title: HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.
abstract: BACKGROUND
  Maturation inhibitors are an experimental class of antiretrovirals that inhibit Human Immunodeficiency Virus (HIV) particle maturation, the structural rearrangement required to form infectious virus particles. This rearrangement is triggered by the ordered cleavage of the precursor Gag polyproteins into their functional counterparts by the viral enzyme protease. In contrast to protease inhibitors, maturation inhibitors impede particle maturation by targeting the substrate of protease (Gag) instead of the protease enzyme itself. Direct cross-resistance between protease and maturation inhibitors may seem unlikely, but the co-evolution of protease and its substrate, Gag, during protease inhibitor therapy, could potentially affect future maturation inhibitor therapy. Previous studies showed that there might also be an effect of protease inhibitor resistance mutations on the development of maturation inhibitor resistance, but the exact mechanism remains unclear. We used wild-type and protease inhibitor resistant viruses to determine the impact of protease inhibitor resistance mutations on the development of maturation inhibitor resistance.
  
  
  RESULTS
  Our resistance selection studies demonstrated that the resistance profiles for the maturation inhibitor bevirimat are more diverse for viruses with a mutated protease compared to viruses with a wild-type protease. Viral replication did not appear to be a major factor during emergence of bevirimat resistance. In all in vitro selections, one of four mutations was selected: Gag V362I, A364V, S368N or V370A. The impact of these mutations on maturation inhibitor resistance and viral replication was analyzed in different protease backgrounds. The data suggest that the protease background affects development of HIV-1 resistance to bevirimat and the replication profiles of bevirimat-selected HIV-1. The protease-dependent bevirimat resistance and replication levels can be explained by differences in CA/p2 cleavage processing by the different proteases.
  
  
  CONCLUSIONS
  These findings highlight the complicated interactions between the viral protease and its substrate. By providing a better understanding of these interactions, we aim to help guide the development of second generation maturation inhibitors.
authors.affiliation: Department of Virology, Medical Microbiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Fun
authors.forename: Noortje M
authors.initials: NM
authors.lastname: van Maarseveen
authors.forename: Jana
authors.initials: J
authors.lastname: Pokorná
authors.forename: Renée Em
authors.initials: RE
authors.lastname: Maas
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Schipper
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D013386:Succinates / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D019065:Virus Assembly / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism; D053978:Pentacyclic Triterpenes
chemical_list: D016333:HIV Protease; D017320:HIV Protease Inhibitors; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C083868:gag protein p1, Human immunodeficiency virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes