Sato A, Kodama M, Abe K, Miki S, Nishimura M, Suyama A, Ogata M, Toyoda T, Sugimoto H, Yoshie O
Shionogi Institute for Medical Science, Osaka, Japan.
Antiviral Res. 1995 May;27(1-2):151-63. doi: 10.1016/0166-3542(95)00004-6.
In vivo efficacy of anti-HIV compounds is affected by various factors such as bioavailability, metabolism, clearance, and toxicity. Here we report a simple and rapid method that might be useful for preliminary evaluation of in vivo efficacy of anti-HIV compounds. MT-4 cells carrying proviral HTLV-1 were infected with HIV-1 in vitro and injected into the peritoneal cavity of SCID mice or BALB/c mice. Inoculated cells survive for 1-2 days, and support one to two cycles of viral replication which can be monitored by RT activity or p24 content in the supernatants of peritoneal wash fluids. Test compounds were administered either orally or subcutaneously. AZT, DDC and DDI, the nucleoside-type RT inhibitors currently in clinical use, all showed potent anti-HIV-1 activities in this mouse/MT-4 assay. HEPT (E-EBUdM), a non-nucleoside RT inhibitor, also showed potent anti-HIV-1 activity in vivo, whereas TIBO (R82913), another non-nucleoside RT inhibitor, was less active. In protease inhibitors KNI-272 and Ro 31-8959 showed good in vivo activities, while KNI-144, a compound closely related to KNI-272, showed poor in vivo activity. This mouse/MT-4 assay, although having a number of shortcomings as an animal model for HIV-1 infection, may be of some practical utility for preliminary evaluation of in vivo efficacy of potential anti-HIV compounds.
抗HIV化合物的体内疗效受生物利用度、代谢、清除率和毒性等多种因素影响。在此，我们报告一种简单快速的方法，可能有助于对抗HIV化合物的体内疗效进行初步评估。携带前病毒HTLV-1的MT-4细胞在体外感染HIV-1后，注入SCID小鼠或BALB/c小鼠的腹腔。接种的细胞可存活1 - 2天，并支持一到两个病毒复制周期，这可通过腹膜冲洗液上清液中的RT活性或p24含量进行监测。受试化合物通过口服或皮下给药。目前临床使用的核苷类RT抑制剂AZT、DDC和DDI在这种小鼠/MT-4试验中均显示出有效的抗HIV-1活性。非核苷类RT抑制剂HEPT（E-EBUdM）在体内也显示出有效的抗HIV-1活性，而另一种非核苷类RT抑制剂TIBO（R82913）活性较低。蛋白酶抑制剂KNI-272和Ro 31-8959在体内显示出良好的活性，而与KNI-272密切相关的化合物KNI-144在体内活性较差。这种小鼠/MT-4试验虽然作为HIV-1感染的动物模型有许多缺点，但对于潜在抗HIV化合物的体内疗效初步评估可能具有一定的实际应用价值。
