Suchergebnisse

Massive activation of infected CD4+ T cells during acute HIV-1 infection leads to reservoir seeding and T-cell destruction. During T-cell activation, the antiviral effect of the innate factor SAMHD1 is neutralized through phosphorylation at T592, allowing HIV-1 infection. Dasatinib, a tyrosine kinase inhibitor currently used for treating chronic myeloid leukemia, has been described to control HIV-1 replication through its negative effect on T-cell proliferation and viral entry. We demonstrate that Dasatinib can actually interfere with SAMHD1 phosphorylation in human peripheral blood lymphocytes, preserving its antiviral activity against HIV-1. Dasatinib prevented SAMHD1 phosphorylation in vitro and ex vivo, impairing HIV-1 reverse transcription and proviral integration. This was the major mechanism of action because the presence of Vpx, which degrades SAMHD1, in HIV-1 virions impeded the inhibitory effect of Dasatinib on HIV-1 replication. In fact, infection with VSV-pseudotyped HIV-1 virions and fusion of BlaM-Vpr-containing HIV-1 viruses with activated PBMCs in the presence of Dasatinib suggested that Dasatinib was not acting at fusion level. Finally, PBMCs from patients on chronic treatment with Dasatinib showed a lower level of SAMHD1 phosphorylation in response to activating stimuli and low susceptibility to HIV-1 infection ex vivo. Consequently, Dasatinib is a compound currently used in clinic that preserves the antiviral function of SAMHD1. Using Dasatinib as adjuvant of antiretroviral therapy during early primary HIV-1 infection would contribute to reduce viral replication and spread, prevent reservoir seeding, and preserve CD4 counts and CTL responses. These events would create a more favorable virologic and immunologic environment for future interventional studies aiming at HIV-1 eradication. ; This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2010-18388, SAF2013-44677-R, FIS PI12/00506, and FIS PI12/00969); the SPANISH AIDS Research Network RD12/0017/0015 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Bristol-Myers Squibb (BMS AI471-041); AIM-HIV Network of Excellence of the EU, grant number HEALTH-F3-2012-305938; joined program of the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (ANRS AO2014-2); and the European FP7-HEALTH project HIT HIDDEN HIV. The work of Elena Mateos is supported by the Instituto de Salud Carlos III (Spain) (MPY 1371/12). The work of Sara Rodríguez-Mora is supported by a fellowship of Sara Borrell from Spanish Ministry of Economy and Competitiveness. The work of María Rosa López-Huertas is supported by a fellowship of the European Union Programme Health 2009 (CHAARM). The work of Dr Benjamin Descours is supported by the 31 European FP7-HEALTH project HIT HIDDEN HIV. 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). Dr. Juan Ambrosioni developed this work in the framework of a 'Juan de la Cierva 2012' post- doctoral program, Ministerio de Competitividad, Madrid, Spain. ; Sí

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. ; Sí

Background. CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized. Methods. We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART. Results. A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively. Conclusions. After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts. ; This work is jointly funded by the UK Medical Research Council (MRC) (grant number MR/J002380/1) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 program supported by the European Union. J. A. C. S. is funded by a National Institute for Health Research Senior Investigator award ...