CD4:gp120 binds to chemokine co-receptor CCR5/CXCR4

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Human immunodeficiency virus 1
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Once the viral gp120 protein has bound to cellular CD4, its bridging sheet region becomes exposed/formed as a result of conformation changes in the V1 and V2 loops as well as a conformational change in the gp120 core domain. Once this region is exposed, it is free to bind the HIV co-receptors CCR5 or CXCR4 (also known as chemokine receptors). Different viruses use different co-receptors (CCR5 or CXCR4) for entry, and many studies investigated the structural determinants of interaction between gp120 and the co-receptor.
Studies of CCR5 binding by gp120 revealed that active regions in the second extracellular loop (ECL2), the N-terminal extracellular domain (specifically the NYYTSE motif) and at the junction between the fifth transmembrane domain and third cytoplasmic loop of the receptor are important for viral attachment and subsequent fusion. The N-terminal region likely interacts with the core of gp120 (bridging sheet and adjacent regions) and the base of V3, while ECL2 may be important for interacting with the tip of V3. The transmembrane 5 / cytoplasmic loop 3 junction of CCR5 has been shown to influence the conformation of the receptor which allows for subsequent binding of gp120 (Wang et al.,1999). Deletion of the V3 loop in gp120 abolished Env interaction with co-receptor without affecting the binding of soluble gp120 to CD4, underscoring the importance of this loop in chemokine receptor, but not CD4, binding. Furthermore, the V3 loop is a major determinant of coreceptor specificity, with amino acid at positions 11 and 25 being partly predictive of CCR5 or CXCR4 use. Single amino acid changes in V3 can alter coreceptor use, however sequences outside of V3 can also contribute to coreceptor specificity.

Literature References
PubMed ID Title Journal Year
9641677 Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

Sodroski, J, Hendrickson, WA, Sweet, RW, Robinson, J, Wyatt, R, Kwong, PD

Nature 1998
9632396 A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding

Sodroski, J, Hendrickson, WA, Rizzuto, CD, Sun, Y, Hernandez-Ramos, N, Kwong, PD, Wyatt, R

Science 1998
10497202 CCR5 HIV-1 coreceptor activity. Role of cooperativity between residues in N-terminal extracellular and intracellular domains.

Schweickart, V, Sun, Y, Lee, B, Murray, JL, Wang, Z, Zhang, T, Bonneau, F, Peiper, SC

J Biol Chem 1999
8674119 The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates

Sodroski, J, Rollins, B, Sun, Y, Choe, H, Wu, L, Gerard, C, Sullivan, N, Newman, W, Mackay, CR, LaRosa, G, Ponath, PD, Gerard, N, Farzan, M

Cell 1996
16284180 Structure of a V3-containing HIV-1 gp120 core

Sodroski, J, Stanfield, RL, Huang, CC, Majeed, S, Kwong, PD, Wyatt, R, Dimitrov, DS, Zhang, MY, Korber, B, Montabana, E, Wilson, IA, Tang, M

Science 2005
8658171 CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1

Murphy, PM, Combadiere, C, Feng, Y, Alkhatib, G, Berger, EA, Kennedy, PE, Broder, CC

Science 1996
8649511 Identification of a major co-receptor for primary isolates of HIV-1

Choe, S, Littman, DR, Hill, CM, Marmon, S, Ellmeier, W, Liu, R, Sutton, RE, Di Marzio, P, Davis, CB, Unutmaz, D, Burkhart, M, Schall, TJ, Deng, H, Landau, NR, Peiper, SC

Nature 1996
9721247 Interactions among HIV gp120, CD4, and CXCR4: dependence on CD4 expression level, gp120 viral origin, conservation of the gp120 COOH- and NH2-termini and V1/V2 and V3 loops, and sensitivity to neutralizing antibodies

Sodroski, J, Mondor, I, Wyatt, R, Sattentau, QJ, Moulard, M, Ugolini, S, Delaunay, T, Amara, A, Hoxie, J, Klasse, PJ

Virology 1998
9311827 Coreceptor usage of primary human immunodeficiency virus type 1 isolates varies according to biological phenotype

Littman, DR, Fenyo, EM, Colognesi, C, Albert, J, Bjorndal, A, Karlsson, A, Fiore, JR, Deng, H, Jansson, M, Scarlatti, G

J Virol 1997
8906796 CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5

Moore, JP, Cheng-Mayer, C, Olson, WC, Arthos, J, Robinson, J, Maddon, PJ, Binley, JM, Dragic, T, Trkola, A, Allaway, GP

Nature 1996
9499113 Human immunodeficiency virus (HIV) envelope binds to CXCR4 independently of CD4, and binding can be enhanced by interaction with soluble CD4 or by HIV envelope deglycosylation

Gorny, MK, Zolla-Pazner, S, Baleaux, F, Hoxie, JA, Bandres, JC, Wang, QF, O'Leary, J, Amara, A

J Virol 1998
Name Identifier Synonyms
Human immunodeficiency virus infectious disease DOID:526 HIV infection
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