Acute Infection of Cynomolgus Monkeys with Simian Immunodeficiency Virus (SIV_SM) as a Model to Evaluate Antiviral Compounds. Effects of 3′-Azido, 3′-Deoxythymidine, Foscarnet and 2′,3′-Dideoxycytidine

Abstract

Screening of compounds with potential use in the treatment of human immunodeficiency virus (HIV) infections and acquired immunodeficiency syndrome (AIDS) can currently be made in cell culture systems, but there is a need for relevant animal models. We have infected cynomolgus monkeys with simian immunodeficiency virus of sooty mangabey origin (SIVSM) and investigated the influence of multiplicity of infection (MOI) and the effects of three different anti-HIV compounds, 3′-azido-3′-deoxythymidine (AZT), foscarnet (PFA) and 2′,3′-dideoxycytidine (ddC) on the acute infection. To secure a maximal effect of treatment this was started 8h before challenge with SIVSM and the drugs were given subsequently every 8h for 7–9 days. The appearance of viral antigen and antibodies in serum was determined. In control animals the mean day for SIV antigen appearance was Day 5.9 post-infection, whereas in animals treated with 3 × 25 mg kg−1 day−1 of AZT and 3 × 65 mg kg−1 day−1 of PFA there were significant delays in SIV antigen appearance of 1.0 and 3.6 days, respectively. Some delay in antigen appearance was indicated in animals treated with 3 × 0.2 mg kg−1 day−1 of ddC. A delayed antibody response was only seen in animals treated with PFA. Viral infection was not prevented at the multiplicity used with any of the drugs, despite treatment prior to virus inoculation. The animal model described offers attractive features for in vivo evaluation of potential anti-HIV compounds.

Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors.

“…The strong antiviral effects in vitro do not correlate well with the efficacies observed in vivo. Infection of macaques with simian immunodeficiency virus (SIV) and HIV type 2 (HIV-2) seems to offer better models for predicting antiviral effects of some drugs in humans (8)(9)(10)(11)(12)(13)(14)(15). Since the infection of macaques with SIV closely mimics HIV-1 infection in humans and since SIV-infected monkeys develop a disease very similar to the acquired immunodeficiency syndrome (AIDS) (16)(17)(18)(19), it is a model in which the effect of antiretroviral therapy on disease progression could be studied.…”

Inhibition of SIV and HIV-2 Replication in Cynomolgus Monkeys by (-)9-[4-Hydroxy-2-(Hydroxymethyl)-Butyl]Guanine (H2G)

“…The effect found was very similar to that observed when the same mg dose of AZT was used (Lundgren et al, 1991). Also PFA, ddl and d4T have been evaluated in the SIV/macaque model and have in a similar way shown effect on viral antigenaemia during the acute infection (Lundgren et al, 1990;B6ttiger et al, 1991). Treatment for 4 days using 3x15 mg kg-1 day'" of H2G gave a similar result (Fig.…”

“…SIV sm was grown in human peripheral blood mononuclear cells (PBMCs) (Lundgren et al, 1990) and HIV-2 in cynomolgus monkey PBMCs (Putkonen et al, 1991b).…”

“…Aliquots from frozen stocks of cell free HIV-2 and SIV sm were titrated in vivo in monkeys as described previously (Lundgren et al, 1990;Putkonen et al, 1991a;1991b). SIV sm was grown in human peripheral blood mononuclear cells (PBMCs) (Lundgren et al, 1990) and HIV-2 in cynomolgus monkey PBMCs (Putkonen et al, 1991b).…”

“…Evaluation of anti-HIV compounds such as AZT, 2',3'-dideoxyinosine (ddl), foscarnet (PFA), 3'-fluorothymidine (FLT) and 2',3'-didehydro-2',3'-dideoxythymidine (d4T) in monkeys infected with SIV sm and HIV-2 has shown that antiviral effects are achieved in these models at doses similar to those giving antiviral effects in HIV/AIDS patients (Lundgren et al, 1990;Bottlqer et al, 1991;1992a;1992b;1992c;Ljungdahl-Stahle et al, 1992;Sandstrom and Oberg, 1993a;1993b).…”