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J Virol, April 1998, p. 3235-3240, Vol. 72, No. 4
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Synergistic Neutralization of Simian-Human Immunodeficiency Virus SHIV-vpu+ by Triple and Quadruple Combinations of Human Monoclonal Antibodies and High-Titer Anti-Human Immunodeficiency Virus Type 1 Immunoglobulins

An Li,1,2 Hermann Katinger,3 Marshall R. Posner,2,4 Lisa Cavacini,2,4 Susan Zolla-Pazner,5 Miroslaw K. Gorny,5 Joseph Sodroski,2,6 Ting-Chao Chou,7 Timothy W. Baba,1,2,8 and Ruth M. Ruprecht1,2,*

Laboratory of Viral Pathogenesis1 and Division of Human Retrovirology,6 Dana-Farber Cancer Institute, and Harvard Medical School,2 Boston, Massachusetts 02115; Institute of Applied Microbiology, University of Agriculture, A-1190 Vienna, Austria3; Division of Hematology and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 022154; Research Center for AIDS and HIV Infection, Veterans Affairs Medical Center, New York, New York 100105; Laboratory of Preclinical Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 100217; and Division of Newborn Medicine, Department of Pediatrics, Tufts University School of Medicine, Boston, Massachusetts 021118

Received 25 August 1997/Accepted 18 December 1997

We have tested triple and quadruple combinations of human monoclonal antibodies (MAbs), which are directed against various epitopes on human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, and a high-titer anti-HIV-1 human immunoglobulin (HIVIG) preparation for their abilities to neutralize a chimeric simian-human immunodeficiency virus (SHIV-vpu+). This virus encodes the HIV-1 strain IIIB env, tat, rev, and vpu genes. The quantitative nature of the Chou-Talalay method (Adv. Enzyme Regul. 22:27-55, 1984) allows ranking of various combinations under identical experimental conditions. Of all triple combinations tested, the most potent neutralization was seen with MAbs 694/98D plus 2F5 plus 2G12 (directed against domains on V3, gp41, and gp120, respectively) as measured by the total MAb concentration required to reach 90% neutralization (90% effective concentration [EC90], 2.0 µg/ml). All triple combinations involving MAbs and/or HIVIG that were tested yielded synergy with combination index values of <1; the dose reduction indices (DRIs) ranged from 3.1 to 26.2 at 90% neutralization. When four MAbs (the previous three plus MAb F105, directed against the CD4 binding site) were combined, higher neutralization potency (EC90, 1.8 µg/ml) and a higher degree of synergy compared to any triple combination were seen. The mean DRIs of the quadruple combination were approximately twice that of the most synergistic triple combination. We conclude that human MAbs targeting different HIV-1 envelope glycoprotein epitopes exhibit strong synergy when used in combination, a fact that could be exploited clinically for passive immunoprophylaxis against HIV-1.

* Corresponding author. Mailing address: Laboratory of Viral Pathogenesis, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3719. Fax: (617) 632-3112. E-mail: ruth_ruprecht{at}dfci.harvard.edu.




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