EFFECTS OF SKF-108922, AN HIV-1 PROTEASE INHIBITOR, ON RETROVIRUS REPLICATION IN MICE

Rationally designed synthetic inhibitors of retroviral proteases inhib it the processing of viral polypeptides in cultures of human T lymphoc ytes infected with human immunodeficiency virus type 1 (HIV-1) and the refore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) a nd the lentivirus simian immunodeficiency virus (SIV). The same compou nds which blocked the infectivity of HIV-1 also inhibited the infectiv ity of RMuLV and SIV in vitro. This report extends these findings by t esting the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) wi th either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (IF) route. Compared with excipi ent control, SKF 108922, formulated with hydroxypropyl-beta-cyclodextr in (HPB), reduced virus-induced splenomegaly, viremia, and serum rever se transcriptase (RT) levels, while SKF 109273 was inactive. The HPB v ehicle by itself enhanced replication of RMuLV. The effects of changin g the formulation and the route of administration were examined. SKF 1 08922, formulated in HPB, had similar antiviral activity when administ ered by the IP or subcutaneous (SC) routes. However, SKF 108922 admini stered as a colloidal suspension in cholesterol sulfate (CS) had no de tectable antiviral effect. Measurements of the circulating levels of t he protease inhibitor in plasma explained this result. Plasma concentr ations of SKF 108922 exceeded 1000 nM within 10 min after SC administr ation of the compound solubilized in HPB, but SKF 108922 was not detec ted in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, R MuLV should provide a good model for the preclinical evaluation and de velopment of this class of agents for the treatment of HIV.