Moreover, by using DNA extracted from spleens, the mean HIV:HLA PCR product ratio, which takes into account individual variation in immune system reconstitution, were 0.50 and 0.40 for MDL 74,968 and PMEA treatments, respectively, whereas animals receiving the placebo control had significantly higher levels of HIV proviral DNA (mean 0.78 P < 0.02). Quantitation of virus recovery by endpoint titration of spleen cells in coculture with mitogen-activated PBMCs demonstrated that MDL 74,968 as well as PMEA significantly reduced the amount of virus (P < 0.02). Treatment by continuous subcutaneous infusion of MDL 74,968 or PMEA at the daily dose of 20 mg/kg in the hu-PBL-SCID.beige murine model of HIV infection significantly reduced the severity of infection compared with that in placebo-treated controls. Engraftment levels of human cells in the NOD scid were reported to be 5-10 fold higher than in the parental SCID mouse. Furthermore, no adverse effects of MDL 74,968 were apparent when mice were treated at doses of 200 mg/kg twice daily for 5 days. Crossing the NOD and SCID mice produced the NOD scid, defective in both T and B cell functions, as well as having an increased deficiency in macrophage function, complement-dependent hemolytic activity, and NK activity. Model Description Genetic Background: C.B-17 Background Origin: The scid-beige Spontaneous mutant model was developed by Dr. SCID/Beige mice, defective in the development of T and B cells and NK-cell activity, are dependent on constitutive nonadaptive defense mechanisms for protection. The incidence of Ig will increase as the mice age. Scid mice are homozygous for the Prkdc scid mutation. SCID mice possess an autosomal recessive mutation developed in C.B-17 mice, which are a congenic and inbred strain of BALB mice. Studies of acute toxicity in CD-1 mice showed that MDL 74,968 was not toxic at doses of 1,600 mg/kg of body weight via the intraperitoneal route or at doses of 500 mg/kg via the intravenous route. The C.B-17 scid mice exhibit extremely low levels of Ig in 20 of the mice at 12 weeks of age. MDL 74,968 was at least fourfold less toxic than PMEA to MT-4 cells or PBMCs, thereby producing a more favorable in vitro selectivity index for the former compound. Furthermore, in tumor-bearing SCID/Beige mice, a significant delayed tumor progression and prolonged survival was observed after infusion of ZA-primed NK. The novel acyclonucleotide derivative of guanine, 9- guanine (MDL 74,968), had antiviral activity comparable to those of 9-(2-phosphonomethoxyethyl) adenine (PMEA) and 2',3'-dideoxyinosine against laboratory strains of both human immunodeficiency virus (HIV) types 1 and 2 cultured in MT-4 cells and several clinical HIV isolates cultured in human peripheral blood mononuclear cells (PBMCs).

Beige scid mice