Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: Increased potency against 3′-azido-3′-deoxythymidine-resistant HIV-1 strains

Douglas L. Mayers, Judy A. Mikovits, Bharat Joshi, Indira K. Hewlett, Joseph S. Estrada, Alan D. Wolfe, Gregory E. Garcia, B. P. Doctor, Donald S. Burke, Richard K. Gordon, James R. Lane, Peter K. Chiang

Research output: Contribution to journalArticle

Abstract

3-Deazaadenosine (DZA), 3-deaza-(±)-aristeromycin (DZAri), and 3-deazaneplanocin A (DZNep) are powerful modulators of cellular processes. When tested against H9 cells infected acutely with two different strains of human immunodeficiency virus 1 (HIV-1) and in the chronically infected monocytoid cell lines U1 and THP-1, the 3-deazanucleosides caused a marked reduction in p24 antigen production. Similar reductions in p24 antigen were seen in phytohemagglutinin-stimulated peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Strikingly, in comparing the therapeutic indices between the paired pre- and post-3′-azido-3′-deoxythymidine (AZT) treatment HIV-1 isolates, DZNep and neplanocin A showed an increase of 3- to 18-fold in their potency against AZT-resistant HIV-1 isolates. In H9 cells treated with DZNep and DZAri, the formation of triphosphate nucleotides of DZNep and DZAri was observed. The mode of action of DZNep and DZAri appears complex, at least in part, at the level of infectivity as shown by decreases in syncytia formation in HIV-1-infected H9 cells and at the level of transcription as both drugs inhibited the expression of basal or tat-induced HIV-1 long terminal repeat chloramphenicol acetyltransferase activity in stably transfected cell lines. Since DZNep induced in H9 cells a rapid expression of nuclear binding factors that recognize the AP-1 transcription site, the anti-HIV-1 activity of the DZA analogs could partly be the induction of critical factors in the host cells. Thus, the 3-deazanucleoside drugs belong to an unusual class of anti-HIV-1 drugs, which may have therapeutic potential, in particular against AZT-resistant strains.

Original languageEnglish (US)
Pages (from-to)215-219
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number1
DOIs
StatePublished - Jan 3 1995

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: Increased potency against 3′-azido-3′-deoxythymidine-resistant HIV-1 strains'. Together they form a unique fingerprint.

  • Cite this

    Mayers, D. L., Mikovits, J. A., Joshi, B., Hewlett, I. K., Estrada, J. S., Wolfe, A. D., Garcia, G. E., Doctor, B. P., Burke, D. S., Gordon, R. K., Lane, J. R., & Chiang, P. K. (1995). Anti-human immunodeficiency virus 1 (HIV-1) activities of 3-deazaadenosine analogs: Increased potency against 3′-azido-3′-deoxythymidine-resistant HIV-1 strains. Proceedings of the National Academy of Sciences of the United States of America, 92(1), 215-219. https://doi.org/10.1073/pnas.92.1.215