311   Coreceptor Trap Therapy: Combination of CCR5 and CXCR4 Inhibitors Blocks Human Immunodeficiency Virus Type I Infection In Vivo.

G. Picchio*¹, R. Sabbe¹, M. Neal¹, G. Henson², R. Macfarland², O. Chaloin³, R. Offord³, and D. Mosier¹.
¹The Scripps Res. Inst., La Jolla, CA;²AnorMed, Inc., Vancouver, BC, Canada; and³Ctr. Med. Univ., Geneva, Switzerland.

Background:Inhibition of human immunodeficiency virus type I (HIV-1) binding to target cells by coreceptor blocking agents is an attractive potential therapy. Treatment of human peripheral blood leukocyte-reconstituted SCID (hu-PBL-SCID) mice with the CCR5-inhibitor NNY-RANTES prevented R5 HIV-1 infection in the majority of animals but selected for NNY-RANTES resistance and R5X4 coreceptor use in some animals (Mosier et al., J. Virol. 73:3544, 1999). Combined treatment with both CCR5 and CXCR4 inhibitors should prevent this outcome.

Methods:In the current experiments, hu-PBL-SCID mice were treated with NNY-RANTES, the CXCR4 inhibitor AMD3100, or a combination of both inhibitors.

Results:Each inhibitor alone was only partially effective in blocking R5 or X4 HIV-1 infection, respectively, but the combination of inhibitors completely blocked infection with R5 virus and prevented emergence of CXCR4- using variants.

Conclusions:Combinations of R5 and X4 inhibitors may prevent coreceptor switch variants and provide increased safety compared to single coreceptor inhibitors.