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Journal of Virology, March 2000, p. 2584-2593, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Containment of Simian Immunodeficiency Virus Infection: Cellular Immune Responses and Protection from Rechallenge following Transient Postinoculation Antiretroviral Treatment

Jeffrey D. Lifson,1,* Jeffrey L. Rossio,1 Ramy Arnaout,2 Li Li,1 Thomas L. Parks,1 Douglas K. Schneider,1 Rebecca F. Kiser,1 Vicky J. Coalter,1 Geneva Walsh,1 Robert J. Imming,1 Bradley Fisher,3 Bernard M. Flynn,3 Norbert Bischofberger,4 Michael Piatak Jr.,1 Vanessa M. Hirsch,5 Martin A. Nowak,2 and Dominik Wodarz2

AIDS Vaccine Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 217021; Program in Theoretical Biology, Institute for Advanced Study, Princeton, New Jersey 085402; Animal Sciences Branch, National Cancer Institute, Bethesda, Maryland 208923; Gilead Sciences, Inc., Foster City, California 944044; and Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Rockville, Maryland 208525

Received 20 August 1999/Accepted 23 December 1999

To better understand the viral and host factors involved in the establishment of persistent productive infection by primate lentiviruses, we varied the time of initiation and duration of postinoculation antiretroviral treatment with tenofovir {9-[2-(R)-(phosphonomethoxy)propyl]adenine}while performing intensive virologic and immunologic monitoring in rhesus macaques, inoculated intravenously with simian immunodeficiency virus SIVsmE660. Postinoculation treatment did not block the initial infection, but we identified treatment regimens that prevented the establishment of persistent productive infection, as judged by the absence of measurable plasma viremia following drug discontinuation. While immune responses were heterogeneous, animals in which treatment resulted in prevention of persistent productive infection showed a higher frequency and higher levels of SIV-specific lymphocyte proliferative responses during the treatment period compared to control animals, despite the absence of either detectable plasma viremia or seroconversion. Animals protected from the initial establishment of persistent productive infection were also relatively or completely protected from subsequent homologous rechallenge. Even postinoculation treatment regimens that did not prevent establishment of persistent infection resulted in downmodulation of the level of plasma viremia following treatment cessation, compared to the viremia seen in untreated control animals, animals treated with regimens known to be ineffective, or the cumulative experience with the natural history of plasma viremia following infection with SIVsmE660. The results suggest that the host may be able to effectively control SIV infection if the initial exposure occurs under favorable conditions of low viral burden and in the absence of ongoing high level cytopathic infection of responding cells. These findings may be particularly important in relation to prospects for control of primate lentiviruses in the settings of both prophylactic and therapeutic vaccination for prevention of AIDS.

* Corresponding author. Mailing address: Retroviral Pathogenesis Laboratory, AIDS Vaccine Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Building 535, Fifth Floor, Frederick, MD 21702. Phone: (301) 846-1408. Fax: (301) 846-5588. E-mail: lifson{at}avpaxp1.ncifcrf.gov.

Journal of Virology, March 2000, p. 2584-2593, Vol. 74, No. 6
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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