CCR5/CXCR4 discriminating sites in the HIV-1 Gp120 core

HIV-1 requires engagement of host co-receptor CCR5 or CXCR4 in order to infect human cells. Amino acid identity at positions 11 and/or 25 in the V3 loop of HIV-1 gp120 (positions 306 and 322 in terms of standard HXB2 gp120 numbering) has been shown to strongly influence which co-receptor is utilized by a viral strain. To identify additional sites in other gp120 regions that may influence co-receptor usage, we compared, position-by-position, the electrostatic charge distributions at each location in the 3D structure of X4-tropic gp120 core domains to each structurally equivalent location in R5-tropic gp120 core domains. Seven sites in the gp120 core showed a significant difference in charge distribution between the viral sets. The two strongest differences were positions 440 and 373, both located adjacent to the origin of the V3 loop, suggesting that the co-receptor binding surface of gp120 is a single hotspot formed by the V3 loop and adjacent gp120 core regions.