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Journal of Virology, July 2006, p. 6357-6367, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02240-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rapid Virus Dissemination in Infant Macaques after Oral Simian Immunodeficiency Virus Exposure in the Presence of Local Innate Immune Responses

Center for Comparative Medicine,¹ California National Primate Research Center,² Department of Internal Medicine, Division of Infectious Diseases, School of Medicine,³ Department of Pathology, School of Medicine,⁴ Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California at Davis, Davis, California,⁵ Department of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana⁶

Received 24 October 2005/ Accepted 11 April 2006

A vaccine to protect human immunodeficiency virus (HIV)-exposed infants is an important goal in the global fight against the HIV pandemic. Two major challenges in pediatric HIV vaccine design are the competence of the neonatal/infant immune system in comparison to the adult immune system and the frequent exposure to HIV via breast-feeding. Based on the hypothesis that an effective vaccine needs to elicit antiviral immune responses directly at the site of virus entry, the pattern of virus dissemination in relation to host immune responses was determined in mucosal and lymphoid tissues of infant macaques at 1 week after multiple oral exposures to simian immunodeficiency virus (SIV). The results show that SIV disseminates systemically by 1 week. Infant macaques can respond rapidly to virus challenge and mount strong innate immune responses. However, despite systemic infection, these responses are most pronounced in tissues close to the viral entry site, with the tonsil being the primary site of virus replication and induction of immune responses. Thus, distinct anatomic compartments are characterized by unique cytokine gene expression patterns. Importantly, the early response at mucosal entry sites is dominated by the induction of proinflammatory cytokines, while cytokines with direct antiviral activity, alpha/beta interferons, are only minimally induced. In contrast, both antiviral and proinflammatory cytokines are induced in lymphoid tissues. Thus, although infant macaques can respond quickly to oral viral challenge, the locally elicited immune responses at mucosal entry sites are likely to favor immune activation and thereby virus replication and are insufficient to limit virus replication and dissemination.

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