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J Virol, May 1998, p. 4265-4273, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Effectiveness of Postinoculation (R)-9-(2-Phosphonylmethoxypropyl)Adenine Treatment for Prevention of Persistent Simian Immunodeficiency Virus SIVmne Infection Depends Critically on Timing of Initiation and Duration of Treatment

Che-Chung Tsai,1,* Peter Emau,1 Kathryn E. Follis,1 Thomas W. Beck,1 Raoul E. Benveniste,2 Norbert Bischofberger,3 Jeffrey D. Lifson,4 and William R. Morton1

Regional Primate Research Center, University of Washington, Seattle, Washington 981951; Laboratory of Viral Carcinogenesis, NCI-FCRDC,2 and Laboratory of Retroviral Pathogenesis, AIDS Vaccine Program, SAIC-Frederick NCI-FCRDC,4 Frederick, Maryland 21702; and Gilead Sciences, Foster City, California 944043

Received 18 November 1997/Accepted 30 January 1998

(R)-9-(2-Phosphonylmethoxypropyl)adenine (PMPA), an acyclic nucleoside phosphonate analog, is one of a new class of potent antiretroviral agents. Previously, we showed that PMPA treatment for 28 days prevented establishment of persistent simian immunodeficiency virus (SIV) infection in macaques even when therapy was initiated 24 h after intravenous virus inoculation. In the present study, we tested regimens involving different intervals between intravenous inoculation with SIV and initiation of PMPA treatment, as well as different durations of treatment, for the ability to prevent establishment of persistent infection. Twenty-four cynomolgus macaques (Macaca fascicularis) were studied for 46 weeks after inoculation with SIV. All mock-treated control macaques showed evidence of productive infection within 2 weeks postinoculation (p.i.). All macaques that were treated with PMPA for 28 days beginning 24 h p.i. showed no evidence of viral replication following discontinuation of PMPA treatment. However, extending the time to initiation of treatment from 24 to 48 or 72 h p.i. or decreasing the duration of treatment reduced effectiveness in preventing establishment of persistent infection. Only half of the macaques treated for 10 days, and none of those treated for 3 days, were completely protected when treatment was initiated at 24 h. Despite the reduced efficacy of delayed and shortened treatment, all PMPA-treated macaques that were not protected showed delays in the onset of cell-associated and plasma viremia and antibody responses compared with mock controls. These results clearly show that both the time between virus exposure and initiation of PMPA treatment as well as the duration of treatment are crucial factors for prevention of acute SIV infection in the macaque model.

* Corresponding author. Mailing address: UW Research Laboratory, 11th Floor, Pacific Medical Center, 1200 Twelfth Ave. South, Seattle, WA 98144. Phone: (206) 325-4863. Fax: (206) 325-5134. E-mail: cctsai{at}bart.rprc.washington.edu

J Virol, May 1998, p. 4265-4273, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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