3t3c

Publication Abstract from PubMed

During the last few decades, the treatment of HIV-infected patients by highly active antiretroviral therapy, including protease inhibitors (PIs), has become standard. Here, we present the analysis of a patient-derived, multi-resistant HIV-1 CRF02_AG recombinant strain with a highly mutated protease (PR) encoding sequence, where up to 19 coding mutations have accumulated in the PR. Biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and exhibiting also a very poor catalytic activity. Determination of the crystal structure revealed prominent changes in the flap elbow region and S1/S1' active site subsites. While viral loads in the patient were found to be high, the insertion of the patient-derived PR into a subtype B backbone resulted in reduction of infectivity by three orders of magnitude. Fitness compensation was not achieved by elevated Pol expression, but the introduction of patient derived gag and pol sequences in a CRF02_AG backbone rescued viral infectivity near to wild-type levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1 and p6pol/PR proteins lead much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient co-evolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure.

Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease.,Kozisek M, Henke S, Saskova KG, Jacobs GB, Schuch A, Buchholz B, Muller V, Krausslich HG, Rezacova P, Konvalinka J, Bodem J Antimicrob Agents Chemother. 2012 May 29. PMID:22644035^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.