ENGINEERING HUMAN-IMMUNODEFICIENCY-VIRUS-1 PROTEASE HETERODIMERS AS MACROMOLECULAR INHIBITORS OF VIRAL MATURATION

Dimerization of human immunodeficiency virus type 1 protease (HIV-1 PR ) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disrupti on of the dimer interface inhibits this activity as does formation of heterodimers between wild-type and defective monomers. A structure-bas ed approach was used to identify amino acid substitutions at the dimer interface of HIV-1 PR that facilitate preferential association of het erodimers and inhibit self-association of the defective monomers. Expr ession of the designed PR monomers inhibits activity of wild-type HIV- 1 PR and viral infectivity when assayed in an ex vivo model system. Th ese results show that it is possible to design PR monomers as macromol ecular inhibitors that may provide an alternative to small molecule in hibitors for the treatment of HIV infection.