The Expanding Therapeutic Perspective of CCR5 Blockade

Abstract

CCR5 and its interaction with chemokine ligands have been crucial for understanding and tackling HIV-1 entry into target cells. However, over time, CCR5 has witnessed an impressive transition from being considered rather unimportant in physiology and pathology to becoming central in a growing number of pathophysiological conditions. It now turns out that the massive efforts devoted to combat HIV-1 entry by interfering with CCR5, and the subsequent production of chemokine ligand variants, small chemical compounds, and other molecular entities and strategies, may set the therapeutic standards for a wealth of different pathologies. Expressed on various cell types, CCR5 plays a vital role in the inflammatory response by directing cells to sites of inflammation. Aside HIV-1, CCR5 has been implicated in other infectious diseases and non-infectious diseases such as cancer, atherosclerosis, and inflammatory bowel disease. Individuals carrying the CCR5Δ32 mutation live a normal life and are warranted a natural barrier to HIV-1 infection. Therefore, CCR5 antagonism and gene-edited knockout of the receptor gained growing interest for the therapeutic role that CCR5 blockade may play in the attenuation of the severity or progression of numerous diseases.

Keywords: CCL5; CCR5; HIV-1; cancer; inflammation.

Figure 1

CCR5 blockade. CCR5 blockade may occur (i) naturally (triangle on the bottom), by the CCR5Δ32 deletion that prevents the receptor to be transported to the cell surface; (ii) via gene editing strategies (triangle on the left) that ablate the CCR5 gene; or (iii) by receptor antagonism (triangle on the right) using different molecular entities. The cell membrane is represented with a green rectangle. Ribbon representation of CCR5 and 5p7-CCL5 three-dimensional structures were generated using PyMOL from PDB entry 5UIW (10), MVC from PDB entry 4MBS (11), and the FAB fragment of RoAb13 from PDB entry 4S2S (12).