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Journal of Virology, July 2009, p. 7337-7348, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00110-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Elite Neutralizers: Individuals with Broad and Potent Neutralizing Activity Identified by Using a High-Throughput Neutralization Assay together with an Analytical Selection Algorithm ^,

Melissa D. Simek,^1*, Wasima Rida,^10, Frances H. Priddy,¹ Pham Pung,² Emily Carrow,⁹ Dagna S. Laufer,¹ Jennifer K. Lehrman,¹ Mark Boaz,^1, Tony Tarragona-Fiol,¹⁷ George Miiro,⁵ Josephine Birungi,⁶ Anton Pozniak,⁸ Dale A. McPhee,⁷ Olivier Manigart,⁴ Etienne Karita,⁴ André Inwoley,¹¹ Walter Jaoko,¹² Jack DeHovitz,¹³ Linda-Gail Bekker,¹⁴ Punnee Pitisuttithum,¹⁵ Robert Paris,¹⁶ Laura M. Walker,³ Pascal Poignard,³ Terri Wrin,² Patricia E. Fast,¹ Dennis R. Burton,³ and Wayne C. Koff¹

International AIDS Vaccine Initiative, New York, New York,¹ Monogram Biosciences, Inc., South San Francisco, California,² Department of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, California,³ Rwanda Zambia HIV Research Group, Emory University, Atlanta, Georgia,⁴ Uganda Virus Research Institute-Medical Research Council, Entebbe, Uganda,⁵ Uganda Virus Research Institute-International AIDS Vaccine Initiative, Entebbe, Uganda,⁶ National Serology Reference Laboratory, National Center in HIV-1 Epidemiology and Clinical Research, Fitzroy, Victoria, Australia,⁷ St. Stephens AIDS Trust, London, United Kingdom,⁸ Advanced BioAdjuvants, LLC, Omaha, Nebraska,⁹ Arlington, Virginia,¹⁰ Diagnostic Center and Research on AIDS and Opportunistic Diseases, CeDReS, Abidjan, Ivory Coast,¹¹ Kenya AIDS Vaccine Initiative, University of Nairobi, Nairobi, Kenya,¹² Department of Preventive Medicine, SUNY-Downstate Medical Center, Brooklyn, New York,¹³ Desmond Tutu HIV-1 Foundation, University of Cape Town, Cape Town, South Africa,¹⁴ Department of Clinical Tropical Medicine, Clinical Infectious Disease Research Unit, Vaccine Trial Center, Mahidol University, Bangkok, Thailand,¹⁵ Department of Retrovirology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand,¹⁶ IAVI Core Laboratory, Imperial College London, South Kensington, London, United Kingdom,¹⁷

Received 16 January 2009/ Accepted 22 April 2009

The development of a rapid and efficient system to identify human immunodeficiency virus type 1 (HIV-1)-infected individuals with broad and potent HIV-1-specific neutralizing antibody responses is an important step toward the discovery of critical neutralization targets for rational AIDS vaccine design. In this study, samples from HIV-1-infected volunteers from diverse epidemiological regions were screened for neutralization responses using pseudovirus panels composed of clades A, B, C, and D and circulating recombinant forms (CRFs). Initially, 463 serum and plasma samples from Australia, Rwanda, Uganda, the United Kingdom, and Zambia were screened to explore neutralization patterns and selection ranking algorithms. Samples were identified that neutralized representative isolates from at least four clade/CRF groups with titers above prespecified thresholds and ranked based on a weighted average of their log-transformed neutralization titers. Linear regression methods selected a five-pseudovirus subset, representing clades A, B, and C and one CRF01_AE, that could identify top-ranking samples with 50% inhibitory concentration (IC₅₀) neutralization titers of 100 to multiple isolates within at least four clade groups. This reduced panel was then used to screen 1,234 new samples from the Ivory Coast, Kenya, South Africa, Thailand, and the United States, and 1% were identified as elite neutralizers. Elite activity is defined as the ability to neutralize, on average, more than one pseudovirus at an IC₅₀ titer of 300 within a clade group and across at least four clade groups. These elite neutralizers provide promising starting material for the isolation of broadly neutralizing monoclonal antibodies to assist in HIV-1 vaccine design.

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* Corresponding author. Mailing address: International AIDS Vaccine Initiative, 110 William Street, 27th Floor, New York, NY 10028. Phone: (212) 847-1098. Fax: (212) 847-1113. E-mail: Msimek{at}iavi.org

Published ahead of print on 13 May 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

M.D.S. and W.R. contributed equally to this work.

Present address: Sanofi Pasteur, Discovery Drive, Swiftwater, PA.

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Journal of Virology, July 2009, p. 7337-7348, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.00110-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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