Human Serum Attenuates the Activity of Protease Inhibitors toward Wild-Type and Mutant Human Immunodeficiency Virus

• Published in: Virology (New York, N.Y.) Vol. 250; no. 2; pp. 255 - 262
• Main Authors: Molla, Akhteruzzaman, Vasavanonda, Sudthida, Kumar, Gondi, Sham, Hing L., Johnson, Marianne, Grabowski, Brian, Denissen, Jon F., Kohlbrenner, William, Plattner, Jacob J., Leonard, John M., Norbeck, Daniel W., Kempf, Dale J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.1998
• Subjects: AIDS/HIV; Blood Proteins - metabolism; Cell Line, Transformed; HIV Protease Inhibitors - metabolism; HIV Protease Inhibitors - pharmacology; HIV-1 - genetics; Human immunodeficiency virus; Humans; Lopinavir; Mutation; Pyrimidinones - metabolism; Ritonavir - metabolism
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1006/viro.1998.9383

The potency of therapeutic regimens containing human immunodeficiency virus (HIV) protease inhibitors is related to the ability to maintain concentrations of drug in the plasma of patients that are sufficient for blocking viral replication. The estimation of concentrations required forin vivoactivity usingin vitroassays is complicated by the fact that extensive binding of many protease inhibitors to serum proteins attenuates their antiviral potency. To provide insight into the relativein vivopotency of current protease inhibitors, we assayed theirin vitroactivity against wild-type and mutant HIV in the presence of human serum (HS). Using this assay, ABT-378, a new protease inhibitor with trough levels in humans far in excess of the EC50in the presence of 50% HS, was identified. The antiviral activity of ABT-378 was only modestly attenuated by HS, in contrast to ritonavir, saquinavir, and nelfinavir. Examination of the effect of individual serum components suggested that the activity of ABT-378 is affected predominantly by binding to α1-acid glycoprotein (AGP) while the activity of ritonavir is modulated by both AGP and albumin. The method described here may provide insight into thein vivopotency of protease inhibitors and be useful for the preclinical evaluation and selection of new protease inhibitors for clinical studies.