9-[2-(PHOSPHONOMETHOXY)PROPYL]ADENINE THERAPY OF ESTABLISHED SIMIAN IMMUNODEFICIENCY VIRUS-INFECTION IN INFANT RHESUS MACAQUES

The long-term therapeutic and toxic effects of 9-[2-(phosphonomethoxy) propyl]adenine (PMPA) were evaluated in simian immunodeficiency virus (SIV)-infected newborn rhesus macaques, Four untreated SIV-infected ne wborn macaques developed persistently high levels of viremia, and thre e of the four animals had rapidly fatal disease within 3 months, In co ntrast, long-term PMPA treatment of four newborn macaques starting 3 w eeks after virus inoculation resulted in a rapid, pronounced, and pers istent reduction of viremia in three of the four animals. Emergence of virus with fivefold-decreased susceptibility to PMPA occurred in all four PMPA-treated animals and was associated with the development of a lysine-to-arginine substitution at amino acid 65 (K65R mutation) and additional mutations in the reverse transcriptase; however, the clinic al implications of this low-level drug resistance are unclear, No toxi c side effects have been seen, and all PMPA-treated animals have remai ned disease-free for more than 13 months, Our data suggest that PMPA h olds much promise for the treatment of human immunodeficiency virus-in fected human infants and adults.