A Mutation in Human Immunodeficiency Virus Type 1 Protease, N88S, That Causes In Vitro Hypersensitivity to Amprenavir

Rainer Ziermann,1 Kay Limoli,1 Kalyan Das,2 Edward Arnold,2 Christos J. Petropoulos,1 and Neil T. Parkin1,*

ViroLogic Inc., South San Francisco, California 94080,1 and Center for Advanced Biotechnology and Medicine (CABM) and Rutgers University Chemistry Department, Piscataway, New Jersey 08854-56382

Received 25 October 1999/Accepted 18 January 2000

Journal of Virology, May 2000, p. 4414-4419, Vol. 74, No. 9

This was initially reported at last Summer's Resistance Workshop in San Diego:


Amprenavir (Agenerase, 141-W94, VX-478) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PRI) recently approved for the treatment of HIV-1 infection in the United States. A major cause of treatment failure is the development of resistance to PRIs. One potential use for amprenavir is as salvage therapy for patients for whom treatment that includes one (or more) of the other four currently approved PRIssaquinavir, indinavir, ritonavir, and nelfinavirhas failed. We evaluated the cross-resistance to amprenavir of viruses that evolved during treatment with the two most commonly prescribed PRIs, nelfinavir and indinavir. Unexpectedly, a dramatic increase in susceptibility (2.5- to 12.5-fold) was observed with 20 of 312 (6.4%) patient viruses analyzed. The most pronounced increases in susceptibility were strongly associated with an N88S mutation

in protease. All viruses that carried the N88S mutation were hypersensitive to amprenavir. Site-directed mutagenesis studies confirmed the causal role of N88S in determining amprenavir hypersensitivity. The presence of the N88S mutation and associated amprenavir hypersensitivity may be useful in predicting an improved clinical response to amprenavir salvage therapy.