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Journal of Virology, November 2000, p. 9987-9993, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Induction of Human Immunodeficiency Virus (HIV)-Specific CD8 T-Cell Responses by Listeria monocytogenes and a Hyperattenuated Listeria Strain Engineered To Express HIV Antigens

Rachel S. Friedman,1,dagger Fred R. Frankel,2 Zhan Xu,1 and Judy Lieberman1,*

Center for Blood Research, Harvard Medical School, Boston Massachusetts 02115,1 and Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 2 March 2000/Accepted 8 August 2000

Induction of cell-mediated immunity may be essential for an effective AIDS vaccine. Listeria monocytogenes is an attractive bacterial vector to elicit T-cell immunity to human immunodeficiency virus (HIV) because it specifically infects monocytes, key antigen-presenting cells, and because natural infection originates at the mucosa. Immunization with recombinant L. monocytogenes has been shown to protect mice from lymphocytic choriomeningitis virus, influenza virus, and tumor inoculation. L. monocytogenes expressing HIV gag elicits sustained high levels of Gag-specific cytotoxic T lymphocytes (CTLs) in mice. We have examined the ability of Listeria to infect human monocytes and present HIV antigens to CD8 T lymphocytes of HIV-infected donors to induce a secondary T-cell immune response. Using this in vitro vaccination protocol, we show that L. monocytogenes expressing the HIV-1 gag gene efficiently provides a strong stimulus for Gag-specific CTLs in HIV-infected donor peripheral blood mononuclear cells. Listeria expressing Nef also elicits a secondary in vitro anti-Nef CTL response. Since L. monocytogenes is a pathogen, before it can be seriously considered as a human vaccine vector, safety concerns must be addressed. We therefore have produced a highly attenuated strain of L. monocytogenes that requires D-alanine for viability. The recombinant bacteria are attenuated at least 105-fold. We show that when these hyperattenuated bacteria are engineered to express HIV-1 Gag, they are at least as efficient at stimulating Gag-specific human CTLs in vitro as wild-type recombinants. These results suggest that attenuated Listeria is an attractive candidate vaccine vector to induce T-cell immunity to HIV in humans.

* Corresponding author. Mailing address: Center for Blood Research, 800 Huntington Ave., Boston, MA 02115. Phone: (617) 278-3381. Fax: (617) 278-3493. E-mail: lieberman{at}cbr.med.harvard.edu.

dagger Present address: Department of Immunology, Corixa Corporation, Seattle, WA 98104.

Journal of Virology, November 2000, p. 9987-9993, Vol. 74, No. 21
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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