title: Dual role of prostratin in inhibition of infection and reactivation of human immunodeficiency virus from latency in primary blood lymphocytes and lymphoid tissue.
abstract: To design strategies to purge latent reservoirs of human immunodeficiency virus type 1 (HIV-1), we investigated mechanisms by which a non-tumor-promoting phorbol ester, prostratin, inhibits infection of CD4(+) T lymphocytes and at the same time reactivates virus from latency. CD4(+) T lymphocytes from primary blood mononuclear cells (PBMC) and in blocks of human lymphoid tissue were stimulated with prostratin and infected with HIV-1 to investigate the effects of prostratin on cellular susceptibility to the virus. The capacity of prostratin to reactivate HIV from latency was tested in CD4(+) T cells harboring preintegrated and integrated latent provirus. Prostratin stimulated CD4(+) T cells in an aberrant way. It induced expression of the activation markers CD25 and CD69 but inhibited cell cycling. HIV-1 uptake was reduced in prostratin-stimulated CD4(+) T PBMC and tissues in a manner consistent with a downregulation of CD4 and CXCR4 receptors in these systems. At the postentry level, prostratin inhibited completion of reverse transcription of the viral genome in lymphoid tissue. However, prostratin facilitated integration of the reverse-transcribed HIV-1 genome in nondividing CD4(+) T cells and facilitated expression of already integrated HIV-1, including latent forms. Thus, while stimulation with prostratin restricts susceptibility of primary resting CD4(+) T cells to HIV infection at the virus cell-entry level and at the reverse transcription level, it efficiently reactivates HIV-1 from pre- and postintegration latency in resting CD4(+) T cells.
authors.affiliation: Unité de Pathogénie des Infections à Lentivirus, Parc Scientifique et Technologique de Luminy, INSERM U372, Marseille, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Biancotto
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Grivel
authors.forename: Françoise
authors.initials: F
authors.lastname: Gondois-Rey
authors.forename: Lise
authors.initials: L
authors.lastname: Bettendroffer
authors.forename: Robert
authors.initials: R
authors.lastname: Vigne
authors.forename: Stephen
authors.initials: S
authors.lastname: Brown
authors.forename: Leonid B
authors.initials: LB
authors.lastname: Margolis
authors.forename: Ivan
authors.initials: I
authors.lastname: Hirsch
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D037181:Lectins, C-Type; D008221:Lymphoid Tissue / Q000821:virology*; D010703:Phorbol Esters / Q000494:pharmacology*; D011533:Proviruses / Q000187:drug effects; D012327:RNA Virus Infections; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D014775:Virus Activation; D016662:Virus Integration / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D037181:Lectins, C-Type; D010703:Phorbol Esters; D019718:Receptors, CXCR4; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens; C070999:prostratin