Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages.
Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2',3'-dideoxy-3'-azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5'-triphosphate moieties. GM-CSF increased the levels of AZT-5'-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5'-triphosphate/thymidine-5'-triphosphate. In contrast, M-CSF-induced increases in AZT-5'-triphosphate were roughly matched by increases in thymidine-5'-triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5'-triphosphate were associated with parallel increases in the levels of deoxycytidine-5'-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5'-triphosphate/deoxycytidine-5'-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.
Perno
C F
CF
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
Cooney
D A
DA
Gao
W Y
WY
Hao
Z
Z
Johns
D G
DG
Foli
A
A
Hartman
N R
NR
Caliò
R
R
Broder
S
S
Yarchoan
R
R
D000998:Antiviral Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D016049:Didanosine / Q000378:metabolism / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004921:Erythropoietin / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology; D014779:Virus Replication; D016047:Zalcitabine / Q000378:metabolism / Q000494:pharmacology; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology
D000998:Antiviral Agents; D016207:Cytokines; D015224:Dideoxynucleosides; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D015215:Zidovudine; D016047:Zalcitabine; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016049:Didanosine