JVI Accepts, published online ahead of print on 29 April 2009

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J. Virol. doi:10.1128/JVI.00272-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Vaccine-induced Cellular Responses Control SIV Replication After Heterologous Challenge

Nancy A. Wilson^*, Brandon F. Keele, Jason S. Reed, Shari M. Piaskowski, Caitlin E. Mac Nair, Andrew J. Bett, Xiaoping Liang, Fubao Wang, Elizabeth Thoryk, Gwendolyn J. Heidecker, Michael R. Citron, Lingyi Huang, Jing Lin, Salvatore Vitelli, Chanook D. Ahn, Masahiko Kaizu, Nicholas J. Maness, Matthew R. Reynolds, Thomas C. Friedrich, John T. Loffredo, Eva G. Rakasz, Stephen Erickson, David B. Allison, Michael Piatak Jr., Jeffrey D. Lifson, John W. Shiver, Danilo R. Casimiro, George M. Shaw, Beatrice H. Hahn, and David I. Watkins

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI; Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; Merck Research Labs, West Point, Pennsylvania; SAIC Frederick, Inc., NCI-Frederick, Frederick, Maryland

^* To whom correspondence should be addressed. Email: nwilson{at}primate.wisc.edu.

All HIV vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly-reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T cell responses against 11-34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical human HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both peak (1.9 log reduction p<0.03) and at set point (3.3 log reduction p<0.003) than those of control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 vRNA copy Eq/ml and to less than 100 vRNA copy Eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T cell based vaccines may have greater potential than previously appreciated.

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