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Antimicrobial Agents and Chemotherapy, September 2001, p. 2510-2516, Vol. 45, No. 9
National Centre for HIV Virology Research,
Infectious Diseases Laboratories, Institute of Medical and Veterinary
Science,1 and Department of Molecular
Biosciences, University of Adelaide, North
Terrace,2 Adelaide, Australia 5000;
Laboratory of Medicinal Chemistry, Division of Basic Sciences,
National Cancer Institute, Bethesda, Maryland
208923; National Centre for HIV Virology
Research, Macfarlane Burnet Centre for Medical Research, Fairfield,
Victoria, Australia 31414; and Amrad
Operations, Richmond, Victoria, Australia, 31215
Received 20 February 2001/Returned for modification 21 May
2001/Accepted 11 June 2001
To study the effect of potential human immunodeficiency virus type
1 (HIV-1) integrase inhibitors during virus replication in cell
culture, we used a modified nested Alu-PCR assay to quantify integrated
HIV DNA in combination with the quantitative analysis of
extrachromosomal HIV DNA. The two diketo acid integrase inhibitors (L-708,906 and L-731,988) blocked the accumulation of integrated HIV-1
DNA in T cells following infection but did not alter levels of newly
synthesized extrachromosomal HIV DNA. In contrast, we demonstrated that
L17 (a member of the bisaroyl hydrazine family of integrase inhibitors)
and AR177 (an oligonucleotide inhibitor) blocked the HIV replication
cycle at, or prior to, reverse transcription, although both drugs
inhibited integrase activity in cell-free assays. Quercetin dihydrate
(a flavone) was shown to not have any antiviral activity in our system
despite reported anti-integration properties in cell-free assays. This
refined Alu-PCR assay for HIV provirus is a useful tool for screening
anti-integration compounds identified in biochemical assays for their
ability to inhibit the accumulation of integrated HIV DNA in cell
culture, and it may be useful for studying the effects of these
inhibitors in clinical trials.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2510-2516.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Specific Inhibition of Human Immunodeficiency Virus
Type 1 (HIV-1) Integration in Cell Culture: Putative Inhibitors of
HIV-1 Integrase
*
Corresponding author. Mailing address: National Centre
for HIV Virology Research, Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Frome Road, Adelaide, Australia 5000. Phone: 61 8 82223574. Fax: 61 8 82223543. E-mail:
nicholas.vandegraaf{at}imvs.sa.gov.au.
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