Beyond HIV infection: Neglected and varied impacts of CCR5 and CCR5Δ32 on viral diseases

Abstract

The interactions between chemokine receptors and their ligands may affect susceptibility to infectious diseases as well as their clinical manifestations. These interactions mediate both the traffic of inflammatory cells and virus-associated immune responses. In the context of viral infections, the human C-C chemokine receptor type 5 (CCR5) receives great attention from the scientific community due to its role as an HIV-1 co-receptor. The genetic variant CCR5Δ32 (32 base-pair deletion in CCR5 gene) impairs CCR5 expression on the cell surface and is associated with protection against HIV infection in homozygous individuals. Also, the genetic variant CCR5Δ32 modifies the CCR5-mediated inflammatory responses in various conditions, such as inflammatory and infectious diseases. CCR5 antagonists mimic, at least in part, the natural effects of the CCR5Δ32 in humans, which explains the growing interest in the potential benefits of using CCR5 modulators for the treatment of different diseases. Nevertheless, beyond HIV infection, understanding the effects of the CCR5Δ32 variant in multiple viral infections is essential to shed light on the potential effects of the CCR5 modulators from a broader perspective. In this context, this review discusses the involvement of CCR5 and the effects of the CCR5Δ32 in human infections caused by the following pathogens: West Nile virus, Influenza virus, Human papillomavirus, Hepatitis B virus, Hepatitis C virus, Poliovirus, Dengue virus, Human cytomegalovirus, Crimean-Congo hemorrhagic fever virus, Enterovirus, Japanese encephalitis virus, and Hantavirus. Subsequently, this review addresses the impacts of CCR5 gene editing and CCR5 modulation on health and viral diseases. Also, this article connects recent findings regarding extracellular vesicles (e.g., exosomes), viruses, and CCR5. Neglected and emerging topics in "CCR5 research" are briefly described, with focus on Rocio virus, Zika virus, Epstein-Barr virus, and Rhinovirus. Finally, the potential influence of CCR5 on the immune responses to coronaviruses is discussed.

Keywords: C-C chemokine receptor type 5; Chemokine; Host-pathogen interactions; Immunogenetics; Inflammation; Viral infection.

Fig. 1

Crystal structure of CCR5. Crystal structure of CCR5 from RCSB PDB data bank (https://www.rcsb.org/) presented with ChimeraX molecular visualization program. A) 4MBS (CCR5, resolution 2.71 Angstroms) molecule, without contact with any ligand/inhibitor, display of the entire domain is shown in cartoon mode and colored in blue. The surface with transparency in red highlights only transmembrane regions of CCR5. B) 5UIW (CCR5 in complex with high potency HIV entry inhibitor 5P7−CCL5, resolution 2.20 Angstroms) molecule display of the entire domain is shown in cartoon mode and colored in purple. The surface with transparency (colored in orange) emphasizes subtle changes in the spatial conformation of the molecule when in contact with the inhibitor colored in green. Crystallography: Tan et al. (2013) for 4MBS and Zheng et al. (2017) for 5UIW.

Fig. 2

Fundamental aspects of CCR5 (panel A) and frequency of the Δ32 allele in selected countries (panel B). This figure was created using Servier Medical Art illustrations (available at https://smart.servier.com, under a Creative Commons Attribution 3.0 Unported License). The bar chart was plotted using GraphPad Prism 5.01 software (GraphPad Software, Inc., San Diego, CA, USA). The Δ32 allele frequencies were obtained from Solloch et al. (2017).

Fig. 3

Phenotypic effects of the polymorphism CCR5Δ32 in human cells. WT/WT: wild-type homozygous genotype. WT/Δ32: heterozygous genotype. Δ32/Δ32: variant homozygous genotype. This figure was created using Servier Medical Art illustrations (available at https://smart.servier.com, under a Creative Commons Attribution 3.0 Unported License).

Fig. 4

Effects of the CCR5Δ32 (homozygous genotype) on HIV infection (upper panel) and the main achievements of the research involving CCR5 and HIV infection (bottom panel). This figure was created using Servier Medical Art illustrations (available at https://smart.servier.com, under a Creative Commons Attribution 3.0 Unported License).

Fig. 5

Effects of the polymorphism CCR5Δ32 on HIV and WNV infections. Upper panel: effects observed in individuals with the wild-type homozygous genotype (WT/WT). Bottom panel: effects observed in individuals with the homozygous genotype variant (Δ32/Δ32). This figure was created using Servier Medical Art illustrations (available at https://smart.servier.com, under a Creative Commons Attribution 3.0 Unported License).