Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2',3'-dideoxynucleoside analogs in resting and activated human cells

W. Y. Gao, R. Agbaria, J. S. Driscoll, H. Mitsuya

Research output: Contribution to journalArticlepeer-review

219 Scopus citations

Abstract

The mechanism of divergent anti-human immunodeficiency virus type 1 (HIV- 1) activity of various 2',3'-dideoxynucleoside analogs (ddNs) in peripheral blood mononuclear cells (PBM) was studied. We demonstrate that the in vitro anti-HIV-1 activity of various ddNs varies profoundly and that the divergent antiviral activity is related to the extent of anabolic phosphorylation of each ddN and its counterpart 2'-deoxynucleoside (dN). We also show that certain ddNs cause a reduction of their counterpart dNTP formation in PBM in the following order: 2',3'-dideoxycytidine (ddC) >> 2',3'-didehydro-2',3'- dideoxythymidine (d4T), 3'-thia-2',3'-dideoxycytidine (3TC), 2',3'- dideoxyinosine (ddI), 2',3'-dideoxyguanosine (ddG) > 3'-azido-2',3'- dideoxythymidine (AZT) > 2'-β-fluoro-2',3'-dideoxyadenosine (F-ara-ddA). Based on the phosphorylation profiles, anti-HIV-1 ddNs can be classified into two groups: (i) cell-activation-dependent ddNs such as AZT and d4T that are preferentially phosphorylated, yield higher ratios of ddNTP/dNTP, and exert more potent anti-HIV-1 activity in activated cells than in resting cells; and (ii) cell-activation-independent ddNs including ddI (and 2',3'- dideoxyadenosine), F-ara-ddA, ddG, ddC, and 3TC that produce higher ratios of ddNTP/dNTP and exert more potent anti-HIV-1 activity in resting cells. These data should provide a basis for the elucidation of the mechanism of the divergent antiretroviral activity of ddNs.

Original languageEnglish
Pages (from-to)12633-12638
Number of pages6
JournalJournal of Biological Chemistry
Volume269
Issue number17
StatePublished - 1 Jan 1994
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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