title: LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions.
abstract: BACKGROUND
  LEDGINs are novel allosteric HIV integrase (IN) inhibitors that target the lens epithelium-derived growth factor (LEDGF)/p75 binding pocket of IN. They block HIV-1 integration by abrogating the interaction between LEDGF/p75 and IN as well as by allosterically inhibiting the catalytic activity of IN.
  
  
  RESULTS
  Here we demonstrate that LEDGINs reduce the replication capacity of HIV particles produced in their presence. We systematically studied the molecular basis of this late effect of LEDGINs and demonstrate that HIV virions produced in their presence display a severe replication defect. Both the late effect and the previously described, early effect on integration contribute to LEDGIN antiviral activity as shown by time-of-addition, qPCR and infectivity assays. The late effect phenotype requires binding of LEDGINs to integrase without influencing proteolytic cleavage or production of viral particles. LEDGINs augment IN multimerization during virion assembly or in the released viral particles and severely hamper the infectivity of progeny virions. About 70% of the particles produced in LEDGIN-treated cells do not form a core or display aberrant empty cores with a mislocalized electron-dense ribonucleoprotein. The LEDGIN-treated virus displays defective reverse transcription and nuclear import steps in the target cells. The LEDGIN effect is possibly exerted at the level of the Pol precursor polyprotein.
  
  
  CONCLUSIONS
  Our results suggest that LEDGINs modulate IN multimerization in progeny virions and impair the formation of regular cores during the maturation step, resulting in a decreased infectivity of the viral particles in the target cells. LEDGINs thus profile as unique antivirals with combined early (integration) and late (IN assembly) effects on the HIV replication cycle.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.
authors.forename: Belete Ayele
authors.initials: BA
authors.lastname: Desimmie
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.forename: Doortje
authors.initials: D
authors.lastname: Borrenberghs
authors.forename: Caroline
authors.initials: C
authors.lastname: Weydert
authors.forename: Wannes
authors.initials: W
authors.lastname: Thys
authors.forename: Sofie
authors.initials: S
authors.lastname: Vets
authors.forename: Barbara
authors.initials: B
authors.lastname: Van Remoortel
authors.forename: Johan
authors.initials: J
authors.lastname: Hofkens
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Jelle
authors.initials: J
authors.lastname: Hendrix
authors.forename: Norbert
authors.initials: N
authors.lastname: Bannert
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
mesh_terms: D002478:Cells, Cultured; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D055503:Protein Multimerization / Q000187:drug effects*; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1