Inhibition of HIV infection of resting peripheral blood lymphocytes by nucleosides.
T cells in the peripheral blood are largely in the resting state and represent a significant pool of potential targets for HIV infection. The protection of these cells from infection is an important goal of nucleoside therapy. Resting PBL may not be protected effectively by such nucleosides as azidothymidine (AZT) since anabolic phosphorylation of thymidine nucleosides is reported to be limited in these cells. In this study we used DNA amplification procedures to follow HIV proviral DNA formation in resting T cells and to determine the ability of azidodeoxythymidine (AZT), dideoxyinosine (ddI), and dideoxycytosine (ddC) to inhibit this process. Experiments confirm that resting PBL synthesize HIV proviral DNA sequences. Drug titrations showed that this synthesis could be inhibited by nucleosides. ddC was the most potent drug, inhibiting transcription at the U5 region. ddI and AZT at similar concentrations (10 microM) did not inhibit. ddI in the concentration range of 10-100 microM was able to inhibit production of transcripts containing U3 and env sequences in resting cells. Similar inhibition levels were accomplished by AZT at 10-100-fold lower drug concentrations. These results demonstrate that resting T cells can be protected from HIV infection by nucleosides and that thymidine nucleosides are effective inhibitors despite the limited potential for anabolic phosphorylation.
Watson
A J
AJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Wilburn
L M
LM
D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral / Q000096:biosynthesis; D016049:Didanosine / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000382:microbiology*; D014779:Virus Replication / Q000187:drug effects; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
D004279:DNA, Viral; D015215:Zidovudine; D016047:Zalcitabine; D016049:Didanosine