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215 C Clade HGP-30 (p17 aa 86(115)-Based Peptide Conjugates as Potential Therapeutic and Prophylactic HIV-1 Vaccine Antigens
M. Siwek, D. Winship, M. Manner, and D. Zimmerman*,
CEL-SCI Corp., Vienna, VA, USA
Background: HGP-30, a 30-amino acid synthetic peptide analogue of a conserved region of HIV-1, B clade, p17 (aa86(115), has been shown to elicit cellular and humoral immune responses in man, when administered as a KLH conjugate. Peripheral blood mononuclear cells (PBMC) from immunized persons showed protection from HIV infection in the Hu-PBL-SCID mouse virus challenge model. We have evaluated a new approach to vaccine antigen design utilizing antigen peptides and other smaller peptides that preferentially activate cellular immune responses, and we have demonstrated protection in murine challenge models for HSV and malaria. Better protection from challenge was associated with induction of TH1 immune responses- delayed type hypersensitivity, higher IgG2a/IgG1 antibody ratios (>0.5), activation of CD4+ cells and IFN-gamma. Similar peptide G (MHC II beta chain peptide) and J (beta-2-microglobulin peptide) conjugates of HGP-30 (1:1) were immunogenic and G conjugates elicited higher titers (4- to 8-fold) with better cross-clade reactivity. Both demonstrated low IgG2a/IgG1 ratios, 0.2 and 0.14, respectively. Elsewhere, C clade analogue conjugates of HGP-30 to KLH elicited superior responses compared with the B clade conjugates in mice. In this study peptide conjugates of B and C clade HGP-30 analogues were prepared and studied.
Methods: C clade conjugate analogues of HGP-30 were prepared and mice were immunized subcutaneously with 5 nmol and ISA 51 as adjuvant. Sera were collected and analyzed for antibody titers, cross-clade reactivity, and isotype using ELISA.
Results C clade HGP-30 peptide conjugates of peptide J elicited higher IgG2a/IgG1 ratios (0.6) compared with G conjugates (0.13). Furthermore, the J conjugates elicited higher titer (1- to 2-fold) antibodies having better cross-clade reactivity, especially to clade B and D peptides. As expected, the G conjugates of modified HGP-30 were more immunogenic and elicited better cross-clade reactivity than the J constructs.
Conclusions: The data suggest that the C clade HGP-30 analogue conjugate with the beta-2-microglobulin peptide is a potential clinical therapeutic and prophylactic candidate antigen designed to preferentially induce protective TH1 immune responses.
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