AAC Accepts, published online ahead of print on 13 November 2006

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00690-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification and Structural Characterization of I84C and I84A Mutations that are Associated with High-Level Resistance to HIV Protease Inhibitors and Impair Viral Replication

Hongmei Mo, Neil Parkin, Kent D. Stewart, Liangjun Lu, Tatyana Dekhtyar, Dale Kempf, and Akhteruzzaman Molla^*

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois; Monogram, Inc, South San Francisco, CA

^* To whom correspondence should be addressed. Email: Akhter.m.molla{at}abbott.com.

Two novel HIV protease mutations, I84C and I84A, were identified in patient isolates. The I84C mutants displayed high-level (median at least 56-fold) resistance to nelfinavir and saquinavir, but the majority remained susceptible to lopinavir. In contrast, I84A isolates exhibited 33-fold median resistance to nelfinavir, indinavir, amprenavir, ritonavir, lopinavir, saquinavir and atazanavir. I84A or I84C tended to be more resistant than isolates I84V. Modeling of the structure of the mutant proteases indicated that I84V, I84C and I84A mutations all create unoccupied volume in the active site, with I84A introducing the greatest change in accessible surface area from the wild-type structure.

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