Selection and characterization of HIV-1 with a novel S68 deletion in reverse transcriptase.

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 ?-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (DFC; Dexelvucitabine; Reverset) produced a novel deletion of AGT at codon 68 (S68?) alone and in combination with K65R that differentially affects drug response. Dual-approach clone techniques utilizing TOPO cloning and pyrosequencing confirmed the novel S68? in the HIV-1 genome. The S68? 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 S68? displayed a 10- to 30-fold increase in resistance to DFC, lamivudine, emtricitabine, tenofovir, abacavir, and amdoxovir and modest resistance to stavudine, ?-d-2',3'-oxa-5-fluorocytidine, or 9-(?-D-1,3-dioxolan-4-yl)guanine and remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxyinosine (ddI), 1-(?-D-dioxolane)thymine (DOT) and lopinavir. Modeling revealed a central role for S68 in affecting conformation of the ?3-?4 finger region and provides a rational for the selective resistance. These data indicate that the novel S68? is a previously unrecognized deletion that may represent an important factor in NRTI multidrug resistance treatment strategies.

SUBMITTER: Schinazi RF 

PROVIDER: S-EPMC3088218 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature