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Journal of Virology, February 2009, p. 1216-1227, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01870-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Incorporation of CD40 Ligand into the Envelope of Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Enhances Immunogenicity{triangledown}

Fan-ching Lin,1 Yue Peng,1 Leslie A. Jones,1 Paulo H. Verardi,1 and Tilahun D. Yilma1,2*

International Laboratory of Molecular Biology for Tropical Disease Agents, School of Veterinary Medicine,1 Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, California 956162

Received 4 September 2008/ Accepted 17 November 2008

A vaccine for the prevention of human immunodeficiency virus (HIV) infection is desperately needed to control the AIDS pandemic. To address this problem, we developed vesicular stomatitis virus glycoprotein-pseudotyped replication-defective simian immunodeficiency viruses (dSIVs) as an AIDS vaccine strategy. The dSIVs retain characteristics of a live attenuated virus without the drawbacks of potential virulence caused by replicating virus. To improve vaccine immunogenicity, we incorporated CD40 ligand (CD40L) into the dSIV envelope. CD40L is one of the most potent stimuli for dendritic cell (DC) maturation and activation. Binding of CD40L to its receptor upregulates expression of major histocompatibility complex class I, class II, and costimulatory molecules on DCs and increases production of proinflammatory cytokines and chemokines, especially interleukin 12 (IL-12). This cytokine polarizes CD4+ T cells to Th1-type immune responses. DC activation and mixed lymphocyte reaction (MLR) studies were performed to evaluate the immunogenicity of CD40L-dSIV in vitro. Expression levels of CD80, CD86, HLA-DR, and CD54 on DCs transduced with the dSIV incorporating CD40L (CD40L-dSIV) were significantly higher than on those transduced with dSIV. Moreover, CD40L-dSIV-transduced DCs expressed up to 10-fold more IL-12 than dSIV-transduced DCs. CD40L-dSIV-transduced DCs enhanced proliferation and gamma interferon secretion by naive T cells in an MLR. In addition, CD40L-dSIV-immunized mice exhibited stronger humoral and cell-mediated immune responses than dSIV-vaccinated animals. The results show that incorporating CD40L into the dSIV envelope significantly enhances immunogenicity. As a result, CD40L-dSIVs can be strong candidates for development of a safe and highly immunogenic AIDS vaccine.

* Corresponding author. Mailing address: International Laboratory of Molecular Biology for Tropical Disease Agents, University of California, Davis, CA 95616. Phone: (530) 752-8306. Fax: (530) 752-1354. E-mail: tdyilma{at}ucdavis.edu

{triangledown} Published ahead of print on 26 November 2008.

Journal of Virology, February 2009, p. 1216-1227, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01870-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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