Abstract
To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1.
Highlights
The CD4 protein expressed on the membrane of T lymphocytes and mononuclear phagocytic cells serves as the primary HIV-1 receptor, which mediates binding of the viral envelope (Env) to the cellular membrane
Balb/c mice were immunized with autologous NIH-3T3 cells infected for 24 hours with a recombinant vaccinia virus encoding the complete HIV-1 Env gp160 gene cloned from an R5 viral isolate (Ba-L), treated with 2D-CD4 (20 mg/106 cells) for 30 minutes and fixed with paraformaldehyde before injection
Since a major concern with the potential clinical use of antibodies directed against T cell-expressed antigens is the risk of inducing immunosuppression, we evaluated the effects of Monoclonal antibodies (MAbs) DB81 on nominal antigen-induced T-cell proliferation
Summary
The CD4 protein expressed on the membrane of T lymphocytes and mononuclear phagocytic cells serves as the primary HIV-1 receptor, which mediates binding of the viral envelope (Env) to the cellular membrane. Binding of Env to CD4 initiates a chain of events, including major conformational changes in the external Env glycoprotein gp120 that reshuffle its fine antigenic structure[4] This process leads to the unraveling or de novo formation of specific epitopes, which are critically involved in subsequent interactions with the coreceptors [5], culminating in the exposure of the hydrophobic fusion domain of the transmembrane envelope subunit, gp. Antibodies directed towards determinants positioned far from the receptor-binding site have been identified in sera from gp
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
