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Journal of Virology, June 2005, p. 7707-7720, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7707-7720.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Immunization of Macaques with Single-Cycle Simian Immunodeficiency Virus (SIV) Stimulates Diverse Virus-Specific Immune Responses and Reduces Viral Loads after Challenge with SIVmac239

David T. Evans,1* Jennifer E. Bricker,1 Hannah B. Sanford,1 Sabine Lang,1 Angela Carville,1 Barbra A. Richardson,2 Michael Piatak Jr.,3 Jeffrey D. Lifson,3 Keith G. Mansfield,1 and Ronald C. Desrosiers1

New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102,1 Department of Biostatistics, Box 359909, University of Washington, Seattle, Washington 98104,2 Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute at Frederick, Frederick, Maryland 217023

Received 8 November 2004/ Accepted 7 February 2005

Genetically engineered simian immunodeficiency viruses (SIV) that is limited to a single cycle of infection was evaluated as a nonreplicating AIDS vaccine approach for rhesus macaques. Four Mamu-A*01+ macaques were inoculated intravenously with three concentrated doses of single-cycle SIV (scSIV). Each dose consisted of a mixture of approximately equivalent amounts of scSIV strains expressing the SIVmac239 and SIVmac316 envelope glycoproteins with mutations in nef that prevent major histocompatibility complex (MHC) class I downregulation. Viral loads in plasma peaked between 104 and 105 RNA copies/ml on day 4 after the first inoculation and then steadily declined to undetectable levels over the next 4 weeks. SIV Gag-specific T-cell responses were detected in peripheral blood by MHC class I tetramer staining (peak, 0.07 to 0.2% CD8+ T cells at week 2) and gamma interferon (IFN-{gamma}) enzyme-linked immunospot (ELISPOT) assays (peak, 50 to 250 spot forming cells/106 peripheral blood mononuclear cell at week 3). Following the second and third inoculations at weeks 8 and 33, respectively, viral loads in plasma peaked between 102 and 104 RNA copies/ml on day 2 and were cleared over a 1-week period. T-cell-proliferative responses and antibodies to SIV were also observed after the second inoculation. Six weeks after the third dose, each animal was challenged intravenously with SIVmac239. All four animals became infected. However, three of the four scSIV-immunized animals exhibited 1 to 3 log reductions in acute-phase plasma viral loads relative to two Mamu-A*01+ control animals. Additionally, two of these animals were able to contain their viral loads below 2,000 RNA copies/ml as late as 35 weeks into the chronic phase of infection. Given the extraordinary difficulty in protecting against SIVmac239, these results are encouraging and support further evaluation of lentiviruses that are limited to a single cycle of infection as a preclinical AIDS vaccine approach.

* Corresponding author. Mailing address: New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772-9102. Phone: (508) 624-8025. Fax: (508) 786-3317. E-mail: devans{at}hms.harvard.edu.

Journal of Virology, June 2005, p. 7707-7720, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7707-7720.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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