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Journal of Virology, March 2003, p. 2859-2865, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.2859-2865.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Neutralization of Human Immunodeficiency Virus Type 1 by sCD4-17b, a Single-Chain Chimeric Protein, Based on Sequential Interaction of gp120 with CD4 and Coreceptor

Barna Dey,{dagger} Christie S. Del Castillo, and Edward A. Berger*

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 26 August 2002/ Accepted 25 November 2002

We designed a novel single-chain chimeric protein, designated sCD4-17b, for neutralization of human immunodeficiency virus type 1 (HIV-1). The recombinant protein contains domains 1 and 2 of soluble CD4 (sCD4), connected via a flexible polypeptide linker to a single-chain variable region construct of 17b, a human monoclonal antibody that targets a conserved CD4-induced epitope on gp120 overlapping the coreceptor binding region. We hypothesized that the sCD4 moiety would bind gp120 and expose the 17b epitope; the 17b moiety would then bind, thereby blocking coreceptor interaction and neutralizing infection. The sCD4-17b protein, expressed by a recombinant vaccinia virus, potently neutralized a prototypic R5 clade B primary isolate, with a 50% inhibitory concentration of 3.2 nM (0.16 µg/ml) and >95% neutralization at 32 nM (1.6 µg/ml). The individual components (sCD4 and 17b, singly or in combination) had minimal effects at these concentrations, demonstrating that the activity of sCD4-17b reflected the ability of a single chimeric molecule to bind gp120 simultaneously via two independent moieties. sCD4-17b was highly potent compared to the previously characterized broadly cross-reactive neutralizing monoclonal antibodies IgGb12, 2G12, and 2F5. Multiple primary isolates were neutralized, including two previously described as antibody resistant. Neutralization occurred for both R5 and X4 strains and was not restricted to clade B. However, several primary isolates were insensitive over the concentration range tested, despite the known presence of binding sites for both CD4 and 17b. sCD4-17b has potential utility for passive immunization against HIV-1 in several contexts, including maternal transmission, postexposure prophylaxis, and sexual transmission (topical microbicide).

* Corresponding author. Mailing address: Building 4, Room 237, National Institutes of Health, Bethesda, MD 20892-0445. Phone: (301) 402-2481. Fax: (301) 480-1147. E-mail: edward_berger{at}nih.gov.

{dagger} Present address: Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892.

Journal of Virology, March 2003, p. 2859-2865, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.2859-2865.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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