title: Prostaglandin E2 reduces the release and infectivity of new cell-free virions and cell-to-cell HIV-1 transfer.
abstract: BACKGROUND
  The course of human immunodeficiency virus type-1 (HIV-1) infection is influenced by a complex interplay between viral and host factors. HIV infection stimulates several proinflammatory genes, such as cyclooxigense-2 (COX-2), which leads to an increase in prostaglandin (PG) levels in the plasma of HIV-1-infected patients. These genes play an indeterminate role in HIV replication and pathogenesis. The effect of prostaglandin E2 (PGE2) on HIV infection is quite controversial and even contradictory, so we sought to determine the role of PGE2 and the signal transduction pathways involved in HIV infection to elucidate possible new targets for antiretrovirals.
  
  
  RESULTS
  Our results suggest that PGE2 post-infection treatment acts in the late stages of the viral cycle to reduce HIV replication. Interestingly, viral protein synthesis was not affected, but a loss of progeny virus production was observed. No modulation of CD4 CXCR4 and CCR5 receptor expression, cell proliferation, or activation after PGE2 treatment was detected. Moreover, PGE2 induced an increase in intracellular cAMP (cyclic AMP) levels through the EP2/EP4 receptors. PGE2 effects were mimicked by dbcAMP and by a specific Epac (exchange protein directly activated by cyclic AMP) agonist, 8-Cpt-cAMP. Treatment with PGE2 increased Rap1 activity, decreased RhoA activity and subsequently reduced the polymerization of actin by approximately 30% compared with untreated cells. In connection with this finding, polarized viral assembly platforms enriched in Gag were disrupted, altering HIV cell-to-cell transfer and the infectivity of new virions.
  
  
  CONCLUSIONS
  Our results demonstrate that PGE2, through Epac and Rap activation, alters the transport of newly synthesized HIV-1 components to the assembly site, reducing the release and infectivity of new cell-free virions and cell-to-cell HIV-1 transfer.
authors.affiliation: Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain ; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Clemente
authors.affiliation: Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain ; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Álvarez
authors.affiliation: Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain ; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Serramía
authors.affiliation: Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain ; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martínez-Bonet
authors.affiliation: Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain ; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain ; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Muñoz-Fernández
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015728:Receptors, HIV / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000502:physiology; D034501:Telomere-Binding Proteins / Q000378:metabolism; D014771:Virion / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D015728:Receptors, HIV; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D000242:Cyclic AMP; D015232:Dinoprostone