GSBS Student Publications

Title

Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate

Student Author(s)

Madhavi Kolli

GSBS Program

Biochemistry & Molecular Pharmacology

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology

Date

4-10-2006

Document Type

Article

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

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Microbiology

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.

Rights and Permissions

Citation: Virology. 2006 Apr 10;347(2):405-9. Epub 2006 Jan 20. Link to article on publisher's site

Related Resources

Link to article in PubMed

Journal Title

Virology

PubMed ID

16430939