Selection and Characterization of HIV-1 with a Novel S68 Deletion in Reverse Transcriptase

• Type of Material: Article
• Authors: Raymond F Schinazi, Emory University; Ivana Massud, Atlanta Veterans Affairs Medical Center; Kimberly L. Rapp, Atlanta Veterans Affairs Medical Center; Meta Cristiano, Emory University; Mervi Acuzar Detorio, Emory University; Richard A. Stanton, Emory University; Matthew A. Bennett, Atlanta Veterans Affairs Medical Center; Monique Kierlin-Duncan, Atlanta Veterans Affairs Medical Center; Johan Lennerstrand, Atlanta Veterans Affairs Medical Center; James H Nettles, Emory University
• Language: English
• Date: 2011-05
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2011, American Society for Microbiology.
• Final Published Version (URL): http://aac.asm.org/content/55/5/2054
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• Volume: 55
• Issue: 5
• Start Page: 2054
• End Page: 2060
• Grant/Funding Information: This study was supported in part by Public Health Service grants 5R37-AI-0419801; and 5P30-AI-50409 (CFAR) and by the Department of Veterans Affairs.; Computational modeling was performed with assistance of the Emory School of Medicine Biomolecular Computing Resource (BIMCORE).; Hardware and software was supported in part through an Academic Excellence Grant from Sun Microsystems and an Academic Research Award from Accelrys Corp.
• Research Categories: Biology, Microbiology; Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

Resistance to human immunodeficiency virus type 1 (HIV-1) represents a significant problem in the design of novel therapeutics and the management of treatment regimens in infected persons. Resistance profiles can be elucidated by defining modifications to the viral genome conferred upon exposure to novel nucleoside reverse transcriptase (RT) inhibitors (NRTI). In vitro testing of HIV-1LAI-infected primary human lymphocytes treated with β-d-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68Δ) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68Δ in the HIV-1 genome. The S68Δ HIV-1 RT was phenotyped against various antiviral agents in a heteropolymeric DNA polymerase assay and in human lymphocytes. Drug susceptibility results indicate that the S68Δ displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, β-d-2′,3′-oxa-5-fluorocytidine, or 9-(β-d-1,3-dioxolan-4-yl)guanine and remained susceptible to 3′-azido-3′-deoxythymidine, 2′,3′-dideoxyinosine (ddI), 1-(β-d-dioxolane)thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the β3-β4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68Δ is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies.