Viral fusion presents a unique target for antiviral therapy. As viral fusion, and the entire process of viral entry have become better defined, ways in which these processes could be inhibited have also become more clear. The three main points of the viral entry process are described below.

The first step in the process of viral entry involves the interaction between HIV's external viral envelope glycoprotein, gp120, and domains on the CD4 receptors that allow binding and attachment to occur. Investigational attachment inhibitors target this initial stage of CD4 receptor binding to viral gp120 and disrupt the process that brings viral gp120 into close proximity with the coreceptors.

Following the interaction of gp120 with the CD4 receptors, a structural change is believed to occur within gp120 that allows further interaction between gp120 and the major HIV coreceptors, CCR5 and CXCR4. CCR5 and CXCR4 inhibitors in development target the process of gp120 binding to these coreceptors.

Conformational changes occur in gp41 following the interaction between gp120 and the CD4 receptors and coreceptors. These changes allow gp41 to anchor to the host cell membrane and drive fusion of the viral membrane with the cell membrane. Membrane fusion creates a fusion pore large enough to allow the HIV capsid to pass into the CD4 cell. Synthetic peptide fusion inhibitors block key structural changes in gp41 that facilitate membrane fusion, thereby preventing the insertion of the viral genome into the healthy CD4 cell. Peptide fusion inhibitors are in late-stage clinical development.

To view an animated representation of fusion and cell entry, click on the image below.



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