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Journal of Virology, November 2007, p. 12368-12374, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.00822-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

No Evidence for Consistent Virus-Specific Immunity in Simian Immunodeficiency Virus-Exposed, Uninfected Rhesus Monkeys{triangledown}

Norman L. Letvin,1,2* Srini S. Rao,2 Vi Dang,2 Adam P. Buzby,1 Birgit Korioth-Schmitz,1 Dilani Dombagoda,1 Jenny G. Parvani,1 Ryon H. Clarke,1 Liat Bar,1 Kevin R. Carlson,1 Pamela A. Kozlowski,3 Vanessa M. Hirsch,4 John R. Mascola,2 and Gary J. Nabel2

Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,1 Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892,2 Division of Gastroenterology, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115,3 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208924

Received 17 April 2007/ Accepted 26 July 2007

Defining the immune correlates of the protection against human immunodeficiency virus type 1 (HIV-1) acquisition in individuals who are exposed to HIV-1 but do not become infected may provide important direction for the creation of an HIV-1 vaccine. We have employed the simian immunodeficiency virus (SIV)/rhesus monkey model to determine whether monkeys can be repeatedly exposed to a primate lentivirus by a mucosal route and escape infection and whether virus-specific immune correlates of protection from infection can be identified in uninfected monkeys. Five of 18 rhesus monkeys exposed 18 times by intrarectal inoculation to SIVmac251 or SIVsmE660 were resistant to infection, indicating that the exposed/uninfected phenotype can be reproduced in a nonhuman primate AIDS model. However, routine peripheral blood lymphocyte gamma interferon enzyme-linked immunospot (ELISPOT), tetramer, and intracellular cytokine staining assays, as well as cytokine-augmented ELISPOT and peptide-stimulated tetramer assays, failed to define a systemic antigen-specific cellular immune correlate to this protection. Further, local cell-mediated immunity could not be demonstrated by tetramer assays of these protected monkeys, and local humoral immunity was not associated with protection against acquisition of virus in another cohort of mucosally exposed monkeys. Therefore, resistance to mucosal infection in these monkeys may not be mediated by adaptive virus-specific immune mechanisms. Rather, innate immune mechanisms or an intact epithelial barrier may be responsible for protection against mucosal infection in this population of monkeys.

* Corresponding author. Mailing address: Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, RE113, P.O. Box 15732, Boston, MA 02215. Phone: (617) 667-2766. Fax: (617) 667-8210. E-mail: nletvin{at}bidmc.harvard.edu

{triangledown} Published ahead of print on 8 August 2007.

Journal of Virology, November 2007, p. 12368-12374, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.00822-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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