Abstract
CD4 binding on gp120 leads to the exposure of highly conserved regions recognized by the HIV co-receptor CCR5 and by CD4-induced (CD4i) antibodies. A covalent gp120-CD4 complex was shown to elicit CD4i antibody responses in monkeys, which was correlated with control of the HIV virus infection (DeVico, A., Fouts, T., Lewis, G. K., Gallo, R. C., Godfrey, K., Charurat, M., Harris, I., Galmin, L., and Pal, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 17477-17482). Because the inclusion of CD4 in a vaccine formulation should be avoided, due to potential autoimmune reactions, we engineered small sized CD4 mimetics (miniCD4s) that are poorly immunogenic and do not induce anti-CD4 antibodies. We made covalent complexes between such an engineered miniCD4 and gp120 or gp140, through a site-directed coupling reaction. These complexes were recognized by CD4i antibodies as well as by the HIV co-receptor CCR5. In addition, they elicit CD4i antibody responses in rabbits and therefore represent potential vaccine candidates that mimic an important HIV fusion intermediate, without autoimmune hazard.
Highlights
Despite the development of effective drugs targeting the HIV virus, AIDS remains a major health problem worldwide
Intermolecular Disulfide Bond Exchange Concept—After the failure to conciliate cross-linking with antigenic properties using standard strategies, we developed an original coupling method between a miniCD4-SH and gp120 based on intermolecular disulfide bond exchange
It has been shown that the chemokine co-receptor-binding site of HIV-1 from clades A–F and H and the circulating recombinant forms CRF01, CRF02, and CRF11 elicit high titers of CD4i antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 [42]
Summary
Despite the development of effective drugs targeting the HIV virus, AIDS remains a major health problem worldwide. A single chain construct formed by gp120BaL-rhesus macaque CD4D1D2, evaluated as an immunogen in rhesus macaques challenged with SHIVSF162P3, was found to elicit an antibody response that correlated with an accelerated clearance of plasma viremia and an absence of long term tissue viremia [26] Taken together, these data emphasize the usefulness of CD4-gp120 covalent complexes as a vaccine candidate. This study describes the generation of a stable covalent complex between a engineered miniCD4 and an Envderived protein, with no antigenic properties altering the virus protein This complex was shown to elicit a CD4i antibody response in rabbits, and the sera were able to neutralize a few tested virus strains
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