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Journal of Virology, November 2002, p. 11365-11378, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11365-11378.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Live, Attenuated Simian Immunodeficiency Virus SIVmac-M4, with Point Mutations in the Env Transmembrane Protein Intracytoplasmic Domain, Provides Partial Protection from Mucosal Challenge with Pathogenic SIVmac251

Barbara L. Shacklett,1* Karen E. S. Shaw,2 Lou A. Adamson,2 David T. Wilkens,1 Catherine A. Cox,1 David C. Montefiori,3 Murray B. Gardner,2 Pierre Sonigo,4 and Paul A. Luciw2

Gladstone Institute of Virology and Immunology, University of California—San Francisco, San Francisco,1 Center for Comparative Medicine, University of California—Davis, Davis, California,2 Department of Surgery, Duke University Medical Center, Durham, North Carolina,3 INSERM U567/CNRS UMR8104, Institut Cochin, Paris, France4

Received 4 April 2002/ Accepted 15 August 2002

Attenuated molecular clones of simian immunodeficiency virus (SIVmac) are important tools for studying the correlates of protective immunity to lentivirus infection in nonhuman primates. The most highly attenuated SIVmac mutants fail to induce disease but also fail to induce immune responses capable of protecting macaques from challenge with pathogenic virus. We recently described a novel attenuated virus, SIVmac-M4, containing multiple mutations in the transmembrane protein (TM) intracytoplasmic domain. This domain has been implicated in viral assembly, infectivity, and cytopathogenicity. Whereas parental SIVmac239-Nef+ induced persistent viremia and simian AIDS in rhesus macaques, SIVmac-M4 induced transient viremia in juvenile and neonatal macaques, with no disease for at least 1 year postinfection. In this vaccine study, 8 macaques that were infected as juveniles (n = 4) or neonates (n = 4) with SIVmac-M4 were challenged with pathogenic SIVmac251 administered through oral mucosa. At 1 year postchallenge, six of the eight macaques had low to undetectable plasma viremia levels. Assays of cell-mediated immune responses to SIVmac Gag, Pol, Env, and Nef revealed that all animals developed strong CD8+ T-cell responses to Gag after challenge but not before. Unvaccinated control animals challenged with SIVmac251 developed persistent viremia, had significantly weaker SIV-specific T-cell responses, and developed AIDS-related symptoms. These findings demonstrate that SIVmac-M4, which contains a full-length Nef coding region and multiple point mutations in the TM, can provide substantial protection from mucosal challenge with pathogenic SIVmac251.

* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, University of California, San Francisco, P.O. Box 419100, San Francisco, CA 94141-9100. Phone: (415) 378-6312. Fax: (415) 826-8449. E-mail: bshacklett{at}gladstone.ucsf.edu.

Journal of Virology, November 2002, p. 11365-11378, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11365-11378.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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