title: Human Immunodeficiency Virus Gag and protease: partners in resistance.
abstract: Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.
authors.affiliation: Department of Virology, Medical Microbiology, University Medical Center Utrecht, HP G04,614, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
authors.forename: Axel
authors.initials: A
authors.lastname: Fun
authors.forename: Annemarie M J
authors.initials: AM
authors.lastname: Wensing
authors.forename: Jens
authors.initials: J
authors.lastname: Verheyen
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
mesh_terms: D001665:Binding Sites; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006801:Humans; D009154:Mutation; D012641:Selection, Genetic; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease