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.

COVID-19: Therapeutics and Their Toxicities

“…Chemokine receptor 5 (CCR5) was first characterized for its role as a co-receptor in human immunodeficiency virus (HIV) viral entry into white blood cells [55]. We now recognize that other pathogens, such as Dengue [56] or Staphylococcus aureus [57] also use the CCR5 signaling pathway for entry or as a virulence factor. Leronlimab is being repurposed and investigated as a treatment option for patients with COVID-19 who experience respiratory complications as a result of COVID-19.…”

Hematopoietic Stem/Progenitor Cells and the Pathogenesis of HIV/AIDS

“…Recent evidence suggests that CCR5 is involved in inflammation (Kitade et al, 2012;Barashi et al, 2013;Duan et al, 2014) because the lack of a functional CCR5 allele is associated with the severity of viral infection, possibly due to altered immune responses (Lim et al, 2008). On the other hand, the pathological roles of CCR5 in various infectious and non-infectious diseases, e.g., autoimmune diseases, have been suggested (Vangelista and Vento, 2017). For example, the depletion of CCR5 was associated with attenuation of the adverse effects of inflammation (Muntinghe et al, 2009), and blockade of CCR5 inhibited leukocyte trafficking and reportedly reduced inflammation in a murine model of colitis (Mencarelli et al, 2016).…”

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

“…Such studies address the CCR5 molecule per se (Castanheira et al, 2019; Jiao et al, 2018; Liu et al, 2018; Umansky, Blattner, Gebhardt, & Utikal, 2017), CCR5 pharmacological blockade (Moy et al, 2017; Pervaiz et al, 2019), CCR5 gene editing (Xie, Zhan, Ge, & Tang, 2019) and the genetic variant CCR5Δ32 (Fatima et al, 2019; Kaminski, Ellwanger, Sandrim, Pontillo, & Chies, 2019; Kletenkov et al, 2019; Słomiński et al, 2017; Toson et al, 2017; Troncoso et al, 2018). The resurgence of research involving these different aspects of CCR5 is due to two main factors: the advancement of gene‐editing technologies, which allow the exploration of the metabolic and pathophysiological effects of CCR5 editing (Allen et al, 2018; Qi et al, 2018; Vangelista & Vento, 2018; Xu et al, 2017), and the development of CCR5 blockers for clinical use (Vangelista & Vento, 2018). Recently, the different effects of CCR5 editing were much debated (Ellwanger, Kaminski, & Chies, 2019; Wang & Yang, 2019; Xie et al, 2019) after a Chinese scientist alleged to had performed this procedure on human embryos (Cyranoski & Ledford, 2018).…”