IntroductionHuman cytomegalovirus (HCMV) is an opportunistic pathogen of widespread medical importance, causing congenital disease following a primary infection during pregnancy, as well as a wide range of organ-specific diseases following reactivation in immunocompromised patients. 1 Murine CMV (MCMV) has proven to be an excellent model of HCMV infection and disease, providing information on the basic patterns of pathogenesis, latency, immunity, and dissemination. 2-4 Dissemination of HCMV or MCMV requires a population of host mononuclear leukocytes that traverse the bloodstream. [5][6][7] Based on comparisons of wild-type and mutant MCMV-infected mice, MCMV enhances dissemination levels by expressing a pro-inflammatory chemokine-like gene product called MCMV chemokine (MCK). 2,7,8 MCK appears to increase the recruitment of leukocytes to initial sites of infection and to allow a greater number of virus-positive leukocytes to traverse the bloodstream to salivary glands (SGs), 3,7 a site of prolonged replication and shedding. This process likely provides a source of virus for transmission to naive mice. 2 The human pathogen HCMV also encodes chemokine homologs: one CC chemokine homolog (UL128) that may be analogous to MCK, 9 as well as one very potent CXC chemokine (gpUL146/vCXCL1) that is as potent as human interleukin-8 (IL-8) and acts via CXCR2. 10 The carboxyl terminal 81 aa m131 ORF encodes a predicted gene product, MCK-1, 8 that elicits both calcium mobilization and adherence in resident or elicited peritoneal exudate cells (PECs). 11 mRNA splicing adds 199 aa to this chemokine-like domain to make MCK-2 the natural, secreted gene product. 12 Studies on virusinfected mice have suggested that MCK-2 influences levels of viremia as well as patterns of dissemination 11,13 by increasing the inflammatory response at sites of infection. 14 An MCK-2-dependent influx of leukocytes into initial sites of infection is followed by a mononuclear-cell (MNC)-associated viremia that peaks at day 5 after infection 14 and leads to viral seeding of the SGs. 2,15-17 Although MCK-2 is pro-inflammatory and a determinant of both viremia and dissemination 11,14 and was also associated with both natural killer and adaptive immune defects, 13 this chemokinelike function is not involved in immune evasion. On the one hand, MCK-2 control of viremia and dissemination is preserved in mice that lack the ability to mount an adaptive immune response. 2,16 On the other hand, virus replication levels and clearance from inoculated foot pads (FPs) or sites of systemic infection, including 11,16,17,[20][21][22][23] and latency 22,24,25 ; however, these cells also have been implicated in host defense. 20,23,[26][27][28] The differentiation-dependent susceptibility of monocytes and macrophages to MCMV infection 22,23 has led to a consensus view that nonpermissive monocytes may disseminate infection and differentiate into permissive mature cells upon entry into tissues. This pattern is similar to that proposed to explain viral reactivation from lat...
