© 2005 The Japanese Biochemical Society
Regular Paper |
Suppression of Multiclade R5 and X4 Human Immunodeficiency Virus Type-1 Infections by a Coreceptor-Based Anti-HIV Strategy
1 Department of Pharmaceutical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973; 2 Tsukuba Primate Center for Medical Science, National Institute of Infectious Diseases, Tsukuba, Ibaraki 305-0843; and 3 Research Laboratory, Nissui Pharmaceutical Co., Ltd., Ibaraki 307-0036
To whom correspondence should be addressed. Tel. +81-96-371-4362, Fax: +81-96-362-7800, E-mail: shoji{at}gpo.kumamoto-u.ac.jp
A cyclic chimeric dodecapeptide (cCD) mimicking the conformation-specific domains of CCR5 and CXCR4 was prepared in which Gly-Asp links the amino and carboxyl termini of two combined pentapeptides (S169–G173 of CCR5; E179-R183 of CXCR4) derived from human immunodeficiency virus type-1 (HIV-1) coreceptors. The immunization of Balb/c mice with cCD conjugated with a multiple-antigen peptide (cCD-MAP) induced seven cCD-specific monoclonal antibodies (mAbs, CPMAb-I to -VII) that reacted with native CCR5 and CXCR4. Among the tested mAbs, CPMAb-I and -II potently inhibited the infection of both the R5 and X4 laboratory strains. CPMAb-III and -VI were effective against only R5 laboratory strains, and also against some X4 and R5 primary isolates. CPMAb-IV and -V had potent antiviral activities against the R5 and X4 primary isolates. In particular, CPMAb-VII was protective against not only R5 and X4 laboratory strains, but also most of the R5 and X4 primary isolates. Moreover, cCD-MAP immunization also induced antibodies that were effective against R5 and X4 multiclade HIV-1 isolates in vitro in two of three cynomolgus monkeys. Taken together, the results suggest that cCD-MAP is a candidate multiclade immunogen that can be used to block multiclade R5 and X4 HIV-1 infections.