Lasting effects of transient postinoculation tenofovir [9-R-(2-Phosphonomethoxypropyl)adenine] treatment on SHIV(KU2) infection of rhesus macaques.
SHIV(KU2) replicates to high levels in inoculated macaques and reproducibly causes an acute depletion of CD4(+) T cells. We evaluated the ability of treatment with the antiretroviral drug 9-R-(2-phosphonomethoxypropyl)adenine (PMPA; tenofovir), begun 7 days postinoculation, to inhibit viral replication and associated pathogenesis. Highly productive infection (plasma viral RNA > 10(6) copy eq/mL) was present and CD4 depletion had started when treatment was initiated. PMPA treatment was associated with a rapid decline in plasma viral RNA to undetectable levels, with parallel decreases in the infectivity of plasma and infectious cells in PBMCs and CSF and stabilization of CD4(+)T-cell levels. Viral dynamics parameters were calculated for the initial phase of exponential viral replication and the treatment-related decline in plasma viremia. Following cessation of treatment after 12 weeks, plasma viral RNA was detectable intermittently at low levels, and spliced viral transcripts were detected in lymph nodes. Although treatment was begun after viral dissemination, high viremia, and CD4 decreases had occurred, following withdrawal of PMPA, CD4(+) T-cell counts normalized and stabilized in the normal range, despite persistent low-level infection. No PMPA-resistance mutations were detected. These results validate the similar viral replicative dynamics of SHIV(KU2) 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.
Smith
M S
MS
Marion Merrell Dow Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. msmith6@kumc.edu
Foresman
L
L
Lopez
G J
GJ
Tsay
J
J
Wodarz
D
D
Lifson
J D
JD
Page
A
A
Wang
C
C
Li
Z
Z
Adany
I
I
Buch
S
S
Bischofberger
N
N
Narayan
O
O
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002555:Cerebrospinal Fluid / Q000821:virology; D004195:Disease Models, Animal; D007700:Kinetics; D008198:Lymph Nodes / Q000821:virology; D008253:Macaca mulatta; D008297:Male; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000302:isolation & purification; D000068698:Tenofovir; D013997:Time Factors; D019562:Viral Load
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D012333:RNA, Messenger; D012367:RNA, Viral; D000068698:Tenofovir; D000225:Adenine