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Journal of Virology, October 1999, p. 8630-8639, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Postinoculation PMPA Treatment, but Not Preinoculation Immunomodulatory Therapy, Protects against Development of Acute Disease Induced by the Unique Simian Immunodeficiency Virus SIVsmmPBj

Shekema Hodge,1 Juliette de Rosayro,2 Amanda Glenn,2 Ifeoma C. Ojukwu,3 Stephen Dewhurst,1 Harold M. McClure,4,5 Norbert Bischofberger,6 Daniel C. Anderson,4 Sherry A. Klumpp,4 and Francis J. Novembre2,7,*

Departments of Microbiology and Immunology1 and Pediatrics,3 University of Rochester Medical Center, Rochester, New York; Divisions of Microbiology and Immunology2 and Research Resources,4 Yerkes Regional Primate Research Center, and Departments of Pathology and Laboratory Medicine5 and Microbiology and Immunology,7 Emory University, Atlanta, Georgia; and Gilead Sciences, Foster City, California6

Received 24 February 1999/Accepted 9 July 1999

The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing.

* Corresponding author. Mailing address: Yerkes Regional Primate Research Center, 954 N. Gatewood Rd., Atlanta, GA 30322. Phone: (404) 727-7216. Fax: (404) 727-7845. E-mail: fnovembr{at}rmy.emory.edu.

Journal of Virology, October 1999, p. 8630-8639, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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