el tiempo es el elemento de la vida, como Ortega y Zambrano supieron ver

Potential role of tyrosine kinase inhibitors during primary HIV-1 infection

This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-44677-R, SAF2016-78480-R); the Instituto de Salud Carlos III (ISCIII-FIS PI16CIII/00034); and the Spanish AIDS Research Network RD16CIII/0002/0001-ISCIII-FEDER. JAM developed this work in the frame of a ‘Juan de la Cierva 2012’ post-doctoral program, Ministerio de Competitividad, Spain. JMM received a personal intensification research grant #INT15/00168 during 2016 from Instituto de Salud Carlos III, Madrid, Spain

Tyrosine kinase inhibitors: potential use and safety considerations in HIV-1 infection

INTRODUCTION: Infection caused by HIV-1 is nowadays a chronic disease due to a highly efficient antiretroviral treatment that is nevertheless, unable to eliminate the virus from the organism. New strategies are necessary in order to impede the formation of the viral reservoirs, responsible for the failure of the antiretroviral treatment to cure the infection. Areas covered: The purpose of this review is to discuss the possibility of using tyrosine kinase inhibitors (TKIs) for the treatment of HIV-1 infection. These inhibitors are successfully used in patients with distinct cancers such as chronic myeloid leukemia. The most relevant papers have been selected and commented. Expert opinion: The family of TKIs are directed against the activation of tyrosine kinases from the Src family. Some of these kinases are essential for the activation of CD4 + T cells, the major target of HIV-1. During acute or primary infection the CD4 + T cells are massively activated, which is mostly responsible for the generation of the reservoirs, the spread of the infection and the destruction of activated CD4 + T cells, infected or not. Consequently, we discuss the possibility of using TKIs as adjuvant of the antiretroviral treatment against HIV-1 infection mostly, but not exclusively, during the acute/recent phase.This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-44677-R, SAF2016-78480-R); the Instituto de Salud Carlos III (INT15/00168, ISCIII-FIS PI16CIII/00034); the Spanish AIDS Research Network RD12/0036/0004, RD16CIII/0002/0001-ISCIII-FEDER and the grant RD12/0036/0004; Bristol-Myers Squibb partially financed our study (grant BMS AI471-041). J Ambrosioni developed this work in the frame of a ‘Juan de la Cierva 2012ʹ postdoctoral program, Spanish Ministry of Economy and Competitiveness, Spain. JMM received a personal intensification research grant INT15/00168 in 2016 from Instituto de Salud Carlos III, Madrid, Spain. The European Regional Development Fund (ERDF) ‘A way to build Europe’ also provided funding.S

Evaluation of resistance to HIV-1 infection ex vivo of PBMCs isolated from patients with chronic myeloid leukemia treated with different tyrosine kinase inhibitors

Current antiretroviral treatment (ART) may control HIV-1 replication but it cannot cure the infection due to the formation of a reservoir of latently infected cells. CD4+ T cell activation during HIV-1 infection eliminates the antiviral function of the restriction factor SAMHD1, allowing proviral integration and the reservoir establishment. The role of tyrosine kinases during T-cell activation is essential for these processes. Therefore, the inhibition of tyrosine kinases could control HIV-1 infection and restrict the formation of the reservoir. A family of tyrosine kinase inhibitors (TKIs) is successfully used in clinic for treating chronic myeloid leukemia (CML). The safety and efficacy against HIV-1 infection of five TKIs was assayed in PBMCs isolated from CML patients on prolonged treatment with these drugs that were infected ex vivo with HIV-1. We determined that the most potent and safe TKI against HIV-1 infection was dasatinib, which preserved SAMHD1 antiviral function and avoid T-cell activation through TCR engagement and homeostatic cytokines. Imatinib and nilotinib showed lower potency and bosutinib was quite toxic in vitro. Ponatinib presented similar profile to dasatinib but as it has been associated with higher incidence of arterial ischemic events, dasatinib would be the better choice of TKI to be used as adjuvant of ART in order to avoid the establishment and replenishment of HIV-1 reservoir and move forward towards an HIV cure.This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2013-44677-R, SAF2016-78480-R, FIS PI12/00506, and FIS PI12/00969); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Bristol-Myers Squibb [BMS AI471-041]. The work of Elena Mateos is supported by the Spanish Ministry of Economy and Competitiveness SAF2016-78480-R. The work of María Rosa López-Huertas is financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER) and by Spanish Ministry of Economy and Competitiveness (PIE 13/00040). Dr. Montserrat Plana is a researcher at the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and is supported by the Spanish Health Institute Carlos III (ISCIII) and the Health Department of the Catalan Government (Generalitat de Catalunya, Spain). Dr. Juan Ambrosioni developed this work in the framework of a ‘Juan de la Cierva 2012’ post-doctoral program, Ministerio de Competitividad. Dr. Jose M. Miró received a personal 80:20 research grant from IDIBAPS (Barcelona, Spain), 2017-2019.S