title: Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate.
abstract: The selective pressure of the competitive protease inhibitors causes both HIV-1 protease and occasionally its substrates to evolve drug resistance. We hypothesize that this occurs particularly in substrates that protrude beyond the substrate envelope and contact residues that mutate in response to a particular protease inhibitor. To validate this hypothesis, we analyzed substrate and protease sequences for covariation. Using the chi2 test, we show a positive correlation between the nelfinavir-resistant D30N/N88D protease mutations and mutations at the p1-p6 cleavage site as compared to the other cleavage sites. Both nelfinavir and the substrate p1-p6 protrude beyond the substrate envelope and contact residue 30, thus possibly making the p1-p6 cleavage site more vulnerable to co-evolution.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Kolli
authors.forename: Stephane
authors.initials: S
authors.lastname: Lastere
authors.forename: Celia A
authors.initials: CA
authors.lastname: Schiffer
mesh_terms: D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D015683:Gene Products, gag / Q000737:chemistry / Q000378:metabolism*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D013379:Substrate Specificity; D054301:gag Gene Products, Human Immunodeficiency Virus
chemical_list: D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; C083868:gag protein p1, Human immunodeficiency virus; C083002:p6 gag protein, Human immunodeficiency virus 1; D016333:HIV Protease; D019888:Nelfinavir