Mutations in Retroviral Genes Associated with Drug Resistance

Shauna A. Clark,¹ Charles Calef,² John Mellors¹

¹ University of Pittsburgh, Scaife Hall, Suite 818, 3550 Terrace St.,

Pittsburgh, PA 15261

² T10, MS K710, Los Alamos National Laboratory, Los Alamos, NM 87545

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 the revised HIV drug resistance database stands as a testimony to the genetic flexibility of HIV. This database, updated in September 2005, lists 872 HIV-1 mutation/drug combinations, of which 28 occur in Gag, 298 occur in Protease, 6 in Integrase, 337 in RT, and 203 in Env. Although the tables are quite comprehensive, the reader should be reminded that the HIV-1 mutations described are predominantly found in clade B virus and not in other HIV genotypes. Thirty-one mutations in HIV-2 RT are listed in the table and a new section for HIV-2 Protease containing 27 entries has been added this year. In addition, 2 mutations in SIV RT are listed.

The column "Selected or Cross-R" describes how the mutations have been identified. "Selected" refers specifically to mutations identified by in vitro passage of virus in increasing concentrations of a compound, or by sequencing isolates from patients on a specific drug therapy. "Cross-R" (cross-resistance) means that virus with a mutation has been shown to have decreased susceptibility to a compound even though selection of the mutation by the compound has not been reported. The "in vitro" column has a "Y" (for yes) when resistance or cross-resistance to the compound is seen using cloned virus or in cell culture studies; the "in vivo" column has a "Y" (for yes) when resistance or cross-resistance to the compound is seen in patients.

In the "Amino Acid Change" column a + means amino acids have been inserted into the sequence, while a Delta indicates a deletion. In the "Drug Class" column, "NRTI" refers to nucleoside or nucleotide reverse transcriptase inhibitors, while non-nucleoside or HIV-1 specific RT inhibitors are called "NNRTI." The abbreviation MN stands for "Multiple Nucleoside" and refers to resistance to combinations of NRTIs. "MDR" or multi-drug resistant is noted in the "Compound" column if a mutation causes resistance to multiple compounds. Other abbreviations are listed in a separate Abbreviations Table.