Human immunodeficiency virus type 1 envelope glycoprotein gp120 CD4-binding site (CD4bs) (HIV-1 gp120 CD4bs)

The HIV-1 gp120 CD4-binding site (CD4bs) is a highly conserved, functionally essential region on the viral envelope glycoprotein gp120 that mediates the initial attachment of the virus to host CD4+ T-cells (UniProt P04578). Binding of the CD4bs to the host CD4 receptor triggers a cascade of conformational changes in the envelope trimer, exposing the coreceptor binding site for CCR5 or CXCR4, which is required for viral entry and infection (PubMed: 20616233). As a critical vulnerability in the HIV-1 life cycle, the CD4bs is the primary target for broadly neutralizing antibodies (bNAbs) such as VRC01 and 3BNC117, which are being investigated for both prevention and treatment (NIH, 2023). Additionally, small molecule inhibitors like temsavir (the active moiety of the prodrug fostemsavir) bind directly to gp120 near this site to prevent the initial attachment to CD4 (PubMed: 32661317). Despite its conservation, the site is protected by a dense glycan shield and conformational masking, posing significant challenges for vaccine design and the development of long-acting therapeutics. Resistance can emerge through mutations in the gp120 protein that alter the binding affinity of drugs or antibodies while maintaining viral fitness.

Other names

CD4-binding siteCD4bsgp120 CD4-binding pocketHIV-1 gp120 CD4-binding domain

Inhibition of viral attachment to host CD4+ T-cells by sterically blocking or inducing conformational changes in the gp120 glycoprotein.