Ln. Martin et al., EFFECTS OF U-75875, A PEPTIDOMIMETIC INHIBITOR OF RETROVIRAL PROTEASES, ON SIMIAN IMMUNODEFICIENCY VIRUS-INFECTION IN RHESUS-MONKEYS, Antimicrobial agents and chemotherapy, 38(6), 1994, pp. 1277-1283
U-75875 inhibits human immunodeficiency virus types 1 and 2 and simian
immunodeficiency virus (SIV) proteases and blocks Gag-Pol protein pro
cessing 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 intrav
enous infusion beginning 6 h prior to intravenous inoculation with 10
monkey 50% infectious doses of SIV Delta B670, and the monkeys were mo
nitored until death. The effects of treatment on the level of SIV p26
antigenemia, the infectious virus titer in serum, and the level of pro
viral DNA in blood mononuclear cells evaluated by PCR were assessed, S
IV 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 wa
s 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 l
evels 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 fo
r 26 days resulted in a dose-related delay in the day of the peak leve
l 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 less than or equal t
o 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 10 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 on SIV in vivo.