Use of standardized SCID-hu Thy/Liv mouse model for preclinical efficacy testing of anti-human immunodeficiency virus type 1 compounds

Abstract

We have developed standardized procedures and practices for infection of SCID-hu Thy/Liv mice with human immunodeficiency virus type 1 for the prophylactic administration of antiviral compounds and for evaluation of the antiviral effect in vivo. Endpoint analyses included quantitation of viral load by intracellular p24 enzyme-linked immunosorbent assay, DNA PCR for the presence of proviral genomes, flow cytometry to measure the representation of CD4 ؉ and CD8 ؉ cells, and cocultivation for the isolation of virus. Efficacy tests in this model are demonstrated with the nucleoside analogs zidovudine and dideoxyinosine and with the nonnucleoside reverse transcriptase inhibitor nevirapine. This small-animal model should be particularly useful in the preclinical prioritization of lead compounds within a common chemical class, in the evaluation of alternative in vivo dosing regimens, and in the determination of appropriate combination therapy in vivo.

Anti-tuberculosis activity and drug interaction with nevirapine of inhalable lipid microspheres containing rifampicin in murine model

“…Unfortunately, the NVP concentrations more than 3 h post-dosing were lower than the limit of quantification by HPLC assay. Therefore, the AUC 0-3 was applied to evaluate the interaction between RFP and NVP in this study, although the plasma NVP concentration in the present study is consistent with those observed in SCID mice in a previous report (Rabin et al 1996).…”

“…On day 5, blood was collected by cardiac puncture under diethyl ether (Wako Pure Chemicals Ltd., Osaka, Japan) anaesthesia at 0.5, 1.5 and 3 h after dosing (4-5 mice per time-point). Plasma of each blood sample was separated by centrifugation at 3500 rpm for 15 min at 4 C and then kept at À30 C. The plasma samples were determined by validated reversed-phase high performance liquid chromatography with ultraviolet detector (JASCO Corp., Tokyo, Japan) using a modified method reported by Rabin et al (1996). The chromatographic separation was achieved with a CrestPak C18T-5 column (C 18 , 250 mm  4.6 mm; 5 mm).…”

From Natural Product to Clinical Trials: Bevirimat, a Plant-Derived Anti-AIDS Drug

“…41 The efficacy of bevirimat was evaluated in vivo using the SCID-hu Thy/Liv mouse model, a well accepted animal model for testing HIV drugs. 53,54 Twicedaily oral administration of bevirimat to HIV-1-infected SCID-hu Thy/Liv mice reduced implant viral loads in a dose-dependent manner, causing reductions of 42 log 10 in HIV-1 RNA and Z 90% both in implant p24 concentration and in percentage of Gag-p24 1 thymocytes at 100 mg/kg per day, while preserving immature and mature T-cell populations. 55 Antiviral activity was observed in the mice at plasma concentrations that are achievable in humans by oral dosing.…”

The discovery of a class of novel HIV-1 maturation inhibitors and their potential in the therapy of HIV

“…The in vitro activity results for DSB have been extended by the demonstration of efficacy in vivo using the severe combined immunodeficiency (SCID)-hu Thy/Liv mouse model, a well-accepted animal model for testing HIV drugs [51,52]. Treatment of HIV-1 implant-infected mice with an orally bioavailable salt form of DSB by twice-daily oral gavage reduced the level of implant-associated virus in a dosedependent manner, causing reductions of ≥ 90% in p24 levels and in Gag-p24 + thymocytes at 30 and 100 mg/kg/day as well as protection of thymocytes from virus-mediated depletion [53].…”