Prophylactic and therapeutic benefits of short-term 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) administration to newborn macaques following oral inoculation with simian immunodeficiency virus with reduced susceptibility to PMPA

Abstract

Simian immunodeficiency virus (SIV) infection of newborn macaques is a useful animal model of human pediatric AIDS to study pathogenesis and to develop intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-¿2-(R)-(phosphonomethoxy)propylădenine (PMPA; tenofovir) was highly effective in protecting newborn macaques against infection with virulent wild-type (i.e., drug-susceptible) SIVmac251. In the present study, we determined how reduced drug susceptibility of the virus inoculum affects the chemoprophylactic success. SIVmac055 is a virulent isolate that has a fivefold-reduced in vitro susceptibility to PMPA, associated with a K65R mutation and additional amino acid changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight newborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently high viremia and developed fatal immunodeficiency within 3 months. Five animals were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 weeks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMPA-treated animals had no evidence of infection. The other three PMPA-treated infant macaques became infected but had a delayed viremia, enhanced antiviral antibody responses, and a slower disease course (AIDS in 5 to 15 months). No reversion to wild-type susceptibility or loss of the K65R mutation was detected in virus isolates from any of the PMPA-treated or untreated SIVmac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The results of this study suggest that prophylactic administration of PMPA to human newborns and to adults following exposure to human immunodeficiency virus will still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.

FIG. 1

Time course of SIVmac055 infection of newborn macaques and the therapeutic effects of PMPA. All newborn macaques were inoculated at birth orally with SIVmac055. The three untreated SIVmac055-infected infant macaques are indicated by solid lines. The dashed lines represent the SIVmac055-inoculated animals that became infected despite four weeks of PMPA treatment starting 1 day prior to virus inoculation (shaded area). The animals which did not become infected had undetectable virus and antibody levels and are not indicated on the graphs for purposes of clarity. Infectious virus levels in PBMC (A) and plasma (B) were determined by limiting-dilution culture of PBMC and plasma, respectively. RNA levels in plasma (C) were measured by the branched-DNA assay; IgG titers to SIV (D) were determined by ELISA and are expressed as the reciprocal of the highest of fourfold dilutions (starting from a 1:100 dilution, with two replicates per dilution) which gave a positive optical density above cutoff value. Euthanasia because of simian AIDS is indicated (+).