2024-03-28T13:39:59Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/139342023-10-05T06:11:03Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_14556com_20.500.12105_2337com_20.500.12105_2336com_20.500.12105_2060com_20.500.12105_2052col_20.500.12105_16988col_20.500.12105_16961col_20.500.12105_14558col_20.500.12105_2061
Repisalud
author
Vigon-Hernandez, Lorena
author
Rodríguez-Mora, Sara
author
Luna, Alejandro
author
Sandonis-Martin, Virginia
author
Mateos, Elena
author
Bautista, Guiomar
author
Steegmann, Juan Luis
author
Climent, Nuria
author
Plana, Montserrat
author
Perez-Romero, Pilar
author
De Ory, Fernando de
author
Alcamí, José
author
García-Gutiérrez, Valentín
author
Planelles, Vicente
author
Lopez-Huertas, Maria Rosa
author
Coiras, Mayte
funder
Ministerio de Economía y Competitividad (España)
funder
Red de Investigación Cooperativa en Investigación en Sida (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
National Institutes of Health (Estados Unidos)
2022-04-06T11:40:21Z
2022-04-06T11:40:21Z
2020-12
Biochem Pharmacol. 2020 Dec;182:114203.
http://hdl.handle.net/20.500.12105/13934
32828803
10.1016/j.bcp.2020.114203
1873-2968
Biochemical pharmacology
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.
eng
HIV-1
Viral reservoir
SAMHD1
Src tyrosine kinases
Chronic myeloid leukemia
Cytotoxic cell populations developed during treatment with tyrosine kinase inhibitors protect autologous CD4+ T cells from HIV-1 infection
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/13934/1/CytotoxicCellPopulationsDeveloped_2020.pdf
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https://repisalud.isciii.es/bitstream/20.500.12105/13934/4/CytotoxicCellPopulationsDeveloped_2020.pdf.txt
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CytotoxicCellPopulationsDeveloped_2020.pdf.txt