Use of chimeric human immunodeficiency virus types 1 and 2 reverse transcriptases for structure-function analysis and for mapping susceptibility to nonnucleoside inhibitors.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Use of chimeric human immunodeficiency virus types 1 and 2 reverse transcriptases for structure-function analysis and for mapping susceptibility to nonnucleoside inhibitors.

J Acquir Immune Defic Syndr Hum Retrovirol. 1996 Apr 1;11(4):326-33. Unique Identifier : AIDSLINE MED/96183595
Yang G; Song Q; Charles M; Drosopoulos WC; Arnold E; Prasad VR; Department of Microbiology and Immunology, Albert Einstein; College of Medicine, New York, New York, USA.

Abstract: The human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2) reverse transcriptases (RTs) are evolutionary related. To study the effect of homologous sequence replacements on polymerase function and to map the determinants of the lack of susceptibility of HIV-2 RT to nonnucleoside drugs, a series of chimeric HIV-1/HIV-2 RTs were constructed. Analysis of the chimeric RTs showed that wild-type levels of RNA-dependent DNA polymerase activity were retained when both finger and palm subdomains were exchanged as a unit between the two parental RTs. Analysis of enzymatically active chimeras for inhibition by the thiobenzimidazolone derivative TIBO R82150 showed that a segment of HIV-2 RT at 212-250, when placed in the HIV-1 RT context, conferred a 40-fold decrease in susceptibility to TIBO R82150. Site-directed mutagenesis of this segment found Tyr227 to be a key residue in this segment for the natural resistance of HIV-2 RT to TIBO R82150.

Keywords: Amino Acids/PHYSIOLOGY Base Sequence Benzodiazepines/*PHARMACOLOGY Chimeric Proteins/CHEMISTRY/METABOLISM Human HIV-1/*ENZYMOLOGY HIV-2/*ENZYMOLOGY Imidazoles/*PHARMACOLOGY Molecular Sequence Data Mutagenesis, Site-Directed Protein Conformation Reverse Transcriptase Inhibitors/*PHARMACOLOGY RNA-Directed DNA Polymerase/CHEMISTRY/GENETICS/*METABOLISM Structure-Activity Relationship Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. JOURNAL ARTICLE
960730
M9670470

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