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.

Perno, Carlo Federico; Yarchoan, Robert; Cooney, David A.; Hartman, Neil R.; Webb, Deborah; Zhang, Hao; Mitsuya, Hiroaki; Johns, David G.; Broder, Samuel

doi:10.1084/jem.169.3.933

Cited by 273 publications

(51 citation statements)

References 52 publications

(80 reference statements)

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“…Perno et al have previously described both increased replication of HIV during GM-CSF exposure and synergistic antiviral activity when GM-CSF was combined with zidovudine in vitro (22). The latter effect was shown to be associated with enhanced cellular uptake of zidovudine, as well as increased phosphorylation of zidovudine to zidovudine triphosphate, the active antiretroviral moiety.…”

Section: Discussionmentioning

confidence: 93%

“…Hemoglobin was below normal at the baseline, with a mean of 10.7 (range, 8.9 to 12.5) g/dl. The mean CD4+ T-cell count before beginning GM-CSF was 22 (range, 4 to 69) cells per mm3. Five patients completed the 4 weeks of GM-CSF treatment, four patients discontinued treatment during the first 4 weeks because of adverse experiences or changes in laboratory values, and two patients died of AIDS dementia complex within 8 weeks of study discontinuation.…”

Section: Resultsmentioning

confidence: 99%

“…This occurred while statistically significant rises in neutrophil, eosinophil, and monocyte counts were observed and thus may represent an in vivo correlation of stimulation of HIV replication by GM-CSF. However, when GM-CSF is combined with zidovudine in vitro, synergistic inhibition of HIV replication occurs (16,22).…”

mentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex

Hewitt

Morse

Lawrence

et al. 1993

Antimicrob Agents Chemother

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Granulocytopenia is a complication of human immunodeficiency virus disease, as well as a toxic manifestation of zidovudine therapy. To evaluate pharmacokinetic and pharmacodynamic relationships, 11 AIDS-AIDSrelated complex patients who had developed zidovudine-associated granulocytopenia (mean absolute neutrophil count, 1,077/mm3) were examined after addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to zidovudine. GM-CSF was administered as a daily (1.0 or 0.3 pg/kg) or every-other-day (0.3 ,gfkg) subcutaneous dose over a 28-day period. Zidovudine was continued at the same daily dosage as was previously being administered. Of 11 patients, 7 (1.0 ,ug/kg, n = 5; 0.3 JLg/kg, n = 2) had a pharmacologic response to GM-CSF with an increase to a mean absolute neutrophil count of 3,189 cells per mm3 at 4 weeks (P < 0.05). The peak concentration of GM-CSF in plasma ranged from 11.5 to 84.4 pg/ml, and the time to peak ranged from 1 to 3 h. No correlation between GM-CSF disposition and hematologic response was noted. A decreased plasma zidovudine-glucuronide/zidovudine ratio was noted after 1 week of GM-CSF, and an increase in the area under the plasma concentration-versus-time curve for zidovudine was found in three patients after 4 weeks. Low doses of GM-CSF can raise the granulocyte count in patients with zidovudine-induced neutropenia. The use of GM-CSF and zidovudine may represent a viable treatment option for persons with human immunodeficiency virus infection who develop neutropenia while receiving zidovudine but do not tolerate alternative nucleoside analogs. Further studies are needed to assess the complex interaction between these two agents.Persons with AIDS and AIDS-related complex (ARC) commonly exhibit leukopenia, anemia, and thrombocytopenia (1,33,35). While human immunodeficiency virus (HIV) infection causes granulocytopenia with a multifactorial etiology, the antiretroviral agent zidovudine is the most impor-

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Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex

Hewitt

Morse

Lawrence

et al. 1993

Antimicrob Agents Chemother

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“…Variability in this assay system was < 5% of the values obtained. activities of AZT and other thymidine analogues, but not that of ddI, are potentiated by the addition of granulocyte macrophage colony-stimulating factor (27), suggesting that the phenomenon is not only with PHA stimulation. The differential antiviral activities of AZT and ddI based on their molarity clearly contrast with the currently recommended doses of AZT and ddI for the therapy ofAIDS, which are both -500 mg and bring about roughly comparable antiviral activities in patients receiving either of the two drugs alone (16)(17)(18)(19)(20).…”

Section: Discussionmentioning

confidence: 95%

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

et al. 1993

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The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentrations which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 ,uM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10-to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in -5-fold and -15-fold lower ratios of ddClP/ dCIP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase.We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy. (J. Clin. Invest. 1993Invest. .91:2326Invest. -2333

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“…The role of GM-CSF and erythropoietin in the pathogenesis of AIDS and their relationship in modulating zidovudine toxicity clinically appears to be less defined with respect to their ability to initiate acceleration of HIV production (Perno et al, 1989;Fischl et al, 1990). Although the clinical use of erythropoietin to reverse the anaemia associated with zidovudine has been documented in several studies (Walker et al, 1988;Fischl et al, 1990) serum erythropoietin levels in the vast majority of AIDS patients not receiving zidovudine can also be elevated significantly (Spivak et al, 1989).…”

Section: Banmentioning

confidence: 99%

Effect of G-CSF and M-CSF on thein vitroToxicity Associated with Zidovudine in Normal Human Bone Marrow Haematopoietic Progenitor Stem Cells

Gallicchio

Hughes

1993

Antivir Chem Chemother

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Zidovudine, the antiviral drug used in the treatment of acquired immunodeficiency syndrome (AIDS), causes toxicity to the haematopoietic system. Although use of the haematopoietic growth factors, GM-CSF and erythropoietin have been investigated in clinical trials to modulate antiviral toxicity, there is scant data which supports their ability to ameliorate zidovudine induced toxicity on haematopoietic progenitor cells when combined in vitro. We describe here the results of studies designed to evaluate the capacity of additional haematopoietic factors such as granulocyte-colony stimulating factor (G-CSF) and macrophage-colony stimulating factor (M-CSF) to modulate zidovudine-induced toxicity on G-CSF and M-CSF dependent-colony formation in the presence or absence of zidovudine in vitro. These factors were also studied combined with erythropoietin in culture for the early erythroid progenitor BFU-E using adherent, T-cell, depleted normal human bone marrow cells in the presence or absence of zidovudine. In the presence of zidovudine at the concentration producing 50% inhibition of G- and M-CSF dependent colony formation, (5 × 10−5M), dose-escalation of either G-CSF or M-CSF failed to ameliorate zidovudine toxicity. However, in the presence of zidovudine at the concentration that produces 50% inhibition of BFU-E (5 × 10−9M), and optimal erythropoietin (1 unit ml−1), G-CSF ameliorated zidovudine inhibition of BFU-E, which was not observed with M-CSF. In the presence of erythropoietin, G-CSF increased significantly normal BFU-E. These studies indicate that G-CSF may be useful in ameliorating zidovudine-induced anaemia and suggest G-CSF may act as a synergistic factor to enhance erythropoietin to support the growth of erythroid progenitors in conditions where erythropoitin is ineffective.

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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.

Cited by 273 publications

References 52 publications

Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex

Pharmacokinetics and pharmacodynamics of granulocyte-macrophage colony-stimulating factor and zidovudine in patients with AIDS and severe AIDS-related complex

Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.

Effect of G-CSF and M-CSF on thein vitroToxicity Associated with Zidovudine in Normal Human Bone Marrow Haematopoietic Progenitor Stem Cells

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