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Journal of Virology, April 2001, p. 3095-3104, Vol. 75, No. 7
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.7.3095-3104.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Target Distinct Phases of Early Reverse Transcription†

C. William Hooker,1,2,3 William B. Lott,1,3 and David Harrich1,2,3,*

HIV-1 and Hepatitis C Units, Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Herston,1 and Australian National Centre in HIV Virology Research2 and CMVC, University of Queenland,3 St. Lucia, Queensland, Australia

Received 25 August 2000/Accepted 5 January 2001

Early HIV-1 reverse transcription can be separated into initiation and elongation phases. Here we show, using PCR analysis of negative-strand strong-stop DNA [(-)ssDNA] synthesis in intact virus, that different reverse transcriptase (RT) inhibitors affect distinct phases of early natural endogenous reverse transcription (NERT). The effects of nevirapine on NERT were consistent with a mechanism of action including both specific and nonspecific binding events. The nonspecific component of this inhibition targeted the elongation reaction, whereas the specific effect seemed principally to be directed at very early events (initiation or the initiation-elongation switch). In contrast, foscarnet and the nucleoside analog ddATP inhibited both early and late (-)ssDNA synthesis in a similar manner. We also examined compounds that targeted other viral proteins and found that Ro24-7429 (a Tat antagonist) and rosmarinic acid (an integrase inhibitor) also directly inhibited RT. Our results indicate that NERT can be used to identify and evaluate compounds that directly target the reverse transcription complex.

* Corresponding author. Mailing address: Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Herston Rd., Herston, Queensland, Australia 4029. Phone: (617) 3636-1679. Fax: (617) 3636-1401. E-mail: d.harrich{at}mailbox.uq.edu.au.

dagger Manuscript 125 from The Sir Albert Sakzewski Virus Research Centre.

Journal of Virology, April 2001, p. 3095-3104, Vol. 75, No. 7
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.7.3095-3104.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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