Based upon an analysis of three different experimental murine animal models of human immunodeficiency virus type 1 (HIV-1) infection in SCID mice, we determined that one model was particularly well-suited to adaptation in the testing of putative antiretroviral agents. Both in terms of reliability and technical feasibility, the SCID-hu-PBL model (involving reconstitution of 8-12 week old SCID mice with fresh peripheral blood mononuclear cells obtained by lymphapheresis from human donors) was selected to test the comparative antiretroviral activity of a new nucleoside analogue, 2--beta-Fluoro-dideoxyadenosine (FddA), relative to zidovudine. Reconstitution of SCID mice by intraperitoneal injection of harvested mononuclear cells led to successful and sustained transfer of lymphocytes that were optimally infectable 2-3 weeks after reconstitution. Human Ig antibody production was demonstrated in reconstituted mice as was trafficking of a small percentage of human lymphocytes to the murine spleen. The optimal titer of infectious HIV-1 IIIB was determined using viral detection by both lymphocyte co- cultivation and polymerase chain reaction methods. In a series of dose- ranging experiments, oral and intraperitoneally-administered FddA demonstrated potent dose-dependent suppression of HIV-1 infection consistently superior to zidovudine in this model. The kinetics of the protective effects of FddA pre- and post-exposure to HIV-1 were explored and revealed that FddA may also have significant chemoprophylactic utility in this regard. In another series of experiments, the adoptive transfer of protective immunity using peripheral blood mononuclear cells and plasma from gp160-immunized donors was studied. No protective effect of the gp160-primed lymphocytes or high-titer plasma could be demonstrated in the SCID-hu-PBL system. Currently, this model is also being adapted for the testing of other putative antiretroviral agents (including a monoclonal antibody directed against the V3 loop of gp120) as well as for an assessment of the relative degree to which infected lymphocytes are resistant to secondary infection by different strains of HIV-1.
