2024-03-29T08:54:35Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/877862019-03-18T14:54:11Zcom_10261_41com_10261_1col_10261_294
2013-11-28T12:50:03Z
urn:hdl:10261/87786
Combination of biological screening in a cellular model of viral latency with virtual screening identifies novel compounds that reactivate HIV-1
Gallastegui, Edurne
Luque, Neus
Terme, Jean-Michel
Gatell, Josep M.
Jordan, Albert
et al.
Although highly active antiretroviral therapy (HAART) has converted HIV into a chronic disease, a reservoir of HIV latently infected resting T cells prevents the eradication of the virus from patients. To achieve eradication, HAART must be combined with drugs that reactivate the dormant viruses. We examined this problem in an established model of HIV postintegration latency by screening a library of small molecules. Initially, we identified eight molecules that reactivated latent HIV. Using them as templates, additional hits were identified by means of similarity-based virtual screening. One of those hits, 8-methoxy-6-methylquinolin-4-ol (MMQO), proved to be useful to reactivate HIV-1 in different cellular models, especially in combination with other known reactivating agents, without causing T-cell activation and with lower toxicity than that of the initial hits. Interestingly, we have established that MMQO produces Jun N-terminal protein kinase (JNK) activation and enhances the T-cell receptor (TCR)/CD3 stimulation of HIV-1 reactivation from latency but inhibits CD3-induced interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α) gene transcription. Moreover, MMQO prevents TCR-induced cell cycle progression and proliferation in primary T cells. The present study documents that the combination of biological screening in a cellular model of viral latency with virtual screening is useful for the identification of novel agents able to reactivate HIV-1. Moreover, we set the bases for a hypothetical therapy to reactivate latent HIV by combining MMQO with physiological or pharmacological TCR/CD3 stimulation.
2013-11-28T12:50:03Z
2013-11-28T12:50:03Z
2012
2013-11-28T12:50:04Z
artículo
Journal of Virology 86(7): 3795-3808 (2012)
http://hdl.handle.net/10261/87786
10.1128/JVI.05972-11
22258251
eng
http://dx.doi.org/10.1128/JVI.05972-11
openAccess
American Society for Microbiology