Extensive polymorphisms observed in HIV–1 clade B protease gene using high–density oligonucleotide arrays

Abstract

Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.

Mutation D30N Is Not Preferentially Selected by Human Immunodeficiency Virus Type 1 Subtype C in the Development of Resistance to Nelfinavir

“…Different subtypes of human immunodeficiency virus type 1 (HIV-1) possess distinct patterns of consensus amino acid sequences in viral proteins, including the protease, a highly polymorphic and flexible enzyme (10) Nearly 47% of the 99 protease amino acids can vary naturally in wild-type viruses (both within and between subtypes) (14). Mutations at 45 amino acid positions have been associated with resistance to one or more of the six presently used protease inhibitors (PIs) (8,17,18,31).…”

Human immunodeficiency virus type 1: drug resistance in treated and untreated Brazilian children

“…This requirement for multiple mutations to overcome the activity of PI has been referred to as a "genetic barrier" to drug resistance (Kempf et al 2001). The L63P protease mutation is common in viruses that have never exposed to PIs (Kozal et al 1996) and may be more prevalent in viruses from patients in whom a protease inhibitorcontaining regimen has failed. Multi-PI resistance arises from accumulation of 4 or more of primary mutations M46I/L, V82A/F/T/S, I84V, L90M and secondary mutations L10F/I/R/V, I54V/M/L (Condra et al 1995).…”

HIV-1 Genotypic Resistance Patterns Predict Response to saquinavir–ritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed

“…Genotypic and phenotypic methods of measuring drug resistance are increasingly available to clinicians (31)(32)(33)(34)(35)(36)(37). However, the role of these tests in clinical practice has not been fully assessed.…”