Immunization with a Modified Vaccinia Virus Expressing Simian Immunodeficiency Virus (SIV) Gag-Pol Primes for an Anamnestic Gag-Specific Cytotoxic T-Lymphocyte Response and Is Associated with Reduction of Viremia after SIV Challenge

Abstract

The immunogenicity and protective efficacy of a modified vaccinia virus Ankara (MVA) recombinant expressing the simian immunodeficiency virus (SIV) Gag-Pol proteins (MVA-gag-pol) was explored in rhesus monkeys expressing the major histocompatibility complex (MHC) class I allele, MamuA*01. Macaques received four sequential intramuscular immunizations with the MVA-gag-pol recombinant virus or nonrecombinant MVA as a control. Gag-specific cytotoxic T-lymphocyte (CTL) responses were detected in all MVA-gagpol-immunized macaques by both functional assays and flow cytometric analyses of CD8 ؉ T cells that bound a specific MHC complex class I-peptide tetramer, with levels peaking after the second immunization. Following challenge with uncloned SIVsmE660, all macaques became infected; however, viral load set points were lower in MVA-gag-pol-immunized macaques than in the MVA-immunized control macaques. MVA-gag-pol-immunized macaques exhibited a rapid and substantial anamnestic CTL response specific for the p11C, C-M Gag epitope. The level at which CTL stabilized after resolution of primary viremia correlated inversely with plasma viral load set point (P ‫؍‬ 0.03). Most importantly, the magnitude of reduction in viremia in the vaccinees was predicted by the magnitude of the vaccine-elicited CTL response prior to SIV challenge.Evidence for a critical role of cytotoxic T lymphocytes (CTLs) in the containment of human immunodeficiency virus (HIV) infection (16,23,36,39) has led to a consensus among those attempting to develop an AIDS vaccine that such a vaccine should generate CTL in addition to broadly neutralizing antibodies (26). An additional hurdle for an AIDS vaccine is the long-term maintenance of levels of CTL and antibody that will be necessary for protection (26). Both effector CTL and neutralizing antibodies induced by vaccination tend to be transient. Therefore, it may not be feasible to maintain immune responses essential for preventing infection. The importance of the magnitude of the vaccine-elicited memory and postinfection anamnestic immune responses thus become a critical issue in developing an AIDS vaccine.At present, viable vaccine strategies that might effectively stimulate CTL include viral vectors, peptides, and DNA immunization (26). Viral vectors under investigation include adenovirus (10, 48), alphaviruses such as Semliki Forest virus (8, 35) and Venezuelan equine encephalitis virus (11), poliovirus replicons (23), and various poxviruses (12,21,29,30,34,43). Among these approaches, use of the poxviruses is a particularly promising vaccine strategy to express viral proteins. Studies with conventional New York Board of Health vaccinia virus demonstrated that priming with a vaccinia virus recombinant expressing simian immunodeficiency virus (SIV) envelope and/or core proteins, followed by boosting the antibody response with recombinant envelope protein, provided protection against a homologous SIV challenge with a biologically cloned strain of limited pathogenicity (SIVmne/E11S) (20). However this app...

Induction of gp120-specific protective immune responses by genetic vaccination with linear polyethylenimine–plasmid complex

“…Vaccine strategies which elicit potent cytotoxic T cell (CTL) responses lead to reduced virus loads and long-term protection against immunodeficiency disease in macaque challenge studies using simian immunodeficiency virus (SIV) or pathogenic simian-human immunodeficiency virus chimeras (SHIV) [8,9]. It has been recently reported that viral escape from CTL recognition can result in the eventual failure of the immune protection induced by candidate AISD vaccines [10] and rhesus macaques infected with SIV/SHIV show significantly higher viral loads if CD8+ T cells are eliminated [11,12].…”

Replicating adenovirus vector prime/protein boost strategies for HIV vaccine development

“…T-cells are also important for control of SIV in the macaque model of AIDS. CD8+ T-cells elicited by vaccines are responsible for reducing viral load [2,[8][9][10][11]. Conversely, in vivo depletion of CD8+ T-cells prior to challenge with SIV results in uncontrolled viral replication [12].…”

Immune-response profiles induced by human immunodeficiency virus type 1 vaccine DNA, protein or mixed-modality immunization: increased protection from pathogenic simian–human immunodeficiency virus viraemia with protein/DNA combination

“…Whilst immunization with simian immunodeficiency virus (SIV) Gag, alone or in combination with HIV-1 Env or Nef and Tat, has already yielded promising results, the data must be interpreted with caution as, in most cases, Mamu A*01-positive animals, which mount a particularly robust response to highly conserved Gag peptides, were used (Amara et al, 2001(Amara et al, , 2002Barouch et al, 2001;Casimiro et al, 2005;Egan et al, 2004;Montefiori et al, 1996;Mooij et al, 2004;Seth et al, 2000;Shiver et al, 2002). Importantly, previous work using an adjuvanted protein vaccine based on Env, Nef and Tat antigens suggested protection from SHIV-induced sustained virus load and CD4 T-cell decline in rhesus monkeys (Voss et al, 2003).…”