Hypervariable Epitope Constructs Representing Variability in Envelope Glycoprotein of SIV Induce a Broad Humoral Immune Response in Rabbits and Rhesus Macaques

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Abstract
Using synthetic peptides, we developed an approach to account for protein epitope variability. We have prepared, in a single synthesis, a cocktail of peptides we have designated a hypervariable epitope construct (HEC), which collectively represents much of the in vivo variability seen in an epitope. Eight HECs representing the in vivo variability seen throughout the envelope glycoprotein of the simian immunodeficiency virus (SIV) were designed and synthesized. The constructs were collectively conjugated to KLH (HEC–KLH) or recombinant gp130 (HEC–rgp130) and used to immunize rabbits and rhesus macaques, respectively. Using sera collected from rabbits immunized with HEC–KLH, we demonstrated that individual components of the immunogen were recognized as antigen in ELISAs, and that the induced antibodies cross-reacted with several strains of SIV as well as with a strain of HIV-2. Following immunization of macaques with HEC–rgp130 antiviral antibodies were induced. These antibodies were still present 9.5 months after the last boost and were also capable of recognizing several different strains of SIV, including SIVmac239, SIVmac251, and SIVsmH3, as well as a strain of HIV-2 (HIV-2ROD). In addition, the antibodies were also capable of neutralizing SIV viral infectivity in vitro. Peripheral blood lymphocytes (PBLs) from immunized macaques proliferated in response to whole proteins and virus. Finally, sera from monkeys immunized with SIV, rgp130, and HIV-2 as well as sera from HIV-2-positive humans recognized HECs in ELISAs, demonstrating the relevance of these epitopes in vivo. This approach can be used as an effective method for generating a strong, broadly cross-reactive humoral response against HIV and can serve as an important component of combination vaccines against HIV and AIDS.