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Journal of Virology, January 2002, p. 185-194, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.185-194.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Vaccine-Induced Immune Responses in Rodents and Nonhuman Primates by Use of a Humanized Human Immunodeficiency Virus Type 1 pol Gene

Danilo R. Casimiro,1* Aimin Tang,1 Helen C. Perry,1 Romnie S. Long,1 Minchun Chen,1 Gwendolyn J. Heidecker,1 Mary-Ellen Davies,1 Daniel C. Freed,1 Natasha V. Persaud,1 Sheri Dubey,1 Jeffrey G. Smith,1 Diane Havlir,2 Douglas Richman,2,3 Michael A. Chastain,1 Adam J. Simon,1 Tong-Ming Fu,1 Emilio A. Emini,1 and John W. Shiver1

Department of Virus and Cell Biology, Merck Research Laboratories, Merck and Company, West Point, Pennsylvania 19486,1 University of California-San Diego,2 VA San Diego Healthcare System, La Jolla, California 921033

Received 29 May 2001/ Accepted 26 September 2001

A synthetic gene consisting of the reverse transcriptase (RT) and integrase (IN) domains of human immunodeficiency virus type 1 (HIV-1) pol was constructed using codons most frequently used in humans. The humanized pol gave dramatically improved levels of Rev-independent, in vitro protein production in mammalian cells and elicited much stronger cellular immunity in rodents than did virus-derived gene. Specifically, BALB/c mice were immunized with plasmids and/or recombinant vaccinia virus constructs expressing the synthetic gene. High frequencies of Pol-specific T lymphocytes were detected in these animals by the gamma interferon enzyme-linked immunospot assay against pools of short overlapping peptides. Characterization of the stimulatory peptides from these pools indicates that the optimized gene constructs are able to effectively activate both CD4+ and CD8+ T cells. Immunization of rhesus macaques with DNA vaccines expressing the humanized pol coupled to a human tissue plasminogen activator leader sequence led to pronounced in vitro cytotoxic T-lymphocyte killing activities and enhanced levels of circulating Pol-specific T cells, comparable to those observed in HIV-1-infected human subjects. Thus, optimizing the immunogenic properties of HIV-1 Pol at the level of the gene sequence validates it as an antigen and provides an important step toward the construction of a potent pol-based HIV-1 vaccine component.

* Corresponding author. Mailing address: Merck and Company WP26-145, West Point, PA 19486. Phone: (215) 652-3129. Fax: (215) 993-0512. E-mail: danilo_casimiro{at}merck.com.

Journal of Virology, January 2002, p. 185-194, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.185-194.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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