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Journal of Virology, May 2004, p. 4710-4719, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4710-4719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Elicitation of Neutralizing Antibodies with DNA Vaccines Expressing Soluble Stabilized Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Trimers Conjugated to C3d

Joseph F. Bower,1 Xinzhen Yang,2 Joseph Sodroski,2 and Ted M. Ross1*

Department of Medicine, Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,1 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Division of AIDS, Harvard Medical School, Boston, Massachusetts2

Received 12 August 2003/ Accepted 24 December 2003

DNA vaccines expressing the envelope (Env) of human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting immune responses. Oligomeric or trimeric (gp140) forms of Env that more closely mimic the native proteins on the virion are often more effective immunogens than monomeric (gp120) envelopes. In this study, several forms of Env constructed from the HIV-1 isolate YU-2 (HIV-1YU-2) were tested for their immunogenic potential: a trimeric form of uncleaved (–) Env stabilized with a synthetic trimer motif isolated from the fibritin (FT) protein of the T4 bacteriophage, sgp140YU-2(–/FT), was compared to sgp140YU-2(–) without a synthetic trimerization domain, as well as to monomeric gp120YU-2. DNA plasmids were constructed to express Env alone or fused to various copies of murine C3d (mC3d). BALB/c mice were vaccinated (day 1 and week 4) with DNA expressing a codon-optimized envelope gene insert, alone or fused to mC3d. Mice were subsequently boosted (week 8) with the DNA or recombinant Env protein. All mice had high anti-Env antibody titers regardless of the use of mC3d. Sera from mice vaccinated with DNA expressing non-C3d-fused trimers elicited neutralizing antibodies against homologous HIV-1YU-2 virus infection in vitro. In contrast, sera from mice inoculated with DNA expressing Env-C3d protein trimers elicited antibody that neutralized both homologous HIV-1YU-2 and heterologous HIV-1ADA, albeit at low titers. Therefore, DNA vaccines expressing trimeric envelopes coupled to mC3d, expressed in vivo from codon-optimized sequences, elicit low titers of neutralizing antibodies against primary isolates of HIV-1.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 871, 3550 Terrace St., Pittsburgh, PA 15261. Phone: (412) 648-8666. Fax: (412) 648-8455. E-mail: RossT{at}msx.dept-med.pitt.edu.

Journal of Virology, May 2004, p. 4710-4719, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4710-4719.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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