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

Abstract

(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.

Role of Fc‐mediated antibody function in protective immunity against HIV‐1

“…1 and refs 7,9,14,15). Although these pathological changes occur over many years, studies in NHPs show that immunological [16][17][18][19] and anti-retroviral interventions 5 very early in infection have lasting and profound effects on post-infection control of viraemia, even if the intervention is transient. 5,16,17 This is also consistent with the relationship between peak viraemia early in HIV infection and viral set-point later in infection.…”

“…1 As indicated above, the first 24 to 72 hr after exposure includes the window of opportunity when acquisition can be blocked. 5 Its outer limit is establishment of the resting memory CD4 + T-cell reservoir, which no known intervention has depleted (reviewed in ref. 28).…”

“…3), consistent with similar studies in NHPs. 5 The window of opportunity is also framed by passive immunization studies in NHPs where transfer of protective neutralizing antibodies 24 hr after infection fails to prevent infection as mentioned above. 38,39 A salient feature of HIV transmission is the low probability of infection per exposure.…”

A forensic nursing protocol for initiating human immunodeficiency virus post-exposure prophylaxis following sexual assault

“…In animal studies, the administration of HIV PEP was most beneficial at reducing or eliminating viral replication when initiated within 24 hours of an exposure, with the most beneficial time frame for initiating prophylaxis being within 1 to 2 hours of an exposure (Otten et al, 2000;Tsai et al, 1998;Wick & Self, 2000). Based on the data collected from these animal studies, HIV PEP should be initiated as soon as possible following a potential exposure.…”

“…In a study conducted by Otten et al (2000), the administration of a single antiretroviral agent for 28 days prevented subsequent seroconversion of all exposed animals. In a study by Tsai et al (1998) different intervals between HIV exposures and initiation of antiretroviral medications and different durations of antiretroviral therapy as it relates to the ability to prevent subsequent HIV seroconversion were evaluated. The study revealed postexposure prophylaxis begun within 24 hours of the initial exposure and continued for 28 days was the most beneficial in preventing seroconversion.…”