A Broad Spectrum Secreted Chemokine Binding Protein Encoded by a Herpesvirus

113

The human cytomegalovirus pUL21.5 protein is a small, secreted glycoprotein whose mRNA is packaged into virions. We demonstrate that pUL21.5 protein is a soluble CC chemokine receptor that functions as a decoy to modulate the host immune response to infection. In contrast to other viral chemokine-binding proteins, which interact promiscuously with multiple chemokines, pUL21.5 selectively binds RANTES (regulated upon activation, normal T cell expressed and secreted) with high affinity. By binding RANTES, pUL21.5 blocks RANTES interaction with its cellular receptors. We propose that human cytomegalovirus directs the synthesis of a secreted, virus-coded protein that modulates the host antiviral response even before the newly infecting viral genome becomes transcriptionally active.

“…3). The RANTES specificity of pUL21.5 is in contrast to the other known viral decoys, which bind multiple chemokines (5)(6)(7)(8)(9).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Human cytomegalovirus encodes a highly specific RANTES decoy receptor

Wang

Bresnahan

Shenk

2004

113

“…An interesting phenomenon relating to viral immune escape is that human herpes virus 8, implicated in the pathogenesis of Kaposi's sarcoma, encodes a chemokine-homolog (vMIP-II) with an antagonistic activity against different chemokine receptors, which inhibits the recruitment of effector cells to the sites of viral replication (24). The observation that vMIP-II dramatically reduces T cell-mediated inflammation in a model for virus-induced inflammation strongly suggests that modulation of chemokine signals represents an important and efficient mechanism for evading host immune responses (25).…”

Section: Discussionmentioning

confidence: 99%

Tumor immune escape by the loss of homeostatic chemokine expression

Pivarcsi

Müller

Hippe

et al. 2007

123

101

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPKsignaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.cancer ͉ CCL27/CTACK ͉ skin ͉ immune surveillance ͉ EGDR/R pathway

“…The recruitment of CD8 ϩ T cells may also be modified by the viral M3 protein, which has been shown recently to have chemokine binding properties (41). It is likely that these large complex viruses have evolved a spectrum of mechanisms that allow persistence in the face of a continuing host response (42,43), many of which have yet to be defined.…”

Section: Discussionmentioning

confidence: 99%

Postexposure vaccination massively increases the prevalence of γ-herpesvirus-specific CD8⁺T cells but confers minimal survival advantage on CD4-deficient mice

Belz

Stevenson

Castrucci

et al. 2000

Mice that lack CD4 ؉ T cells remain clinically normal for more than 60 days after respiratory challenge with the murine ␥-herpesvirus 68 (␥HV-68), then develop symptoms of a progressive wasting disease. The ␥HV-68-specific CD8 ؉ T cells that persist in these I-A b؊/؊ mice are unable to prevent continued, but relatively low level, virus replication. Postexposure challenge with recombinant vaccinia viruses expressing ␥HV-68 lytic cycle epitopes massively increased the magnitude of the ␥HV-68-specific CD8 ؉ population detectable by staining with tetrameric complexes of MHC class I glycoprotein ؉ peptide, or by interferon-␥ production subsequent to in vitro restimulation with peptide. The boosting effect was comparable for ␥HV-68-infected I-A b؊/؊ and I-A b؉/؉ mice within 7 days of challenge, and took more than 110 days to return to prevaccination levels in the I-A b؉/؉ controls. Although the life-span of the I-A b؊/؊ mice was significantly increased, there was no effect on long-term survival. A further boost with a recombinant influenza A virus failed to improve the situation. Onset of weight loss was associated with a decline in ␥HV-68-specific CD8 ؉ T cell numbers, though it is not clear whether this was a cause or an effect of the underlying pathology. Even very high levels of virus-specific CD8 ؉ T cells thus provide only transient protection against the uniformly lethal consequences of ␥HV-68 infection under conditions of CD4 ؉ T cell deficiency.T he murine ␥-herpesvirus 68 (␥HV-68) is related (1, 2) both to Epstein-Barr virus (EBV) and to human herpesvirus 8 (HHV-8). These three ␥HVs are characterized by the establishment of life-long latency in B lymphocytes, subsequent to (at least for ␥HV-68 and EBV) a transient phase of lytic infection in the oropharynx and respiratory epithelium. Increased levels of ␥HV replication and tumorigenesis (EBV and HHV-8) are common consequences (3) of AIDS induced by HIV. It is far from clear whether the escape of these persistent ␥HVs from immune control in AIDS patients is a direct reflection of the compromised CD4 ϩ T cell response (4-6), or is because of the subsequent decline in virus-specific CD8 ϩ T cell numbers.Mice that lack CD4 ϩ T cells as a consequence of homozygous disruption of the H2-IA b gene (I-A bϪ/Ϫ ) remain healthy for 2-3 mo after respiratory challenge with ␥HV-68, then develop symptoms of chronic wasting disease (7-9). Unlike the situation for congenic I-A bϩ/ϩ mice, the ␥HV-68 lytic phase in lung epithelium is never completely controlled. Apparently, both CD4 ϩ and CD8 ϩ effectors are important, with the CD4 ϩ set operating by means of ␥-interferon (IFN-␥) production (9) and the CD8 ϩ