Novel Human Cytomegalovirus Viral Chemokines, vCXCL-1s, Display Functional Selectivity for Neutrophil Signaling and Function

Abstract

Human cytomegalovirus (HCMV) uses members of the hematopoietic system including neutrophils for dissemination throughout the body. HCMV encodes a viral chemokine, vCXCL-1, that is postulated to attract neutrophils for dissemination within the host. The gene encoding vCXCL-1, UL146, is one of the most variable genes in the HCMV genome. Why HCMV has evolved this hypervariability and how this affects the virus’ dissemination/pathogenesis is unknown. Because the vCXCL-1 hypervariability maps to important binding and activation domains, we hypothesized that vCXCL-1s differentially activate neutrophils, which could contribute to HCMV dissemination and/or pathogenesis. In order to test whether these viral chemokines affect neutrophil function, we generated vCXCL-1 proteins from 11 different clades from clinical isolates from HCMV-congenitally infected infants. All vCXCL-1s were able to induce calcium flux at a concentration of 100 nM and integrin expression on human peripheral blood neutrophils (PBNs) in spite of differences in affinity for the CXCR1 and CXCR2 receptors. In fact their affinity for CXCR1 or CXCR2 did not directly correlate with chemotaxis, G protein-dependent and independent (β-arrestin2) activation, or secondary chemokine (CCL22) expression. Our data suggest that vCXCL-1 polymorphisms impact the binding affinity, receptor usage, and differential PBN activation that could contribute to HCMV dissemination and/or pathogenesis.

Multiple-Strain Infections of Human Cytomegalovirus with High Genomic Diversity are Common In Breast Milk from HIV-Positive Women in Zambia

“…It is possible that different genotypes of hypervariable genes, and different combinations of genotypes, provide variable growth properties leading to higher viral loads and specific pathologies. For example, UL74 genotypes differentially affects viral growth properties in vitro [45], and genotypes of UL146, which is the most hypervariable gene in HCMV and encodes a vCXCL1 chemokine, affects neutrophil chemotaxis efficiency [46]. Similarly, host variation would be higher in Africa and may affect susceptibility as a result of HCMV genotype-specific interactions, for example with immunoglobulin variants [47-50].…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…UL146 is involved in neutrophil chemoattraction and activation; amino acid sequences differ by up to 60% among isolates without any proven relationship to disease severity (71,72). Heo et al described polymorphisms in viral CXCL-1 from 11 unique clinical isolates that affect binding affinity, receptor usage and differential peripheral blood neutrophil activation that could contribute to HCMV dissemination and pathogenesis (73).…”

There's Always Another Way! Cytomegalovirus’ Multifaceted Dissemination Schemes

“…Upon CXCR2 stimulation, neutrophils egress from the bone marrow [85]. Because vCXCL-1 has high affinity for CXCR2 [68,70], upon reactivation HCMV could use vCXCL-1 to stimulate neutrophils to leave the bone marrow and subsequently systemically disseminate HCMV. In this scenario, vCXCL-1's main role is following reactivation from latency.…”

“…UL146 and UL147 encode the CXC homologues, vCXCL-1 and vCXCL-2 respectively. While there is no functional data for UL147, UL146 has been extensively studied[68][69][70][71][72][73]. vCXCL-1 is a functional homologue of human chemokines CXCL8, CXCL1, and CXCL2 depending on the source of the vCXCL-1 protein.…”