California Institute of Technology researchers report on the crystal structure of the clade C HIV-1 protein, gp120, complexed with a CD4 receptor and the anti-HIV antibody 21c. Their research has thrown up the unusual finding that the 21c antibody not only reacts with the gp120 protein but also demonstrates autoreactivity to the body’s own T cells.
Caltech post-doctoral researcher, Ron Diskin, Ph.D., and colleagues suggest that this finding represents the first time that this kind of polyreactivity response to more than one antigen has been visualized in the 3-D structure of an HIV-targeting antibody. They state that the phenomenon is likely to mean that additional hurdles will need to be to overcome if an HIV-1 vaccine eliciting 21c-like antibodies is ever to be developed.
The research is published in Nature Structural & Molecular Biology in a paper titled “Structure of a clade C HIV-1 gp120 bound to CD4 and CD4-induced antibody reveals anti-CD4 polyreactivity.”
Group M HIV-1, which is responsible for the majority of HIV-1 infections worldwide, is divided into 10 clades. Clade C is the most abundant subtype in countries with the greatest number of HIV-1 infections and in Africa specifically, according to Dr. Diskin and his team.
However, they point out, high-resolution structural information concerning the envelope spike that mediates binding to host receptors (CD4 and a chemokine receptor) and the fusion of viral and cellular membranes has been limited to structures of gp120 monomers derived from North American and Western European clade B viruses and simian immunodeficiency virus.
To investigate the crystal structure of the clade C gp120 protein and compare it with that from clade B, the Caltech team had to make the gp120 protein suitable for crystallization. They did this by generating a complex of molecules comprising a gp120 monomer, a CD4 receptor, and the anti-HIV antibody 21c. Crystal structure data showed that, as previously posulated, gp120 does indeed look “pretty much the same in clade C as in clade B,” Dr. Diskin reports.
What the researchers weren’t expecting to find, though, was that in this complex, the 21c epitope interacts with both the nonself gp120 antigen and with the CD4 autoantigen. “The most interesting aspect of our structure is the unexpected contact between the antibody and CD4,” admits Pamela J Bjorkman, Ph.D., Max Delbruck professor of biology at Caltech and the team’s leader. “The binding to CD4 suggests that this class of anti-HIV antibodies has autoreactive properties, which raises many interesting questions about how anti-HIV immune responses affect an HIV-infected individual.”
The autoreactive properties of c21 means that researchers may have to think differently about how to develop anti-HIV vaccines that elicit immune responses, the Caltech team points out. The body tends to eliminate autoreactive antibodies, Dr. Diskin explains. “In order to create a good vaccine to produce 21c-like antibodies, researchers will have to overcome this elimination mechanism.”