Induction of simian immunodeficiency virus (SIV)-specific CTL in rhesus macaques by vaccination with modified vaccinia virus Ankara expressing SIV transgenes: influence of pre-existing anti-vector immunity.
A major aim in AIDS vaccine development is the definition of strategies to stimulate strong and durable cytotoxic T lymphocyte (CTL) responses. Here we report that simian immunodeficiency virus (SIV)-specific CTL developed in 4/4 macaques following a single intramuscular injection of modified vaccinia virus Ankara (MVA) constructs expressing both structural and regulatory/accessory genes of SIV. In two animals Nef-specific responses persisted, but other responses diminished and new responses were not revealed, following further vaccination. Vaccination of another two macaques, expressing Mamu A*01 MHC class I, with MVA constructs containing nef and gag-pol under the control of the moderate strength natural vaccinia virus early/late promoter P7.5, again induced an early Nef-specific response, whereas responses to Gag remained undetectable. Anti-vector immunity induced by this immunization was shown to prevent the efficient stimulation of CTL directed to the cognate Gag epitope, p11C C-M, following vaccination with another MVA construct expressing SIV Gag-Pol under a strong synthetic vaccinia virus-specific promoter. In contrast, vaccination of a previously unexposed animal resulted in a SIV-specific CTL response widely disseminated in lymphoid tissues including lymph nodes associated with the rectal and genital routes of SIV entry. Thus, despite the highly attenuated nature of MVA, repeated immunization may elicit sufficient anti-vector immunity to limit the effectiveness of later vaccination.
Sharpe
Sally
S
Centre for Applied Microbiology and Research (CAMR), Salisbury SP4 0JG, UK1.
Polyanskaya
Natasha
N
Centre for Applied Microbiology and Research (CAMR), Salisbury SP4 0JG, UK1.
Dennis
Mike
M
Centre for Applied Microbiology and Research (CAMR), Salisbury SP4 0JG, UK1.
Sutter
Gerd
G
Institut für Molekulare Virologie, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Ingolstädter Landstr. 1, 85764 München-Neuherberg, Germany2.
Hanke
Tomáš
T
MRC Human Immunology Unit, Institute of Molecular Medicine, Oxford OX3 9DS, UK3.
Erfle
Volker
V
Institut für Molekulare Virologie, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Ingolstädter Landstr. 1, 85764 München-Neuherberg, Germany2.
Hirsch
Vanessa
V
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852, USA4.
Cranage
Martin
M
Centre for Applied Microbiology and Research (CAMR), Salisbury SP4 0JG, UK1.
D000818:Animals; D015685:Fusion Proteins, gag-pol / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology; D005822:Genetic Vectors; D008253:Macaca mulatta; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019076:Transgenes; D014611:Vaccination; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*
D015685:Fusion Proteins, gag-pol; D015683:Gene Products, gag