Human immunodeficiency virus type 1 envelope glycoprotein gp120 CD4-induced co-receptor binding site (HIV-1 gp120 CD4i site)

The HIV-1 gp120 CD4-induced (CD4i) co-receptor binding site is a critical functional domain on the viral envelope glycoprotein gp120 that facilitates viral entry into host cells. This site is not fully formed or accessible in the native, unliganded state of the HIV-1 trimer; instead, it is created or exposed through a major conformational change triggered by the binding of gp120 to the primary host receptor, CD4 (PubMed: 9632389). The CD4i site primarily consists of a four-stranded beta-sheet known as the bridging sheet and the base of the V3 loop, which together provide the necessary surface for high-affinity interaction with the host co-receptors CCR5 or CXCR4 (PubMed: 10359824). This interaction is the penultimate step in viral entry, leading to the insertion of the gp41 fusion peptide into the host cell membrane and subsequent membrane fusion. As a therapeutic target, the CD4i site is highly attractive due to its functional conservation across diverse HIV-1 strains, yet it is naturally protected by conformational masking and a dense glycan shield that limits antibody access (PubMed: 25505233). Current research focuses on developing monoclonal antibodies, such as 17b and 48d, and small-molecule CD4 mimetics that can either block this site or prematurely trigger its exposure to render the virus susceptible to neutralization.

Other names

CD4-induced epitopeCD4i sitegp120 bridging sheetCCR5 binding siteCXCR4 binding siteHIV-1 gp120 bridging sheet

Inhibition of viral entry by blocking the interaction between the gp120 CD4-induced site and host co-receptors (CCR5 or CXCR4).