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Journal of Virology, April 2004, p. 3333-3342, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3333-3342.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Qualitative T-Helper Responses to Multiple Viral Antigens Correlate with Vaccine-Induced Immunity to Simian/Human Immunodeficiency Virus Infection

Petra Mooij,1* Ivonne G. Nieuwenhuis,1 Christiaan J. Knoop,1 Robert W. Doms,2 Willy M. J. M. Bogers,1 Peter J. F. ten Haaft,1 Henk Niphuis,1 Wim Koornstra,1 Kurt Bieler,3 Josef Köstler,3 Brør Morein,4 Aurelio Cafaro,5 Barbara Ensoli,5 Ralf Wagner,3 and Jonathan L. Heeney1

Department of Virology, Biomedical Primate Research Center, 2280 GH Rijswijk, The Netherlands,1 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,2 Institut für Medizinische Mikrobiologie und Hygiene der Universität Regensburg, 95053 Regensburg, Germany,3 Isconova AB, Uppsala Science Park, SE 751 83 Uppsala, Sweden,4 Istituto Superiore di Sanità, 00161 Rome, Italy5

Received 23 July 2003/ Accepted 3 December 2003

Evidence is accumulating that CD4+ T-helper (Th) responses play a critical role in facilitating effector responses which are capable of controlling and even preventing human immunodeficiency virus (HIV) infection. The present work was undertaken to determine whether immunization with multiple antigens influenced individual Th responses and increased protection relative to a single antigen. Rhesus macaques were primed with DNA and boosted (immune-stimulating complex-formulated protein) with a combination of regulatory and structural antigens (Tat-Env-Gag) or with Tat alone. Immunization with combined antigens reduced the magnitude of the responses to Tat compared to the single-antigen immunization. Interestingly, the Th immune responses to the individual antigens were noticeably different. To determine whether the qualitative differences in vaccine-induced Th responses correlated with vaccine efficacy, animals were challenged intravenously with simian/human immunodeficiency virus (strain SHIV89.6p) 2 months following the final immunization. Animals that developed combined Th1- and Th2-like responses to Gag and Th2 dominant Env-specific responses were protected from disease progression. Interestingly, one animal that was completely protected from infection had the strongest IFN-{gamma} and interleukin-2 (IL-2) responses prior to challenge, in addition to very strong IL-4 responses to Gag and Env. In contrast, animals with only a marked vaccine-induced Tat-specific Th2 response (no IFN-{gamma}) were not protected from infection or disease. These data support the rationale that effective HIV vaccine-induced immunity requires a combination of potent Th1- and Th2-like responses best directed to multiple antigens.

* Corresponding author. Mailing address: Biomedical Primate Research Centre, Department of Virology, P.O. Box 3306, 2280 GH Rijswijk, The Netherlands. Phone: 31 15 284 3105. Fax: 31 15 284 3986. E-mail: mooij{at}bprc.nl.

Journal of Virology, April 2004, p. 3333-3342, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3333-3342.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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