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Journal of Virology, June 2002, p. 5357-5368, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5357-5368.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Modifications of the Human Immunodeficiency Virus Envelope Glycoprotein Enhance Immunogenicity for Genetic Immunization

Bimal K. Chakrabarti,1 Wing-pui Kong,1 Bei-yue Wu,2 Zhi-Yong Yang,1 Jacques Friborg,1 Xu Ling,1 Steven R. King,2 David C. Montefiori,3 and Gary J. Nabel1*

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-3005,1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0688,2 Department of Surgery, Duke University Medical Center, Durham, North Carolina 277103

Received 29 August 2001/ Accepted 22 February 2002

In this study, we have investigated the effect of specific mutations in human immunodeficiency virus type 1 (HIV-1) envelope (Env) on antibody production in an effort to improve humoral immune responses to this glycoprotein by DNA vaccination. Mice were injected with plasmid expression vectors encoding HIV Env with modifications in regions that might affect this response. Elimination of conserved glycosylation sites did not substantially enhance humoral or cytotoxic-T-lymphocyte (CTL) immunity. In contrast, a modified gp140 with different COOH-terminal mutations intended to mimic a fusion intermediate and stabilize trimer formation enhanced humoral immunity without reducing the efficacy of the CTL response. This mutant, with deletions in the cleavage site, fusogenic domain, and spacing of heptad repeats 1 and 2, retained native antigenic conformational determinants as defined by binding to known monoclonal antibodies or CD4, oligomer formation, and virus neutralization in vitro. Importantly, this modified Env, gp140{Delta}CFI, stimulated the antibody response to native gp160 while it retained its ability to induce a CTL response, a desirable feature for an AIDS vaccine.

* Corresponding author. Mailing address: Vaccine Research Center, NIAID, National Institutes of Health, 40 Convent Dr., Bethesda, MD 20892-3005. Phone: (301) 496-1852. Fax: (301) 480-0274. E-mail: gnabel{at}mail.nih.gov.

Journal of Virology, June 2002, p. 5357-5368, Vol. 76, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.11.5357-5368.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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