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Mutations in HIV-1 gag and pol Compensate for the Loss of Viral Fitness Caused by a Highly Mutated Protease
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SYSNO ASEP 0383709 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Mutations in HIV-1 gag and pol Compensate for the Loss of Viral Fitness Caused by a Highly Mutated Protease Author(s) Kožíšek, Milan (UOCHB-X) RID, ORCID
Henke, S. (DE)
Grantz Šašková, Klára (UOCHB-X) RID, ORCID
Jacobs, G. B. (DE)
Schuch, A. (DE)
Buchholz, B. (DE)
Müller, V. (HU)
Kräusslich, H. G. (DE)
Řezáčová, Pavlína (UOCHB-X) RID, ORCID
Konvalinka, Jan (UOCHB-X) RID, ORCID
Bodem, J. (DE)Number of authors 11 Source Title Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology - ISSN 0066-4804
Roč. 56, č. 8 (2012), s. 4320-4330Number of pages 11 s. Language eng - English Country US - United States Keywords HIV protease ; resistance ; inhibitor ; viral fitness ; AG subtype Subject RIV EE - Microbiology, Virology R&D Projects GAP207/11/1798 GA ČR - Czech Science Foundation (CSF) CEZ AV0Z40550506 - UOCHB-X (2005-2011) UT WOS 000306826300036 DOI https://doi.org/10.1128/AAC.00465-12 Annotation 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 results of analysis of a patient-derived, multiresistant HIV-1 CRF02 AG recombinant strain with a highly mutated protease (PR) coding sequence, where up to 19 coding mutations have accumulated in the PR. The results of biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and that it also exhibits 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 HIV-1 subtype B backbone resulted in reduction of infectivity by 3 orders of magnitude. Fitness compensation was not achieved by elevated polymerase (Pol) expression, but the introduction of patient-derived gag and pol sequences in a CRF02 AG backbone rescued viral infectivity to near wild-type (wt) levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1, and p6pol/PR proteins lead to much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient coevolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2013
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