Effects of bone marrow stimulatory cytokines on human immunodeficiency
virus replication and the antiviral activity of dideoxynucleosides in
cultures of monocyte/macrophages
CF Perno, DA Cooney, WY Gao, Z Hao, DG Johns, A Foli, NR Hartman, R Calio, S Broder and R Yarchoan
Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
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.
Volume 80,
Issue 4,
pp. 995-1003,
08/15/1992
Copyright © 1992 by The American Society of Hematology
