期刊
BIOCHEMICAL PHARMACOLOGY
卷 174, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.113625
关键词
HIV-1; Viral reservoir; NSG mice; Src tyrosine kinases; Dasatinib
资金
- Spanish Ministry of Economy and Competitiveness [SAF2013-44677-R, SAF2016-78480-R, SAF201678480-R]
- Spanish Ministry of Science, Innovation and Universities [FIS PI16CIII/00034-ISCIII-FEDER]
- Spanish AIDS Research Network [RD16CIII/0002/0001]
- ISCIII-Subdireccion General de Evaluacion
- European Funding for Regional Development (FEDER)
- Agence nationale de recherches sur le sida et les hepatites virales [ANRS 20142]
- Bristol-Myers Squibb [BMS AI471-041]
- Sara Borrell fellowship from Spanish Ministry of Economy and Competitiveness
- Spanish Ministry of Education, Culture and Sport [FPU15/03698]
- BEAT-HIV Delaney Collaboratory
HIV-1 infection remains incurable despite the efficient com(b)ined antiretroviral therapy (cART) due to the formation of long-lived viral reservoirs that are mostly settled in CD4+T cells and maintained by homeostatic proliferation. The use of cytostatic drugs such as tyrosine kinase inhibitors (TKIs) as adjuvants to cART could be helpful to avoid the reservoir establishment and replenishment. We determined previously that TKI dasatinib, which is successfully used for treating chronic myeloid leukemia (CML), shows antiviral effect against HIV-1 infection of CD4(+) T cells in vitro. HIV-infected subjects that developed CML may safely combine long-term treatment with TKIs and cART but there is no information about the effect of dasatinib on HIV-1 reservoir in vivo. Therefore, we analyzed the ability of dasatinib to protect NSG mice engrafted with human CD34+ hematopoietic stem cells from HIV-1 infection. Mice were randomly assigned to two groups that received dasatinib or placebo daily by oral gavage. After five days, all mice were infected intraperitoneally with HIV-1 and followed up for 21 days in the absence of cART. Daily administration of dasatinib decreased viral and proviral load in all treated mice, showing in 40% of these mice undetectable viral RNA or DNA in blood. Proviral HIV-1 DNA in gut-associated lymphoid tissue (GALT) was also reduced in all dasatinib-treated mice and under the limit of detection in one of these mice. Finally, treatment with dasatinib modified the distribution of CD4(+) and CD8(+) T-cell subpopulations, delaying their differentiation into memory T-cell subsets that are a major component of the viral reservoir. In conclusion, dasatinib afforded protection of NSG mice from HIV-1 intraperitoneal infection in the absence of cART.
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