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

(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.

We recently used the simian immunodeficiency virus (SIV)-infected macaque model to evaluate the efficacy of (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA), which is an acyclic nucleoside phosphonate analog and a potent antiretroviral compound (1, 2) in the setting of acute retroviral infection (23). In that study, PMPA prevented SIV infection even when treatment was started 24 h after intravenous virus inoculation (23). The increased antiretroviral efficacy of PMPA in SIV-challenged macaques (23), compared with that of other nucleoside analogues such as zidovudine (AZT) (15, 24, 29), may be related to ease of phosphorylation and the longer intracellular half-life for active phosphorylated metabolites of acyclic nucleoside phosphonates than for other nucleoside analogs (1). Although PMPA is highly potent when administered during de novo or early in SIV infection, the optimal treatment regimen of PMPA for preventing establishment of persistent SIV infection has not yet been determined. Therefore, we undertook the present study to determine the impact of increasing intervals between virus inoculation and initiation of PMPA treatment and varying the duration of treatment on the effectiveness of treatment in preventing the establishment of persistent infection.