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

Simian immunodeficiency virus (SIV) infection of newborn macaques is a usef ul animal model of human pediatric AIDS to study pathogenesis and to develo p intervention strategies aimed at preventing infection or delaying disease progression. In previous studies, we demonstrated that 9-[2-(R)-(phosphono methoxy)propyl] adenine (PMPA; tenofovir) was highly effective in protectin g newborn macaques against infection with virulent wild-type (i.e., drug-su sceptible) 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 susce ptibility to PMPA, associated with a K65R mutation and additional amino aci d changes (N69T, R82K, A158S, S211N) in reverse transcriptase (RT). Eight n ewborn macaques were inoculated orally with SIVmac055. The three untreated control animals became SIVmac055 infected; these animals had persistently h igh viremia and developed fatal immunodeficiency within 3 months. Five anim als were treated once daily with PMPA (at 30 mg/kg of body weight) for 4 we eks, starting 24 h prior to oral SIVmac055 inoculation. Two of the five PMP A-treated animals had no evidence of infection. The other three PMPA-treate d infant macaques became infected but had a delayed viremia, enhanced antiv iral antibody responses, and a slower disease course (AIDS in 5 to 15 month s). No reversion to wild-type susceptibility or loss of the K65R mutation w as detected in virus isolates from any of the PMPA-treated or untreated SIV mac055-infected animals. Several additional amino acid changes developed in RT, but they were not exclusively associated with PMPA therapy. The result s of this study suggest that prophylactic administration of PMPA to human n ewborns and to adults following exposure to human immunodeficiency virus wi ll still be beneficial even in the presence of viral variants with reduced susceptibility to PMPA.