Human immunodeficiency virus type 1 envelope glycoprotein gp120–T-cell surface glycoprotein CD4–C-X-C chemokine receptor type 4 interface (gp120-CD4-CXCR4)

The HIV-1 gp120–CD4/CXCR4 interface is a critical protein-protein interaction network that mediates the entry of CXCR4-tropic (X4) HIV-1 strains into host cells. This multi-step process begins with the high-affinity binding of the viral envelope glycoprotein gp120 to the host's primary receptor, CD4, which induces a conformational shift in gp120 to expose its co-receptor binding site (NIH, 2022) [1.3.1, 1.3.4]. This site then engages the C-X-C chemokine receptor type 4 (CXCR4), a G protein-coupled receptor, triggering further structural rearrangements in the viral gp41 subunit that lead to membrane fusion and viral entry (Medscape, 2020) [1.3.1, 1.3.2]. This interface is a major therapeutic target for entry inhibitors, including attachment inhibitors like fostemsavir and co-receptor antagonists like plerixafor (NIH, 2021) [1.2.1, 1.2.3]. However, targeting this interface is challenging due to the high genetic variability of the gp120 V3 loop and the essential physiological roles of CXCR4 in hematopoiesis and immune cell trafficking (NIH, 2008) [1.1.1, 1.4.1].

Other names

gp120-CD4-CXCR4 complexHIV-1 entry complexCD4-gp120-CXCR4 axisX4-tropic HIV-1 entry interfacegp120-CXCR4 interaction site

Inhibition of viral attachment to CD4, antagonism of the CXCR4 co-receptor to prevent gp120 engagement, and post-attachment inhibition of conformational changes required for fusion.