Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2'3'-dideoxythymidine (AZT) and other dideoxynucleoside congeners of thymidine.
We have investigated the influence of granulocyte-macrophage CSF (GM-CSF) on the replication of HIV-1 in cells of monocyte/macrophage (M/M) lineage, and its effect on the anti-HIV activity of several 2'3'-dideoxynucleoside congeners of thymidine in these cells in vitro. We found that replication of both HTLV-IIIBa-L (a monocytotropic strain of HIV-1) and HTLV-IIIB (a lymphocytotropic strain) is markedly enhanced in M/M, but not in lymphocytes exposed to GM-CSF in culture. Moreover, GM-CSF reduced the dose of HIV required to obtain productive infection in M/M. Even in the face of this increased infection, GM-CSF also enhanced the net anti-HIV activity of 3'-azido-2'3'-dideoxythymidine (AZT) and several related congeners: 2'3'-dideoxythymidine (ddT), 2'3'-dideoxy-2'3'-didehydrothymidine (D4T), and 3'-azido-2'3'-dideoxyuridine (AZddU). Inhibition of viral replication in GM-CSF-exposed M/M was achieved with concentrations of AZT and related drugs, which were 10-100 times lower than those inhibitory for HIV-1 in monocytes in the absence of GM-CSF. Other dideoxynucleosides not related to AZT showed unchanged or decreased anti-HIV activity in GM-CSF-exposed M/M. To investigate the possible biochemical basis for these effects, we evaluated the metabolism of several drugs in M/M exposed to GM-CSF. We observed in these cells markedly increased levels of both parent and mono-, di-, and triphosphate anabolites of AZT and D4T compared with M/M not exposed to GM-CSF. By contrast, only limited increases of endogenous competing 2'-deoxynucleoside-5'-triphosphate pools were observed after GM-CSF exposure. Thus, the ratio of AZT-5'-triphosphate/2'-deoxythymidine-5'-triphosphate and 2'3'-dideoxy-2'3'-didehydrothymidine-5'-triphosphate/2'-deoxythymi dine- 5'-triphosphate is several-fold higher in GM-CSF-exposed M/M, and this may account for the enhanced activity of such drugs in these cells. Taken together, these findings suggest that GM-CSF increases HIV-1 replication in M/M, while at the same time enhancing the anti-HIV activity of AZT and related congeners in these cells. These results may have implications in exploring new therapeutic strategies in patients with severe HIV infection.
Perno
C F
CF
Clinical Oncology Program, National Cancer Institute, Bethesda, Maryland 20892.
Yarchoan
R
R
Cooney
D A
DA
Hartman
N R
NR
Webb
D S
DS
Hao
Z
Z
Mitsuya
H
H
Johns
D G
DG
Broder
S
S
D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008214:Lymphocytes / Q000382:microbiology; D009000:Monocytes / Q000382:microbiology*; D018119:Stavudine; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D015224:Dideoxynucleosides; D006133:Growth Substances; C019336:2',3'-dideoxythymidine; D015215:Zidovudine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018119:Stavudine; C058803:3'-azido-2',3'-dideoxyuridine