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HIV-2 protease sequences of subtypes A and B harbor multiple mutations associated with protease inhibitor resistance in HIV-1

Pieniazek, Danuta; Rayfield, Marka; Hu, Dale Jb; Nkengasong, John Nb,c; Soriano, Vincentd; Heneine, Walid; Zeh, Clement; Agwale, Simon Me; Wambebe, Charlesf; Odama, Lilianae; Wiktor, Stefan Zg

Clinical Science

Background: HIV-1 protease inhibitors (PI) have been used for treating HIV-2-infected persons but little is known about amino acid mutations associated with PI resistance in HIV-2 and whether they are similar to those seen in HIV-1.

Objective: To determine the frequency of HIV-1 PI resistance-associated mutations in PI-naive HIV-2-infected individuals.

Design: Using PCR, protease genes were amplified from 76 individuals, directly sequenced, phylogenetically subtyped, and translated into amino acids to analyze PI-associated major and minor mutations.

Results: Of the 76 HIV-2 sequences, 68% belonged to subtype A and 32% to subtype B. All sequences contained at least four codon changes giving substitutions at 10, 30, 32, 36, 46, 47, 71 or 77. The frequency of these mutations was similar in subtype A and B viruses. Two major resistance-conferring mutations, 30N and 46I, were identified in one (1%) and 68 (89%) specimens, respectively. Minor mutations 10V/I, 32I, 36I, 47V, and 71V were predominant (89%–100%), followed by the rare mutation 77I (1%). Of the 76 strains, 89% harbored multiple PI resistance-associated substitutions comprising both the major 46I and minor mutations: 10V/I, 32I, 36I, 46I, 47V, 71V (76%); 10V, 32I, 36I, 46I, 47V (9%); and 10V, 32I, 36I, 46I, 47V 71V, 77I (1.3%), 10V, 32I, 46I, 47V, 71V (1.3%), and 10V, 30N, 32I, 36I, 46I, 47V, 71V (1.3%). The remaining 11% of the sequences had patterns with only minor mutations: 10V, 32I, 36I, 47V, 71V (9%) and 10V, 32I, 36I, 47V (1.3%).

Conclusions: The high frequency of multiple PI-associated substitutions represent natural polymorphisms occurring in HIV-2 strains of subtypes A and B. Phenotypic and clinical studies are needed to determine the relevance of these substitutions.

From the HIV and Retrovirology Branch and the aOffice of the Director, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Atlanta, Georgia, and the bDivision of HIV/AIDS Prevention and cProjet RETRO-CI, Ivory Coast, the dInstituto de Salud Carlos III, Madrid, Spain, the eNational Institute of Pharmaceutical Research and Development and the fFederal Ministry of Health, Abuja, Nigeria, and the gGlobal AIDS Program, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Correspondence to D. Pieniazek, 1600 Clifton Road, Mail Stop G19, Atlanta, GA 30333, USA.

Received: 8 May 2003; revised: 31 July 2003; accepted: 19 August 2003.

© 2004 Lippincott Williams & Wilkins, Inc.