Human immunodeficiency virus type 1 envelope glycoprotein gp120 – CD4 receptor interface (HIV-1 gp120–CD4 interface)

The HIV-1 gp120 – CD4 protein-protein interface is the primary site of attachment between the Human Immunodeficiency Virus type 1 (HIV-1) and host immune cells. This interaction involves the viral envelope glycoprotein gp120 binding to the D1 domain of the host CD4 receptor, which is expressed on T-helper cells, macrophages, and dendritic cells (Kwong et al., 1998). Binding induces a conformational change in the gp120 protein, exposing the coreceptor binding site for CCR5 or CXCR4, which is a prerequisite for viral-cell membrane fusion (UniProt P04578). As a critical step in the viral life cycle, this interface is a major target for entry inhibitors and broadly neutralizing antibodies (bNAbs) (Kozal et al., 2020). Small molecule inhibitors like temsavir bind directly to gp120 to prevent this initial attachment, while monoclonal antibodies such as ibalizumab bind to the CD4 receptor itself to sterically hinder the entry process (Emu et al., 2018). The high genetic diversity and rapid mutation rate of the HIV-1 envelope gene present significant challenges, as they allow the virus to evolve resistance by altering the interface structure. Despite these challenges, targeting this interface remains a cornerstone of therapy for multidrug-resistant HIV-1 infections.

Other names

gp120-CD4 binding siteCD4 binding siteCD4bsHIV-1 entry complexgp120-CD4 interaction site

Attachment inhibition, CD4-binding site (CD4bs) blockade, and viral entry inhibition.