POTENT ACTIVITY OF 2'-BETA-FLUORO-2',3'-DIDEOXYADENOSINE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION IN HU-PBL-SCID MICE

A new antiretroviral agent, 2'-beta-fluoro-2',3'-dideoxyadenosine (Fdd A), is an acid-stable compound whose triphosphate form is a potent rev erse transcriptase inhibitor with in vitro anti-human immunodeficiency virus (HN) activity and a favorable pharmacokinetic profile. Severe c ombined immunodeficiency (SCID) mice reconstituted with human peripher al blood leukocytes (hu-PBL-SCID mice) provide a useful small-animal m odel for HIV research, In the present study we utilized this experimen tal system for the in vivo evaluation of the anti-HIV activity of this new compound when administered prior to infection, Initial studies re vealed that, following a challenge with 50 100% tissue culture infecti ve doses of HIV type 1 lymphadenopathy-associated virus, 39 of 42 (93% ) control mice developed HIV infection, as evidenced by positive cocul ture or positive PCR. Administration of zidovudine decreased the infec tion rate to 5 of 16 (31%), while administration of FddA decreased the infection rate to 0 of 44 (0%), In follow-up controlled studies, the anti-HIV activity of FddA was confirmed, with 18 of 20 control mice sh elving evidence of HIV infection, compared with 4 of 20 FddA-treated m ice, In addition to having direct anti-HIV effects, FddA was found to have a protective effect on human CD4(+) T cells in the face of HIV in fection, Mice treated with FddA were found to have a significantly hig her percentage of CD4(+) T cells than controls (10.3% +/- 3.4% versus 0.27% +/- 0.21%; P = 0.01), Thus, FddA, with its potent anti-HN activi ty in vivo, high oral bioavailability, long intracellular half-life, a nd ability to preserve CD4(+) cells in the presence of HIV, appears to be a promising agent for clinical investigation.