SAFETY AND IMMUNOGENICITY OF RECOMBINANT HUMAN IMMUNODEFICIENCY VIRUS-LIKE PARTICLES IN RODENTS AND RHESUS MACAQUES

Data from long-term non-progressing human immunodeficiency virus (HIV) -infected individuals and populations at high risk suggest that an ear ly cytolytic T cell response rather than the humoral immune response m ight be involved in controlling disease progression. These observation s may be used as a guide to the type of response that a vaccine should induce. To clarify the role of different arms of the immune system in conferring protection, the candidate vaccine should allow a regulated , selective induction of different immune responses. Based on a better understanding of the molecular mechanisms regulating the morphogenesi s of HIV, we developed an autologous, non-replicating and safe antigen delivery system. This system takes advantage of molecular characteris tics of the HIV group-specific antigens (gag) to self-assemble to high ly immunogenic virus-like particles (VLP). The immunogenicity of the g ag-derived VLP was expanded either by replacing defined domains by sel ected HIV-1 cytotoxic T lymphocyte (CTL) epitopes (type 1 VLP) or by s table anchoring derivatives of the HIV-1 envelope protein on the surfa ce of the VLP (type 2 VLP). In complete absence of adjuvants, type 1 a nd type 2 VLP stimulated CD8+ CTL in BALB/c mice, which specifically r ecognised HIV sequences. In contrast to type 1 VLP, generating an HIV- specific CTL response in the absence of env-specific antibodies, type 2 VLP induced both arms of the immune system including reasonable leve ls of neutralising antibodies. Initial studies performed in rhesus mac aques confirmed these results. Thus, depending on the type and formula tion of the VLP, the proposed antigen delivery system allows either th e induction of a CTL response (1) in the absence and (2) the presence of an envelope-specific antibody response. A comparison of these appro aches in appropriate animal models might contribute to further define the correlates of protection.