Cytotoxic T Cells and Neutralizing Antibodies Induced in Rhesus Monkeys by Virus-like Particle HIV Vaccines in the Absence of Protection from SHIV Infection

Abstract

HIV Pr55gag has in the absence of other viral components the capacity to self assemble in budding noninfectious virus-like particles (VLP). The immunological spectrum of the HIV-1IIIB gag-derived VLP was expanded either by stable anchoring of chimeric modified gp 120 on the surface of the VLP (type 1) or by replacing sequences of the Pr55gag precursor by the V3 loop and a linear portion of the CD4 binding domain (type 2). This noninfectious antigen delivery system was evaluated for immunogenicity and efficacy in rhesus macaques without adjuvants. Intramuscular immunization with both types of VLP induced high titers of gag-specific antibodies ranging from 1/8000 to 1/510,000 for type 1 VLP and from 1/4000 to 1/16,000 for type 2 VLP. Only animals immunized with type 1 VLP developed substantial endpoint titers of env-specific antibodies (1/2000-1/32,000) with a neutralizing capacity at serum dilutions of 1/32-1/128. Gag- and env-specific cytotoxic T lymphocyte (CTL) activity was induced by both types of VLP at similar levels. Four weeks after the last immunization animals were challenged intravenously with 20 MID50 of the cell free homologous envelope simian/HIV-1IIIB chimeric challenge stock Despite HIV-1-specific neutralizing and CTL responses, all vaccinated animals became infected.

Potential of Equine Herpesvirus 1 as a Vector for Immunization

“…It has been shown in previous studies that HIV Pr55 gag is a potent inductor of a CD8 ϩ CTL response (12,59). Therefore, we examined whether the generated mutant EHV-1 viruses were able to induce such a response.…”

First Glimpse of the Peptide Presentation by Rhesus Macaque MHC Class I: Crystal Structures of Mamu-A*01 Complexed with Two Immunogenic SIV Epitopes and Insights into CTL Escape

“…This fact underscores the urgent need for an effective AIDS vaccine. Despite vigorous research efforts, preventive (sterilizing) immunization based on raising neutralizing Abs against HIV components has proved fruitless (1)(2)(3). In contrast, it is known that the host CTL responses provide powerful defense to contain the virus postinfection (4,5), and CTL-based immunization is currently the most promising approach toward vaccine development (6).…”

“…As a step toward delineating the molecular basis of CTL escape, we undertook structural studies to reveal how Mamu-A*01 binds these two very different SIV peptides for presentation to the TCR. Previously, several studies have probed the interactions and structures of peptide and class I MHC molecules (pMHC) 3 from human and mice (34 -38). This is the first nonhuman primate pMHC structure ever solved, and the results show that the nonamer and octamer peptides bind to the Mamu-A*01 in a similar way with P3 as an anchor residue.…”

Contribution of Virus-Like Particles to the Immunogenicity of Human Immunodeficiency Virus Type 1 Gag-Derived Vaccines in Mice

“…VLPs resemble viral capsids morphologically and antigenically, and VLPs derived from a broad range of viruses have been shown to be immunogenic (5,10,14,15,21,28,29,32,35,41,45,50,52,59,60). VLPs are appealing as vaccine candidates because antigen is delivered in a noninfectious form in the absence of viral genome or other potentially toxic viral gene products.…”

“…This lipid envelope may contain hostderived proteins (18,43,57). Immunogenicity studies involving HIV-1 Gag VLPs have been carried out with particles derived from insect cells infected with recombinant baculovirus vectors (45,59). These studies demonstrated that HIV-1 Gag-specific immune responses can be generated by parenteral administration of Gag VLPs, even without the coadministration of adjuvants.…”