Structural Basis for Coreceptor Selectivity by The HIV Type 1 V3 Loop

Abstract

The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the beta2-beta3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. This V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was improved over using only the charge of residues 11 and 25. Thus, the data suggest a new " 11/24/25 rule" : a positively charged amino acid at position 11, 24, or 25 defines X4; otherwise R5. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R5. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.

Replication-Competent Variants of Human Immunodeficiency Virus Type 2 Lacking the V3 Loop Exhibit Resistance to Chemokine Receptor Antagonists

“…Unlike V1/V2 and V4, the V3 loop also plays a key functional role in interacting with chemokine receptors, where it determines tropism for CCR5-or CXCR4-expressing cells (8, 9, 12, 20, 23, 39, 55, 69). While a direct interaction of V3 with a chemokine receptor has not been demonstrated (12,18), compelling evidence from mutagenesis and peptide inhibition experiments (12) and from the recently determined V3 structure on a gp120 core (22) is consistent with a model in which the base of V3, contiguous with the bridging sheet, contacts the chemokine receptor N terminus, while more distal regions of V3 interact with the ECLs (2,12,18) (Fig. 8).…”

Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

“…The remarkable difference between R5 tropic and X4 tropic viruses is in the values of V3 net Cardozo et al, 2007). Now, we were able to shift the co-receptor use of the viruses by controlling the net positive charge of V3 (Cardozo et al, 2007). The values for the net positive charge of V3 are generally higher in X4 tropic viruses than in R5 tropic viruses.…”

“…We suggest that the co-receptor tropism of the viruses may be associated with these observations. The remarkable difference between R5 tropic and X4 tropic viruses is in the values of V3 net Cardozo et al, 2007). Now, we were able to shift the co-receptor use of the viruses by controlling the net positive charge of V3 (Cardozo et al, 2007).…”

Fitness Epistasis and Constraints on Adaptation in a Human Immunodeficiency Virus Type 1 Protein Region

“…V3 mutations 4 and 7 have been implicated in affecting coreceptor usage in functional studies (de Jong et al 1992;Fouchier et al 1992;Hung et al 1999; and structural modeling studies (Cardozo et al 2007;Gorry et al 2007;Rosen et al 2006). These mutations had significant pairwise and higher-order interactions with mutations 1 and 3, as well as other mutations.…”