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Journal of Virology, September 2001, p. 8340-8347, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8340-8347.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antibody Protects Macaques against Vaginal Challenge with a Pathogenic R5 Simian/Human Immunodeficiency Virus at Serum Levels Giving Complete Neutralization In Vitro

Paul W. H. I. Parren,1 Preston A. Marx,2,3 Ann J. Hessell,1 Amara Luckay,3 Janet Harouse,3 Cecilia Cheng-Mayer,3 John P. Moore,4 and Dennis R. Burton1,*

Departments of Immunology and Molecular Biology, The Scripps Research Institute, La Jolla, California 920371; Tulane Regional Primate Research Center and School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, Covington, Louisiana 704332; Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 100163; and Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 100214

Received 3 April 2001/Accepted 4 June 2001

A major unknown in human immunodeficiency virus (HIV-1) vaccine design is the efficacy of antibodies in preventing mucosal transmission of R5 viruses. These viruses, which use CCR5 as a coreceptor, appear to have a selective advantage in transmission of HIV-1 in humans. Hence R5 viruses predominate during primary infection and persist throughout the course of disease in most infected people. Vaginal challenge of macaques with chimeric simian/human immunodeficiency viruses (SHIV) is perhaps one of the best available animal models for human HIV-1 infection. Passive transfer studies are widely used to establish the conditions for antibody protection against viral challenge. Here we show that passive intravenous transfer of the human neutralizing monoclonal antibody b12 provides dose-dependent protection to macaques vaginally challenged with the R5 virus SHIV162P4. Four of four monkeys given 25 mg of b12 per kg of body weight 6 h prior to challenge showed no evidence of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significantly reduced and delayed plasma viremia compared to control animals. In contrast, all four monkeys treated with a dose of 1 mg/kg became infected with viremia levels close to those for control animals. Antibody b12 serum concentrations at the time of virus challenge corresponded to approximately 400 (25 mg/kg), 80 (5 mg/kg), and 16 (1 mg/kg) times the in vitro (90%) neutralization titers. Therefore, complete protection against mucosal challenge with an R5 SHIV required essentially complete neutralization of the infecting virus. This suggests that a vaccine based on antibody alone would need to sustain serum neutralizing antibody titers (90%) of the order of 1:400 to achieve sterile protection but that lower titers, around 1:100, could provide a significant benefit. The significance of such substerilizing neutralizing antibody titers in the context of a potent cellular immune response is an important area for further study.

* Corresponding author. Mailing address: Department of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., IMM2, La Jolla, CA 92037. Phone: (858) 784-9298. Fax: (858) 784-8360. E-mail: burton{at}scripps.edu.

Journal of Virology, September 2001, p. 8340-8347, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8340-8347.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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