T-cell surface glycoprotein CD4–HIV-1 envelope glycoprotein gp120–C-C chemokine receptor type 5 complex (CD4–gp120–CCR5 complex) (CD4–gp120–CCR5)

The CD4–gp120–CCR5 complex is a transient molecular assembly essential for the entry of R5-tropic Human Immunodeficiency Virus type 1 (HIV-1) into host cells, primarily CD4+ T lymphocytes and macrophages (Shaik et al., 2019, Nature). The process begins when the viral envelope glycoprotein gp120 binds to the host CD4 receptor, which triggers a conformational shift in gp120 that exposes a conserved coreceptor binding site (Huang et al., 2007, Science). This site then interacts with the extracellular loops and the N-terminus of the CCR5 coreceptor, a G protein-coupled receptor (UniProt P51681). This interaction is the final step before the viral gp41 subunit undergoes a structural rearrangement to mediate the fusion of the viral and host cell membranes. Because this complex is a mandatory bottleneck for viral infection, it serves as a high-value target for entry inhibitors. Drugs such as Maraviroc (Selzentry) bind to CCR5 to allosterically inhibit its interaction with gp120, while monoclonal antibodies like Ibalizumab (Trogarzo) bind to CD4 to prevent the complex from reaching the fusion-competent state (FDA Label: Trogarzo). Therapeutic challenges include the potential for the virus to shift its tropism to the CXCR4 coreceptor and the high genetic diversity of the gp120 protein.

Other names

HIV-1 entry complexgp120–CD4–CCR5 ternary complexR5-tropic HIV-1 entry complexCD4-gp120-CCR5 interfaceHIV-1 pre-fusion complex

Inhibition of HIV-1 entry by blocking the interaction between the CD4-bound viral envelope glycoprotein gp120 and the CCR5 coreceptor.