Lasting effects of transient postinoculation tenofovir [9-R-(2-phosphonomethoxypropyl)adenine] treatment on SHIVKU2 infection of rhesus macaques

SHIVKU2 replicates to high levels in inoculated macaques and reproducibly c auses an acute depletion of CD4(+) T cells. We evaluated the ability of tre atment with the antiretroviral drug 9-R-(2-phosphonomethoxypropyl)adenine ( PMPA; tenofovir), begun 7 days postinoculation, to inhibit viral replicatio n and associated pathogenesis. Highly productive infection (plasma viral RN A > 10(6) copy eq/mL) was present and CD4 depletion had started when treatm ent was initiated. PMPA treatment was associated with a rapid decline in pl asma viral RNA to undetectable levels, with parallel decreases in the infec tivity of plasma and infectious cells in PBMCs and CSF and stabilization of CD4(+)T-cell levels. Viral dynamics parameters were calculated for the ini tial phase of exponential viral replication and the treatment-related decli ne in plasma viremia. Following cessation of treatment after 12 weeks, plas ma viral RNA was detectable intermittently at low levels, and spliced viral transcripts were detected in lymph nodes. Although treatment was begun aft er viral dissemination, high viremia, and CD4 decreases had occurred, follo wing withdrawal of PMPA, CD4(+) T-cell counts normalized and stabilized in the normal range, despite persistent low-level infection. No PMPA-resistanc e mutations were detected. These results validate the similar viral replica tive dynamics of SHIVKU2 and HIV and SIV, and also underscore the potential for long-term modulation of viral replication patterns and clinical course by perturbation of primary infection. (C) 2000 Academic Press.