Journal
VIROLOGY
Volume 347, Issue 2, Pages 405-409Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2005.11.049
Keywords
HIV-1; protease; drug resistance; co-evolution; p1-p6; D30N
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Funding
- NIGMS NIH HHS [R01 GM064347, R00GM65347] Funding Source: Medline
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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 chi(2) 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. (c) 2005 Elsevier Inc. All rights reserved.
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