Selective induction of cell-mediated immunity and protection of rhesus macaques from chronic SHIVKU2 infection by prophylactic vaccination with a conserved HIV-1 envelope peptide-cocktail

Abstract

Infection of Indian-origin rhesus macaques by the simian human immunodeficiency virus (SHIV) is considered to be a suitable preclinical model for directly testing efficacy of vaccine candidates based on the HIV-1 envelope. We used this model for prophylactic vaccination with a peptide-cocktail comprised of highly conserved HIV-1 envelope sequences immunogenic/antigenic in macaques and humans. Separate groups of macaques were immunized with the peptide-cocktail by intravenous and subcutaneous routes using autologous dendritic cells (DC) and Freund's adjuvant, respectively. The vaccine elicited antigen specific IFN-gamma-producing cells and T-cell proliferation, but not HIV-neutralizing antibodies. The vaccinated animals also exhibited efficient cross-clade cytolytic activity against target cells expressing envelope proteins corresponding to HIV-1 strains representative of multiple clades that increased after intravenous challenge with pathogenic SHIV(KU2). Virus-neutralizing antibodies were either undetectable or present only transiently at low levels in the control as well as vaccinated monkeys after infection. Significant control of plasma viremia leading to undetectable levels was achieved in majority of vaccinated monkeys compared to mock-vaccinated controls. Monkeys vaccinated with the peptide-cocktail using autologous DC, compared to Freund's adjuvant, and the mock-vaccinated animals, showed significantly higher IFN-gamma production, higher levels of vaccine-specific IFN-gamma producing CD4(+) cells and significant control of plasma viremia. These results support DC-based vaccine delivery and the utility of the conserved HIV-1 envelope peptide-cocktail, capable of priming strong cell-mediated immunity, for potential inclusion in HIV vaccination strategies.

Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates

“…This adjuvant strategy may be most relevant for therapeutic cancer vaccines but due to the lack of cancer antigens optimized for this model, we immunized animals with a pool of six 9–13mer SLPs derived from HIV-1 envelope glycoprotein (Env) (29). These peptides are well-characterized and immunogenic in rhesus macaques (33, 34), which enabled us to focus on the adjuvant component of the immunization.…”

“…These peptides are well-characterized and immunogenic in rhesus macaques (33, 34), which enabled us to focus on the adjuvant component of the immunization. The peptides should require some degree of processing by APCs for presentation on class I MHC for induction of CD8+ T cell responses (29–32) but could conceivably be loaded directly into class II MHC for induction of CD4+ T cell immunity. Throughout the study, the magnitude and quality of antigen-specific memory CD8+ and CD4+ T cell responses were assessed using multi-parameter flow cytometry and intracellular cytokine staining (ICS).…”

Functional Impairment of Central Memory CD4 T Cells Is a Potential Early Prognostic Marker for Changing Viral Load in SHIV-Infected Rhesus Macaques

“…Cryopreserved peripheral blood mononuclear cells (PBMC) samples from a total 20 rhesus macaques experimentally infected with SHIV 89.6P or SHIV KU2 by the intravenous route in previously published studies [12], [13] were used for the studies in this investigation. The PBMC for this investigation were isolated from the blood samples collected at necropsy of the animals which varied between week 18 and 89 post-challenge, depending on the euthanization performed due to AIDS-related symptoms or end of the study.…”

Safety and immunogenicity of a CTL multiepitope peptide vaccine for HIV with or without GM-CSF in a phase I trial

“…Peptide vaccines designed to elicit HIV-specific cellular responses have been immunogenic in animal models [6, 8]. A cocktail of peptides administered to rhesus macaques in Freund's adjuvant elicited HIV-specific CTL responses and resulted in protection from a pathogenic simian-human immunodeficiency virus (SHIV) challenge [9, 10]. However, peptide-based HIV vaccines have been only modestly immunogenic thus far in human clinical trials [11-13].…”