Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A*01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys

Harvard University, Cambridge, Massachusetts, United States
Journal of Virology (Impact Factor: 4.44). 05/2005; 79(8):4580-8. DOI: 10.1128/JVI.79.8.4580-4588.2005
Source: PubMed


The expression of particular major histocompatibility complex (MHC) class I alleles can influence the rate of disease progression
following lentiviral infections. This effect is a presumed consequence of potent cytotoxic T-lymphocyte (CTL) responses that
are restricted by these MHC class I molecules. The present studies have examined the impact of the MHC class I allele Mamu-A*01 on simian/human immunodeficiency virus 89.6P (SHIV-89.6P) infection in unvaccinated and vaccinated rhesus monkeys by exploring
the contribution of dominant-epitope specific CTL in this setting. Expression of Mamu-A*01 in immunologically naive monkeys was not associated with improved control of viral replication, CD4+ T-lymphocyte loss, or survival. In contrast, Mamu-A*01+ monkeys that had received heterologous prime/boost immunizations prior to challenge maintained higher CD4+ T-lymphocyte levels and better control of SHIV-89.6P replication than Mamu-A*01− monkeys. This protection was associated with the evolution of high-frequency anamnestic CTL responses specific for a dominant
Mamu-A*01-restricted Gag epitope following infection. These data indicate that specific MHC class I alleles can confer protection
in the setting of a pathogenic SHIV infection by their ability to elicit memory CTL following vaccination.

Download full-text


Available from: Sampa Santra, May 20, 2014
  • Source
    • "The studies also showed that RM that express the Class I Mamu-A*01 molecule control viremia after infection by a chimeric lentivirus composed of elements from both HIV and SIV, referred to as SHIV, more effectively than Mamu-A*01 negative animals (Mothe et al., 2003). This improved control of viral replication correlated with the development of a high-frequency dominant epitope Gag-specific CTL response following infection (Seaman et al., 2005). Similarly, the Mamu B*17 alleles also has been associated with slower disease progression in SIV-infected RM (Allen et al., 1998;Evans et al., 2000;Loffredo et al., 2007;Loffredo et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: We have developed a murine model expressing the rhesus macaque (RM) Mamu-A01 MHC allele to characterize immune responses and vaccines based on antigens of importance to human disease processes. Towards that goal, transgenic (Tg) mice expressing chimeric RM (alpha1 and alpha2 Mamu-A01 domains) and murine (alpha3, transmembrane, and cytoplasmic H-2K(b) domains) MHC Class I molecules were derived by transgenesis of the H-2K(b)D(b) double MHC Class I knockout strain. After immunization of Mamu-A01/K(b) Tg mice with rVV-SIVGag-Pol, the mice generated CD8(+) T-cell IFN-gamma responses to several known Mamu-A01 restricted epitopes from the SIV Gag and Pol antigen sequence. Fusion peptides of highly recognized CTL epitopes from SIV Pol and Gag and a strong T-help epitope were shown to be immunogenic and capable of limiting an rVV-SIVGag-Pol challenge. Mamu-A01/K(b) Tg mice provide a model system to study the Mamu-A01 restricted T-cell response for various infectious diseases which are applicable to a study in RM.
    Full-text · Article · Mar 2009 · Virology
  • Source
    • "virus. The Mamu-A*01 status of these animals was determined as recently described (Seaman et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immunization by the SF162gp140 or the DeltaV2gp140 HIV-1 envelope proteins results in the generation of strong homologous neutralizing antibodies (NAbs) that offer similar degree of protection from disease-development to macaques challenged with homologous virus. These two immunogens elicit weak cross-reactive NAbs and their effectiveness against heterologous challenge is currently unknown. To examine this issue, we immunized macaques with SIVGag p55 and either the SF162gp140 or the DeltaV2gp140 and challenged them intravenously with SHIV-89.6P. All animals became infected but previous immunization with SF162gp140 accelerated the development of anti-SHIV89.6P neutralizing antibody responses following infection. DeltaV2gp140 is derived from SF162gp140 following the deletion of 30 amino acids and one N-linked glycosylation site from the V2 loop. Our results suggest that even small differences in HIV Envelope immunogen structure can affect the neutralizing antibody responses generated following infection.
    Full-text · Article · Jul 2006 · Virology
  • Source
    • "This variability among animals could be due, in part, to differences in the major histocompatibility complex (MHC) alleles present among the macaques used. Consistent with this idea, previous studies have demonstrated that MHC allelic composition, including such alleles as Mamu A*01 and B*17, is associated with CTL response, CTL escape and the rate of SIV disease progression in macaques (Bontrop and Watkins, 2005; Loffredo et al., 2004; O'Connor et al., 2003; Seaman et al., 2005a). The implications of these findings are that differences in MHC allelic composition of nonhuman primates in preclinical immunogenicity studies as well as humans in clinical trials may influence the immunological responses noted and the success or failure of HIV-1 vaccine candidates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While DNA vaccines have been shown to prime cellular immune responses, levels are often low in nonhuman primates or humans. Hence, efforts have been directed toward boosting responses by combining DNA with different vaccination modalities. To this end, a polyvalent DNA prime/protein boost vaccine, consisting of codon optimized HIV-1 env (A, B, C, E) and gag (C) and homologous gp120 proteins in QS-21, was evaluated in rhesus macaques and BALB/c mice. Humoral and cellular responses, detected following DNA immunization, were increased following protein boost in macaques and mice. In dissecting cellular immune responses in mice, protein-enhanced responses were found to be mediated by CD4+ and CD8+ T cells with a Th1 cytokine bias. Our study reveals that, in addition to augmenting humoral responses, protein boosting of DNA-primed animals augments cellular immune responses mediated by CD8+ CTL, CD4+ T-helper cells and Th1 cytokines; thus, offering much promise in controlling HIV-1 in vaccinees.
    Full-text · Article · Apr 2006 · Virology
Show more