Mutations in Retroviral Genes Associated with Drug Resistance

Urvi Parikh,¹ Charles Calef,² Brendan Larder,³ Raymond Schinazi,⁴ and John W. Mellors¹

¹ University of Pittsburgh, Scarfe Hall, Suite 818, 3550 Terrace St., Pittsburgh, PA 15261.
² T10, MS K710, Los Alamos National Laboratory, Los Alamos, NM 87545.
³ Virco, U.K., 162A Cambridge Science Park, Milton Road, Cambridge CB4 4GH, U.K.
⁴ Emory University/VAMC, 1670 Clairmont Rd., Decatur, GA 30033.

Introduction

Drug resistance is the inevitable consequence of incomplete suppression of HIV replication. The rapid replication rate of HIV and its inherent genetic variation have led to the identification of many HIV variants that exhibit altered drug susceptibility. The growing number of drug resistance mutations listed in this revised table stands as a testimony to the genetic flexibility of HIV. This table, updated in March 2003, lists 647 HIV-1 mutation/drug combinations, of which 179 occur in protease, 1 in integrase, 305 in RT, and 139 in Env. Although the tables are quite comprehensive, the reader should be reminded that the mutations described are predominantly found in clade B virus and not in other HIV genotypes. The revised table also includes drug resistance mutations that have been identified for SIV and FIV. In the table the phrase "Enzyme resist" refers to inhibition assays done just with a mutated enzyme. Instead of introducing the mutations into a virus and testing the susceptibility of the mutant virus to a drug, researchers introduce the mutation(s) into the enzyme and determine their effect by running enzyme activity assays. This type of susceptibility testing does not take into account changes in other viral proteins (like Gag) that would also help confer resistance, which is the reason for distinguishing enzyme resistance from whole virus resistance. In the "Amino Acid Change'' column a + means amino acids have been inserted into the sequence, while a Delta indicates a deletion. In the "Class of Drug'' column the abbreviation MN stands for "Multiple Nucleoside'' and refers to resistance to combinations of nucleoside RTIs. Other abbreviations used in the table are listed in a separate Abbreviations Table. All of the information contained in this article's printed tables is available at our Web site: http://resdb.lanl.gov/Resist_DB.

Acknowledgments

The authors would like to gratefully acknowledge their colleagues for assistance in assembling this table. This work was supported in part by the National Institutes of Health and the Department of Veterans Affairs.