by Edward Shipwash, PhD

At the molecular level essentially all biological functions are mediated through the selective binding of ligand and receptor.  As a practical matter the study of ligands, receptors and their interactions has proven a highly fruitful path in the development of novel therapeutics.  Microbial pathogens such as viruses and bacteria must bind to a host cell through ligand receptor interactions.  We will soon be able to use stem cell technology and protein engineering to eliminate the binding sites for pathogens.

In addition to CD4, the human immunodeficiency virus (HIV) requires a coreceptor for entry into target cells.  The chemokine receptors CXCR4 and CCR5, have been identified as the principle coreceptors for T-cell tropic and macrophage-tropic HIV respectively.  Genetic findings have yielded major insights into the roles of individual coreceptors and their ligands.  Of particular importance is the discovery of an inactivating mutation in the CCR5 gene, which in homozygous form confers a strong resistance to HIV-1 infection and pathogenesis.  Coreceptors suggest a new strategy for combating the AIDs epidemic using protein engineering and stem cell technologies. 

The binding sites for the AIDs virus receptor on the receptor CD4 and the coreceptors are know.  CD4 is a four domain protein on the T cell’s surface.  The AIDs virus’ receptor binds to the fourth domain on CCD4.  The binding sites for the AIDs virus could be eliminated using known methods.  The binding sites could be replaced with other amino acid sequences or in some cases they could be deleted.  It is even possible to delete the coreceptor genes.  There are many redundancies in biology, and the function of the coreceptor is probably not essential.  Protein engineering and changing certain amino acids, such as binding sites, is well established in the current art, as is the ability to knock out genes.  Furthermore, the known inactivation mutation in the CCR5 gene could be engineered in the AIDs patient’s T-cell precursors using stem cell technology.  The other coreceptor, CXCR4, could have its binding site for HIV deleted or altered.  In this way the AIDs patient would produce millions of T-cells that are resistant to HIV. 

The method of engineering receptors and ligands can be extended to a multitude of diseases.  For example, microbial infections depend on ligand receptor interactions between pathogen and host.  Protein engineering to eliminate pathogen binding sites and stem cell technology should provide a host that is immune to infection from the pathogen.  A multiplicity of other diseases involves detrimental ligand receptor interactions.  So receptor engineering combined with stem cell technology could block infection from any pathogen and lead to the cure of a multitude of ligand receptor based pathologies. 

Figure 1 shows the CD4 and CXCR4 coreceptor on a T-tropic cell with HIV binding and the macrophage, M-tropic cell, with CD4 and coreceptor CCR5 with HIV binding and the mutated coreceptors that block HIV binding and infection.