Univ of Alabama at Birmingham
Background: Entry of HIV into a target cell is the critical first step in the viral life cycle. It involves specific recognition of two cell surface molecules (CD4 and CCR5/CXCR4) by the membrane-spanning, trimeric glycoprotein (Env) spikes of the virion. An initial interaction with CD4 increases the affinity of Env binding to the co-receptor. This biphasic interaction results in a major conformational change in the trimer structure. This is similar to that described for the influenza virus hemagglutinin following acidification, which results in the extrusion of the fusion peptide into the target cell membrane. Additional protein-protein interactions are postulated to bring the membranes sufficiently close for the lipid bilayers to fuse. The driving force for this process appears to be the energy released during the formation of a highly stable, fusion-active form of the TM glycoprotein, gp41. Key stages in this entry process—interaction of the gp120 domain with CD4 and of conformationally altered gp120 with the co-receptor molecule, as well as protein-protein interactions involved in bringing the membranes together—represent novel targets for therapeutic intervention. Preclinical studies have identified compounds that inhibit each of these stages and their mechanisms of action will be discussed. Clinical trials are most advanced for the fusion inhibitor Enfuvirtide, a synthetic peptide that corresponds to a region of HIV-1 gp41. Affinity for co-receptor and the associated kinetics of fusion, as well as changes in gp41 outside of the binding region, can influence susceptibility of viruses to peptide inhibitors, but resistance to the drug in vivo involves selection for changes in the target sequences of gp41. The development of inhibitors targeted to different steps in the HIV entry process provides a high potential for synergistic, combination therapy in the foreseeable future.