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4 Modifications of HIV Envelope Enhance Immunogenicity for Genetic Immunization
B. Chakrabarti*1, W. Kong1, B. Wu2, Z. Y. Yang1, J. Friborg3, X. Ling1, S. R. King4, and G. J. Nabel1
1Vaccine Res. Ctr., NIAID, NIH, Bethesda, MD, USA; 2Handylab, Ann Arbor, MI, USA; 3Bristol-Myers Squibb, Wallingford, CT, USA; and 4Univ. of Michigan, Ann Arbor, USA
Background: In this study, we have investigated the effect of specific mutations in human immunodeficiency virus type 1 (HIV-1) envelope (Env) on humoral and cellular immune responses after DNA vaccination.
Methods: Mice were injected with plasmid expression vectors encoding HIV Env with modifications of conserved glycosylation sites or different COOH-terminal mutations intended to mimic a fusion intermediate.
Results: Elimination of conserved glycosylation sites did not substantially enhance humoral or CTL immunity. In contrast, a modified gp140 with deletions in the cleavage site, fusogenic domain, and spacing of heptad repeats 1 and 2 enhanced humoral immunity without reducing the efficacy of the CTL response. This mutant retained several features relevant to wild-type Env, including native antigenic conformational determinants defined by interactions with known monoclonal antibodies, CD4 binding, and oligomer formation. When injected into small animal models, these immunogens induced neutralizing antibodies to primary HIV isolates and laboratory strains.
Conclusions: Because of its ability to stimulate the antibody response to native gp160 without reducing the CTL response, this modified gp140 or a related derivative may prove to be a useful component of an AIDS vaccine.
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