Efficacy of AZT therapy in reducing p24 antigen burden in a modified SCID mouse model of HIV infection.
A modified severe combined immunodeficient (SCID) mouse model of HIV infection which utilized multiple reconstitutions with human lymphocytes and a large inoculum of HIV was investigated. This mouse model yielded splenic HIV p24 antigen concentrations detectable by standard clinical means. The concentration of p24 exceeded 600 pg/g of spleen through 4 weeks postinfection. A 1-week course of AZT therapy initiated after infection produced a dose responsive reduction in p24 antigen burden. Up to a 95% reduction in p24 antigen burden was observed following AZT therapy at 50 mg/kg/day, while AZT therapy at 5 and 0.5 mg/kg/day produced 52 and 18% reductions. In vitro and pharmacokinetic evaluations correlated potency and tissue concentrations of AZT with treatment efficacy. Active HIV replication in the SCID mice was suggested by both the recovery of viable virus from SCID spleens, and by the efficacy of a brief course of AZT therapy. This SCID mouse model of HIV infection was more quantitative than previous mouse models that utilize PCR-based techniques for detection of HIV. The high HIV burden in this SCID mouse model allowed reductions in p24 concentration to be monitored in response to AZT therapy. A dose response to AZT therapy was demonstrated, even when the first dose was administered after infection. This result suggests greater sensitivity than in previous models in which pretreatment with AZT was required to produce a protective response. This SCID mouse model may be useful for determining efficacy of experimental HIV therapeutics prior to clinical use. An effective animal model could result in a reduction in cost and more rapid development of effective HIV therapeutics.
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D016655:HIV Core Protein p24 / Q000187:drug effects* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013154:Spleen / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology*
D016655:HIV Core Protein p24; D015215:Zidovudine