Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate
Biochemistry & Molecular Pharmacology
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Drug Resistance, Viral; Evolution, Molecular; Gene Products, gag; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Nelfinavir; Substrate Specificity; gag Gene Products, Human Immunodeficiency Virus
Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Microbiology
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.
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Citation: Virology. 2006 Apr 10;347(2):405-9. Epub 2006 Jan 20. Link to article on publisher's site
Kolli, Madhavi; Lastere, Stephane; and Schiffer, Celia A., "Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate" (2006). GSBS Student Publications. 616.