Effects of U-75875, a peptidomimetic inhibitor of retroviral proteases, on simian immunodeficiency virus infection in rhesus monkeys.
U-75875 inhibits human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus (SIV) proteases and blocks Gag-Pol protein processing and viral maturation and replication in vitro. Rhesus monkeys were treated with vehicle alone or with formulated U-75875 at doses of 7 or 20 mg/kg of body weight per day for 26 days by continuous intravenous infusion beginning 6 h prior to intravenous inoculation with 10 monkey 50% infectious doses of SIV Delta B670, and the monkeys were monitored until death. The effects of treatment on the level of SIV p26 antigenemia, the infectious virus titer in serum, and the level of proviral DNA in blood mononuclear cells evaluated by PCR were assessed. SIV infection of the controls resulted in an initial viral antigenemia that began 5 to 10 days postinoculation (p.i.), reached peak values on days 10 to 14 p.i., and lasted for more than 15 days. Proviral DNA was detectable in peripheral blood mononuclear cells by 7 to 11 days p.i., reached the mean peak level by 11 days p.i., and remained at high levels through day 24 p.i. Infectious virus was detected in serum from all of the infected controls by 24 days p.i. Treatment with U-75875 for 26 days resulted in a dose-related delay in the day of the peak level of antigenemia (P = 0.034). The level of proviral DNA in peripheral blood mononuclear cells at 11 days p.i. was significantly decreased in a dose-related fashion in the treated monkeys ( P </- 0.048), with a delay in the attainment of the peak level of proviral DNA in the treated groups. The titer of infectious virus in the serum of the group treated with 20 mg/kg/day was significantly decreased on day 24 p.i. compared with that in the serum of controls ( P = 0.046). Treatment with formulated U-75875 was well tolerated in rhesus monkeys and resulted in an inhibitory effect of SIV in vivo.
Martin
L N
LN
Tulane Regional Primate Research Center, Covington, Louisiana 70433.
Soike
K F
KF
Murphey-Corb
M
M
Bohm
R P
RP
Roberts
E D
ED
Kakuk
T J
TJ
Thaisrivongs
S
S
Vidmar
T J
TJ
Ruwart
M J
MJ
Davio
S R
SR
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000998:Antiviral Agents / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D019012:Integrin beta1; D016023:Integrins / Q000032:analysis; D008253:Macaca mulatta; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000254:growth & development / Q000302:isolation & purification; D016176:T-Lymphocyte Subsets / Q000276:immunology
D015703:Antigens, CD; D000998:Antiviral Agents; D015704:CD4 Antigens; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D019012:Integrin beta1; D016023:Integrins; D009842:Oligopeptides; C065978:U 75875