title: Characterization of rare lens epithelium-derived growth factor/p75 genetic variants identified in HIV-1 long-term nonprogressors.
abstract: OBJECTIVE
  Lens epithelium-derived growth factor (LEDGF)/p75 is a cellular binding partner of HIV-1 integrase and a crucial cofactor for HIV-1 replication. Here, we study two LEDGF/p75 exonic variants I436S and T473I, identified in HIV-1 long-term nonprogressors, together with Q472L.
  
  
  METHODS
  In-vitro binding assays, cell culture complementation, and functional rescue.
  
  
  RESULTS
  Binding affinities of wild-type, I436S, T473I, and Q472L LEDGF/p75 for HIV-1 integrase were comparable. All LEDGF/p75 variants bound equally well to LEDGF/p75 interacting partners JPO2 and PogZ. In addition, HIV-1 replication was evaluated in human somatic LEDGF/p75-knockout cells and LEDGF/p75-knockdown cells complemented with either wild-type LEDGF/p75 or the respective LEDGF/p75 variants. All variants rescued HIV-1 replication to wild-type levels, whereas LEDGF/p75 D366N, defective for interaction with HIV-1 integrase, did not.
  
  
  CONCLUSIONS
  Although identified in a cohort of long-term nonprogressors, our study did not indicate that the I436S or T473I mutation in LEDGF/p75 affects the interaction with HIV-1 integrase.
authors.affiliation: Molecular Virology and Gene Therapy, KU Leuven, Leuven, Flanders, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Schrijvers
authors.forename: Jonas
authors.initials: J
authors.lastname: Demeulemeester
authors.forename: Jan
authors.initials: J
authors.lastname: De Rijck
authors.forename: Frauke
authors.initials: F
authors.lastname: Christ
authors.forename: Melanie
authors.initials: M
authors.lastname: Gérard
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D019380:Anti-HIV Agents / Q000627:therapeutic use; D005091:Exons; D019427:HIV Integrase / Q000378:metabolism*; D020276:HIV Long-Term Survivors; D006679:HIV Seropositivity / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007532:Isoleucine; D017354:Point Mutation; D011485:Protein Binding; D012694:Serine; D013912:Threonine; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019380:Anti-HIV Agents; C504649:PSIP1 protein, human; D014157:Transcription Factors; D007532:Isoleucine; D013912:Threonine; D012694:Serine; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1