Viral antichemokines: from pathogenesis to drug discovery.

Kunkel reviewed the organization of the chemokine system and its important role in the development, differentiation, and deployment of mammalian leukocytes (1). The system is massive (about 50 ligands and 18 receptors are known), reflecting the complexity of its major client, the immune system. Now in this issue of the JCI, Liu and colleagues remind us that an antichemokine system has evolved in viruses, presumably as a strategy to evade the immune system, and they provide the first glimpse of how antichemokines might be exploited clinically as “ready-made” anti-inflammatory drugs (2). Antichemokines comprise a major group of virus-encoded chemokine modulators (Table 1) and consist of three subgroups based on structure and mechanism of action: (a) chemokine homologues that act as chemokine receptor antagonists (e.g., MC148R of Molluscum contagiosum virus [MCV]; ref. 3); (b) plasma membrane–expressed chemokine receptor homologues, which function as chemokine scavengers (e.g., US28 of human cytomegalovirus; ref. 4); and (c) three subtypes of secreted chemokine-binding proteins, which have unique structures and unknown ancestry but function as extracellular chemokine scavengers (examples include M3 of γ-herpesvirus 68 [5, 6] and various poxivirus proteins, including MT7 of myxoma, investigated by Liu et al. in this issue [2]). Three other groups of virus-encoded chemokine modulators have quite different functions. They include (a) chemokine receptor homologues, such as open reading frame 74 of Kaposi’s sarcoma–associated herpesvirus (7), which serves as a growth factor and angiogenic factor; (b) chemokine homologues that function as chemokine receptor agonists, including vMCK-1 of murine cytomegalovirus, which promotes viral dissemination via monocytes (8); and (c) nonchemokine agonists and antagonists of chemokine receptors, encoded by the HIV genome. Viral chemokine modulators, in turn, are part of a larger group of viral proteins with obvious homology to host proteins. These primarily include immunomodulatory, growth factor, and cell cycle control proteins (9). Interestingly, M-T7 is a hybrid. It has one domain homologous to the extracellular region of the IFN-γ receptor, as well as a COOH-terminal chemokine-binding domain. Chemokines bind M-T7 via their COOH-termi-