A Phase I/II Trial of Zidovudine, Interferon- , and Granulocyte-Macrophage Colony-Stimulating Factor in the Treatment of Human Immunodeficiency Virus Type 1 Infection

1991 ◽  
Vol 164 (1) ◽  
pp. 43-52 ◽  
Author(s):  
R. T. Davey ◽  
V. J. Davey ◽  
J. A. Metcalf ◽  
J. J. Zurlo ◽  
J. A. Kovacs, ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Phase I ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Colony Stimulating Factor ◽  
Immunodeficiency Virus ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Human Immunodeficiency Virus Type 1 Infection Inhibits Granulocyte-Macrophage Colony-Stimulating Factor-Induced Activation of STAT5A in Human Monocyte-Derived Macrophages

2003 ◽  
Vol 77 (23) ◽  
pp. 12630-12638 ◽  
Author(s):  
Tammra J. Warby ◽  
Suzanne M. Crowe ◽  
Anthony Jaworowski
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Monocyte ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Immunodeficiency Virus ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1Ba-L, but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the α-chain or common βc-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis.

scholarly journals Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection [see comments]

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 463-472 ◽  
Author(s):  
JM Pluda ◽  
R Yarchoan ◽  
PD Smith ◽  
N McAtee ◽  
LE Shay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Geometric Mean ◽  
Hematologic Toxicity ◽  
Colony Stimulating Factor ◽  
Immunodeficiency Virus ◽  
P24 Antigen ◽  
Macrophage Colony Stimulating Factor ◽  
The Mean ◽  
Macrophage Colony ◽  
Stimulating Factor

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.

scholarly journals Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children

2005 ◽  
Vol 49 (1) ◽  
pp. 336-341 ◽  
Author(s):  
Ram Yogev ◽  
Andrea Kovacs ◽  
Ellen G. Chadwick ◽  
James D. Homans ◽  
Yu Lou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Phase I ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Dose Proportional

ABSTRACT A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration (T max) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC0 → ∞) was dose proportional, and the mean maximum plasma concentration (C max) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life (t 1/2) of 6.17 to 8.28 h. The t 1/2, apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of amprenavir. The results of this study suggest that 20 mg of amprenavir/kg administered twice a day should be used in future pediatric studies.

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