9-[2-(phosphonomethoxy)propyl]adenine (PMPA) therapy prolongs survival of infant macaques inoculated with simian immunodeficiency virus with reduced susceptibility to PMPA

Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human immunodeficiency virus infection for the st udy of the emergence and clinical implications of drug-resistant viral muta nts. We previously demonstrated that SIV-infected infant macaques receiving prolonged treatment with 9 [2-(phosphonomethoxy)propyl] adenine (PMPA) dev eloped viral mutants with fivefold reduced susceptibility to PMPA in vitro and that the development of these mutants was associated with the developme nt of a K65R mutation and additional compensatory mutations in reverse tran scriptase (RT), To study directly the virulence and clinical implications o f these SN mutants, two uncloned SNmac isolates with similar fivefold reduc ed in vitro susceptibilities to PMPA but distinct RT genotypes, SIVmac055 ( K65R, N69T, R82K A158S, S211N) and SIVmac385 (K65R, N69S, I118V), were each inoculated intravenously into six newborn rhesus macaques; 3 weeks later, three animals of each group were started on PMPA treatment. All six untreat ed animals developed persistently high levels of viremia and fatal immunode ficiency within 4 months. In contrast, the six PMPA-treated animals, despit e having persistently high virus levels, survived significantly longer: 5 t o 9 months for the three SIVmac055-infected infants and greater than or equ al to 21 months for the three SIVmac385-infected infants. Virus from only o ne untreated animal demonstrated reversion to wild-type susceptibility and loss of the K65R mutation. In several other animals, additional RT mutation s, including K64R and Y115F, were detected, but the biological role of thes e mutations is unclear since they did not affect the in vitro susceptibilit y of the virus to PMPA, In conclusion, this study demonstrates that althoug h SIVmac mutants with the PMPA-selected K65R mutation in RT were highly vir ulent, PR IPA treatment still offered strong therapeutic benefits. These re sults suggest that the potential emergence of HIV mutants with reduced susc eptibility to PMPA in patients during prolonged PMPA therapy may not elimin ate its therapeutic benefits.