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Journal of Virology, December 2003, p. 13348-13360, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13348-13360.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Multispecific Vaccine-Induced Mucosal Cytotoxic T Lymphocytes Reduce Acute-Phase Viral Replication but Fail in Long-Term Control of Simian Immunodeficiency Virus SIVmac239

Thorsten U. Vogel,1,{dagger} Matthew R. Reynolds,1,2 Deborah H. Fuller,3 Kathy Vielhuber,1 Tim Shipley,3 James T. Fuller,3 Kevin J. Kunstman,4 Gerd Sutter,5 Marta L. Marthas,6 Volker Erfle,5 Steven M. Wolinsky,4 Chenxi Wang,7,8 David B. Allison,7,8 Erling W. Rud,9 Nancy Wilson,1 David Montefiori,10 John D. Altman,11 and David I. Watkins1,2*

Wisconsin Primate Research Center,1 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53715,2 PowderJect Vaccines, Madison, Wisconsin 53711,3 Northwestern University Medical School, Chicago, Illinois 60611,4 GSF-Institute for Molecular Virology, Munich, Germany,5 California National Primate Research Center, University of California, Davis, California 95616,6 Section on Statistical Genetics, Department of Biostatistics,7 Clinical Nutrition Research Center, Department of Nutrition Sciences,University of Alabama at Birmingham, Birmingham, Alabama 35294,8 National Laboratory for HIV Pathogenesis, Health Canada, Ottawa, Ontario K1A 0L2, Canada,9 Center for AIDS Research, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710,10 Vaccine Research Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30311,11

Received 3 June 2003/ Accepted 8 September 2003

Given the current difficulties generating vaccine-induced neutralizing antibodies to human immunodeficiency virus (HIV), the focus of the vaccine community has shifted toward creating cytotoxic-T-lymphocyte (CTL)-based vaccines. Recent reports of CTL-based vaccine trials in macaques challenged with simian/human immunodeficiency virus SHIV-89.6P have supported the notion that such vaccines can ameliorate the course of disease. However, almost all of these studies included Env as an immunogen and since SHIV-89.6P is sensitive to neutralizing antibodies it is difficult to determine the mechanism(s) of protection. Consequently, SHIV-89.6P challenge of macaques may be a poor model for determining vaccine efficacy in humans. To ascertain the effect of vaccine-induced multispecific mucosal CTL, in the absence of Env-specific antibody, on the control of an immunodeficiency virus challenge, we vaccinated Mamu-A*01+ macaques with constructs encoding a combination of CTL epitopes and full-length proteins (Tat, Rev, and Nef) by using a DNA prime/recombinant modified vaccinia virus Ankara (rMVA) boost regimen. The vaccination induced virus-specific CTL and CD4+ helper T lymphocytes with CTL frequencies as high as 20,000/million peripheral blood mononuclear cells. The final rMVA vaccination, delivered intravenously, engendered long-lived mucosal CTL. At 16 weeks after the final rMVA vaccination, the vaccinees and naive, Mamu-A*01+ controls were challenged intrarectally with SIVmac239. Massive early anamnestic cellular immune responses controlled acute-phase viral replication; however, the three vaccinees were unable to control virus replication in the chronic phase. The present study suggests that multispecific mucosal CTL, in the absence of neutralizing antibodies, can achieve a modicum of control over early viral replication but are unable to control chronic-phase viral replication after a high-dose mucosal challenge with a pathogenic simian immunodeficiency virus.

* Corresponding author. Mailing address: Wisconsin Primate Research Center, 1220 Capital Ct., Madison, WI 53715. Phone: (608) 265-3380. Fax: (608) 265-8084. E-mail: watkins{at}primate.wisc.edu.

{dagger} Present address: Aventis Pasteur, Toronto, Ontario M2R 3T4, Canada.

Journal of Virology, December 2003, p. 13348-13360, Vol. 77, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.24.13348-13360.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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