title: Combination of biological screening in a cellular model of viral latency and virtual screening identifies novel compounds that reactivate HIV-1.
abstract: 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.
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spaina; Gladstone Institute of Virology and Immunology, San Francisco, California, USA. albert.jordan@ibmb.csic.es
authors.forename: Edurne
authors.initials: E
authors.lastname: Gallastegui
authors.forename: Brett
authors.initials: B
authors.lastname: Marshall
authors.forename: David
authors.initials: D
authors.lastname: Vidal
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Sanchez-Duffhues
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.forename: Carmen
authors.initials: C
authors.lastname: Alvarez-Fernández
authors.forename: Neus
authors.initials: N
authors.lastname: Luque
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Terme
authors.forename: Josep M
authors.initials: JM
authors.lastname: Gatell
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Sánchez-Palomino
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
authors.forename: Albert
authors.initials: A
authors.lastname: Jordan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D054852:Small Molecule Libraries