Kaposi Sarcoma-associated Herpes Virus Targets the Lymphotactin Receptor with Both a Broad Spectrum Antagonist vCCL2 and a Highly Selective and Potent Agonist vCCL3

Abstract

Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2 was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human XCL1 chemokine in respect to phosphatidylinositol turnover and calcium mobilization as well as chemotaxis. High expression of XCR1 was found in placenta and neutrophils by real-time PCR. These data are consistent with reports of different expression profiles for vCCL2 and vCCL3 during the life cycle of KSHV, indicate a novel, sophisticated exploitation by the virus of specifically the lymphotactin receptor by both agonist and antagonist mechanisms, and suggest a unique physiological importance of this (somewhat overlooked) chemokine receptor.

Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 + CD4 − Dendritic Cells

“…vXCL1 is the first reported CMV-encoded C chemokine that targets XCR1 ϩ CD4 Ϫ DC. This might imply an important physiological function, since Kaposi's sarcoma-associated herpesvirus (KSHV) has also been shown to encode two chemokines, vCCL2 and vCCL3, which likewise target XCR1 at different time points during infection (64,65). The observation that both MuHV8 and KSHV exploit XCR1 with different virally encoded chemokines suggests a substantial importance of this receptor in the defense against herpesviruses.…”

The Cytomegalovirus UL146 Gene Product vCXCL1 Targets Both CXCR1 and CXCR2 as an Agonist

“…CCL2, CCL7, vCCL4 (amino acid residues 21-113 from GenBank TM 000898) and vCXCL2 (amino acid residues 41-159 from GenBank TM AY446871) were chemically synthesized by Ian Clark-Lewis as described previously (18). The virally encoded chemokines MC148 and vCCL3 were purified from cell medium from COS7 cells transfected with their respective genes as described previously (11,14). Lipopolysaccharide (L4391), interferon ␥ (I3265), and IL-1␣ (I2778) were bought from Sigma-Aldrich.…”

“…The virally encoded chemokines have different pharmacological phenotypes, ranging from being very broad spectrum to highly selective and/or behaving as agonists or antagonists (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The sequencing of various wild type CMV strains suggested the presence of additional host interacting genes (17).…”

Autocrine and Paracrine Promotion of Cell Survival and Virus Replication by Human Herpesvirus 8 Chemokines

“…However, only CCR3 and CCR8 are able to support vCCL-2 signal transduction. vCCL-1 signals via CCR8, and vCCL-3 has been reported to be an agonist for CCR4 and XCR1 (13,16,28,45,47).…”