Effect of a human immunodeficiency virus protease inhibitor on human monocyte function.
Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Encoded by the HIV genome are several precursor proteins that undergo proteolytic cleavage to yield functional proteins. The env precursor protein is cleaved by a cellular protease. The gag precursor protein of HIV (p55), however, is cleaved by a virally encoded aspartate protease (HIV Protease). Cleavage of p55 is required for viral maturation and infectivity. There are also several host cell aspartate proteases that serve important homeostatic functions. Cathepsins D and E are lysosomal aspartate proteases which are believed to play an important role in macrophage function, and it has been suggested that inhibition of these enzymes by an HIV protease inhibitor may exacerbate immunosuppression in AIDS patients. We have studied the effect of SK&F 107461 (a hydroxyethylene dipeptide isostere inhibitor of HIV protease), on various host defense functions of human monocytes. Pepstatin A (an inhibitor of most aspartate proteases) and leupeptin (an inhibitor of serine and cysteine proteases) were included as controls. Although less potent than the prototypic aspartate protease inhibitor pepstatin, SK&F 107461 inhibited partially purified cathepsin D in vitro. However, in cell-based assays, SK&F 107461 had no effect on the degradation of hemoglobin, antigen processing of the protein antigen streptokinase, or secretion of 17-kD IL-1 beta by monocytes at concentrations which inhibit maturation of intracellular virus in HIV infected monocytes. Furthermore, SK&F 107461 had no effect on constitutive candidacidal activity. In contrast, leupeptin and pepstatin A partially inhibited accessory cell function of monocytes in the proliferative response to the recall antigen streptokinase. In addition, leupeptin partially inhibited degradation of hemoglobin.(ABSTRACT TRUNCATED AT 250 WORDS)
Bugelski
P J
PJ
Department of Experimental Pathology, SmithKline Beecham Pharmaceuticals, Philadelphia, PA.
Kaplan
J M
JM
Hart
T K
TK
Miller
J
J
Laydon
J T
JT
Lee
J C
JC
Dreyer
G B
GB
Kirsh
R
R
D000938:Antigen-Presenting Cells / Q000187:drug effects; D002176:Candida albicans / Q000276:immunology; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D011506:Proteins / Q000378:metabolism
D017320:HIV Protease Inhibitors; D007375:Interleukin-1; D009842:Oligopeptides; D011506:Proteins; C079535:SK&F 107461; D002402:Cathepsin D