The reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) is the major target for antiretroviral therapy of the acquired immunodeficiency syndrome (AIDS). While some inhibitors exhibit activity against most retroviral RTs, others are specific for the HIV-1 enzyme.To develop an animal model for the therapy of the HIV-1 infection with RT inhibitors, the RT of the simian immunodeficiency virus (SIV) was replaced by the RT of HIV-1.
SllnllnaryHigh-grade malignant nonHodgkin's lymphomas-five lymphoblastic, three pleomorphic, and two immunoblastic-developed in 10/25 cynomolgus monkeys (Macacafascicularis) followed for up to 746 d after infection with simian immunodeficiency virus, strain SIVsm. These lymphomas were shown to be associated with an Epstein-Barr (EB)-like cynomolgus B-lymphotropic herpesvirus (CBLV) by electron microscopy, by Southern blot hybridization with probes against human EBV, and by the expression of antigens corresponding to EBV-associated nuclear antigens (EBNAs) involved in human B cell transformation. Southern blot demonstration ofimmunoglobulin gene rearrangements and homogeneous EBV episomes indicated that all the lymphomas were CBLVassociated monoclonal B cell proliferations. Our findings suggest that these tumors correspond to the EBV-associated malignant lymphomas in acquired immunodeficiency syndrome with respect to clinical, morphological, phenotypic, and genotypic characteristics. The particular susceptibility of SIVsm immunodeficient cynomolgus monkeys for CBLV-associated lymphomagenesis appears therefore a useful model for EBV-associated lymphomas in humans.
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.
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