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Journal of Virology, March 2003, p. 3119-3130, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3119-3130.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Induction of Primary Virus-Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Antibodies in Small Animals by Using an Alphavirus-Derived In Vivo Expression System

Ming Dong,1 Peng Fei Zhang,1 Franziska Grieder,2,{dagger} James Lee,1 Govindaraj Krishnamurthy,2 Thomas VanCott,3 Christopher Broder,2 Victoria R. Polonis,3 Xiao-Fang Yu,4 Yiming Shao,5 Dennis Faix,1 Patricia Valente,1,{ddagger} and Gerald V. Quinnan, Jr.1*

Departments of Preventive Medicine and Biometrics,2 Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda,3 Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville,4 Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland,5 National AIDS Reference Laboratory, Beijing, China1

Received 15 January 2002/ Accepted 1 November 2002

We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160{Delta}CT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160{Delta}CT was released by cells in the form of membrane-bound vesicles. gp160{Delta}CT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.

* Corresponding author. Mailing address: Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814. Phone: (301) 295-3734. Fax: (301) 295-1971. E-mail: gquinnan{at}usuhs.mil.

{dagger} Present address: Comparative Medicine, National Center for Research Resources, National Institutes of Health, Bethesda, MD 20892-7965.

{ddagger} Present address: 4850 Connecticut Ave., N.W., Washington, DC 20008.

Journal of Virology, March 2003, p. 3119-3130, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3119-3130.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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