Macaques infected long-term with attenuated simian immunodeficiency virus (SIVmac) remain resistant to wild-type challenge, despite declining cytotoxic T lymphocyte responses to an immunodominant epitope.
To further investigate mechanisms of protective immunity that are induced by live, attenuated simian immunodeficiency virus (SIV), three macaques were infected with SIVmacGX2, a nef-disrupted molecular clone. In two of these animals, which expressed the MamuA*01 major histocompatibility complex class I allele, loss of functional activity against an SIV-Gag-encoded immunodominant cytotoxic T lymphocyte (CTL) epitope was observed following prolonged infection. Nonetheless, all three animals were resistant to challenge with an uncloned pool of wild-type SIVmac, whereas four naïve controls became infected. Tetramer staining revealed the rapid generation of CD8+ T-cell responses against gag- and tat-encoded immunodominant epitopes in MamuA*01+ challenge controls. The dynamics of these T-cell responses to the wild-type virus were similar to those observed following primary infection of the vaccine group with attenuated virus. In contrast, neither tetramer staining nor gamma interferon ELISpot assay revealed an immediate, systemic, anamnestic response in the wild-type-challenged, attenuated SIV-infected animals. Functional CTL capacity had not been lost in this group, as lytic activity was still evident 17 weeks after challenge. Both attenuated and wild-type viruses induced a disseminated CD8+ T-cell response, which was of a higher magnitude in lymphoid tissues than in the periphery. These results suggest that, at least as measured in the periphery, protection against wild-type infection that is induced by live, attenuated SIV is not dependent on a rechallenge-driven expansion of immunodominant epitope-specific CD8+ T cells and, therefore, pre-existing activity may be sufficient to prevent superinfection.
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Sally A
SA
Sharpe
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Alethea
A
Cope
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Stuart
S
Dowall
Division of Retrovirology, National Institute for Biological Standards and Control, South Mimms, Herts EN6 3QG, UK.
Neil
N
Berry
Division of Retrovirology, National Institute for Biological Standards and Control, South Mimms, Herts EN6 3QG, UK.
Claire
C
Ham
Department of Virology, Biomedical Primate Research Centre, Rijswijk, the Netherlands.
Jonathan L
JL
Heeney
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Donna
D
Hopkins
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Linda
L
Easterbrook
Health Protection Agency, Porton Down, Salisbury SP4 0JG, UK.
Mike
M
Dennis
Division of Retrovirology, National Institute for Biological Standards and Control, South Mimms, Herts EN6 3QG, UK.
Neil
N
Almond
Department of Cellular and Molecular Medicine, St George's Hospital Medical School, London SW17 0RE, UK.
Martin
M
Cranage
D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D003601:Cytotoxicity Tests, Immunologic; D004195:Disease Models, Animal; D017353:Gene Deletion; D015683:Gene Products, gag / Q000032:analysis; D015693:Gene Products, nef / Q000235:genetics; D015696:Gene Products, tat / Q000032:analysis; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D016056:Immunodominant Epitopes / Q000276:immunology; D018655:Lymphocyte Count; D008221:Lymphoid Tissue / Q000276:immunology; D008251:Macaca; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology
D016915:AIDS Vaccines; D016827:CD8 Antigens; D015683:Gene Products, gag; D015693:Gene Products, nef; D015696:Gene Products, tat; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D014613:Vaccines, Attenuated