Viral Chemokines And Chemokine HbLtHIURS

Herpesviruses, -poxviruses, and lentiviruses all encode chemokine and chemokine recep-

(78)

r-like molecules (347). Some of these molecules are structural homologs of chemokines and chemokine receptors, whereas others are |structurally unrelated but bind to either che-Imokine or receptor and alter the function of these molecules. The selective advantage of expressing these chemokine or chemokine re-|ceptors is not yet clear. However, given that fjchemokines play a crucial role in organizing host immune response, it is not surprising that viruses have developed different strate-|gies to interfere with the process.

Chemokine homologs are mostly encoded rhy herpesvirus and include three CC-type chemokines, vMIP-I, vMIP-II, and vMIP-III. yMIP-I is encoded by HHV-8 and binds and ¡induces calcium signals in T-cells through •CCR8. This same receptor also shows high affinity for vMIP-II. However, vMIP-I seems to as an agonist for the receptor and vMIP-II behaves as an antagonist (348). vMIP-II is a proad-spectrum chemokine receptor antago-1 vMIP-III acts as a potent CCR4 agonist attracts mainly Th2 T-cells. r Molluscum contagiosum virus (MCV) is a human poxvirus that encodes a chemokine ho-named vMCC-I (gene product of (349,350).This protein is related to ¡DC chemokines but the mature protein lacks Jive amino acids in the N-terminus that are priticalfor receptor activation. Thus, this molecule binds to several receptors such as CCR1, CCR2, CCR5, CCR8, CXCR1, and CXCR2 but not able to induce signaling, acting instead an antagonist for these receptors. In addition to chemokines, viruses also ex-chemokine receptors. All of them bind multiple chemokine ligands but differ in their Specificity as well as in the signal transduction pathways they engage. One interesting example is the HHS-8-encoded chemokine receptor ORF 74. The HHS-8 virus has been implicated in the development of Kaposi's sarcoma (KS). ORF 74 encodes a constitutively active chemokine receptor that binds several host CC and CXC chemokines. It has been shown that this receptor has angionenic, proinflammatory, and oncogenic activities. When expressed as a transgene in hematopoietic cells, it induces lesions that are histologically similar to those of KS (351). This suggests that ORF 74 may play a role in the pathogenesis of KS in humans.

The chemokine binding protein vCCI (produced by pox viruses) is a broad-spectrum CC chemokine scavenger and completely inhibits their function (350,352). Its strong inhibitory properties are attributed in part to the high of vCCI for CC chemokines, having a subnanomolar dissociation constant for all CC chemokines. The affinity of CC chemokines is greater for vCCI than for the native CC chemokine receptors. In a mouse model of allergic lung inflammation, vCCI has been shown to improve pulmonary function and to reduce inflammation (353). vCCI reduced significantly the number of total leukocytes and eosinophils in bronchoalveolar lavage fluid and lung parenchyma. At the same time, a clear reduction in airway hyperreactivity was observed. These results not only show that intrapulmonary inhibition of chemokines by vCCI is a highly effective inhibitor of airway inflammation and hyperreactivity in a mouse model but also suggest a potential use of this agent for the treatment of asthma.

The above examples represent just a small group of all viral chemokine, chemokine recep-

Table 4.10 Cytokine Families and Some Examples (l)c

Family

Cytokine

Potential Disease Target

IL-I family

Hematopoietic factors

TNF family

IL-18 bFGF aFGF

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