RECOMBINANT HUMAN IMMUNODEFICIENCY PR55(GAG) VIRUS-LIKE PARTICLES PRESENTING CHIMERIC ENVELOPE GLYCOPROTEINS INDUCE CYTOTOXIC T-CELLS AND NEUTRALIZING ANTIBODIES

Very recently, we demonstrated that the replacement of the human immun odeficiency virus type-1 (HIV-1) gp41 transmembrane protein by an Epst ein-Barr virus gp220/350-derived membrane anchor resulted in the incor poration of chimeric envelope (Env) oligomers into pr55(gag) virus-lik e particles (VLPs), exceeding that of wild-type gp160 by a factor of 1 0, In this study, we examined the immunostimulatory properties of Pr55 (gag) VLPs to both (i) chimeric HIV-1 gp120 external envelope proteins and (ii) full-length gp160 presented on the outer surface of the part icles. immunization studies carried out with VLPs presenting different derivatives of the chimeric and wild-type Enu proteins elicited a con sistent anti-Pr55(gag) as well as anti-Env antibody response in comple te absence of additional adjuvants. In both cases, the immune sera exh ibited an in vitro neutralizing activity against homologous HIV-1 infe ction in MT4 cells, Noteworthy, these VLPs were also capable of induci ng a strong CD8+ cytotoxic T-cell (CTL) response in immunized BALB/c m ice that was directed toward a known CTL epitope in the third variable domain V3 of the gp120 external glycoprotein. However, the induction of V3-loop-specific CTLs critically depended on the amounts of Env pro teins that were presented by the Pr55(gag) VLPs. Moreover, the CD8(+) CTL response was not significantly altered by adsorbing the VLPs to al um or by repeated boaster immunizations. These results illustrate that Pr55(gag) VLPS provide a safe and effective means of enhancing neutra lizing humoral responses to particle-entrapped gp120 proteins and are also capable of delivering these proteins to the MHC class i antigen p rocessing and presentation pathway. Therefore, antigenically expanded Pr55(gag) VLPS represent an attractive approach in the design of vacci nes for which specific stimulation of neutralizing antibodies and cyto toxic effector functions to complex glycoproteins is desired. (C) 1997 Academic Press.