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Journal of Virology, October 1999, p. 8549-8558, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Latent Adeno-Associated Virus Infection Elicits Humoral but Not Cell-Mediated Immune Responses in a Nonhuman Primate Model

Yosbani J. Hernandez,1,2,3 Jianming Wang,1,2,3 William G. Kearns,4 Scott Loiler,1,2,3 Amy Poirier,1,2,3 and Terence R. Flotte1,2,3,*

Gene Therapy Center1 and Departments of Pediatrics2 and Molecular Genetics and Microbiology,3 University of Florida College of Medicine, Gainesville, Florida 32610, and Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 212874

Received 6 April 1999/Accepted 18 June 1999

Latent infection with wild-type (wt) adeno-associated virus (AAV) was studied in rhesus macaques, a species that is a natural host for AAV and that has some homology to humans with respect to the preferred locus for wt AAV integration. Each of eight animals was infected with an inoculum of 1010 IU of wt AAV, administered by either the intranasal, intramuscular, or intravenous route. Two additional animals were infected intranasally with wt AAV and a helper adenovirus (Ad), while one additional animal was inoculated with saline intranasally as a control. There were no detectable clinical or histopathologic responses to wt AAV administration. Molecular analyses, including Southern blot, PCR, and fluorescence in situ hybridization, were performed 21 days after infection. These studies indicated that AAV DNA sequences persisted at the sites of administration, albeit at low copy number, and in peripheral blood mononuclear cells. Site-specific integration into the AAVS1-like locus was observed in a subset of animals. All animals, except those infected by the intranasal route with wt AAV alone, developed a humoral immune response to wt AAV capsid proteins, as evidenced by a >= fourfold rise in anti-AAV neutralizing titers. However, only animals infected with both wt AAV and Ad developed cell-mediated immune responses to AAV capsid proteins. These findings provide some insights into the nature of anti-AAV immune responses that may be useful in interpreting results of future AAV-based gene transfer studies.

* Corresponding author. Mailing address: University of Florida Gene Therapy Center, Academic Research Bldg. Rm. R1-191, 1600 SW Archer Rd. (JHMHSC Box 100266), Gainesville, FL 32610-0266. Phone: (352) 846-2739. Fax: (352) 846-2738. E-mail: flotttr{at}peds.ufl.edu.

Journal of Virology, October 1999, p. 8549-8558, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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