Biology Reference
In-Depth Information
The observation that persistent virus replication is correlated with CAV is consistent
with stimulation of viral gene expression and replication by a milieu of mediators
generated by allorecognition of the graft. Viral gene expression and/or replication
could enhance the host inflammatory response and in effect amplify an ongoing
inflammatory process. In support of this mechanism, animal models of transplant
vascular sclerosis have been used to demonstrate that interruption of the virus-host
stimulatory loop can also interrupt the development of vascular disease (Lemstrom
et al. 1993). Either an increased level of immunosuppression or administration of
an antiviral agent can prevent the development transplant vascular sclerosis in animals
undergoing an allograft rejection. In cases in which virus replication is uncontrolled
by host responses, virus infection of endothelial cells could induce a variety of
inflammatory responses, as noted in Sect. 3.1 and the development of endotheliitis
may potentially represent the initial insult leading to vascular sclerosis. Virus could
directly infect and damage the endothelium, or more likely the endothelium could
be damaged either by alloreactive T lymphocytes or as a result of ischemia/
reperfusion at the time of transplantation. Once the inflammatory response is initiated,
a variety of cell adhesion molecules could be upregulated in the endothelium and
recruit mononuclear and polymorphonuclear leukocytes, some of which may be
carrying virus (Craigen et al. 1997). Infection of the endothelium followed by
infection of smooth muscle cells could then lead to increased expression of MHC
molecules, cytokines and chemokines such as MCP-1, MIP-1
and RANTES by
the endothelium and IL-6 by smooth muscle cells (Taylor et al. 1992; Koskinen
et al. 1993; Lemstrom et al. 1993; Arkonac et al. 1997; Grundy et al. 1998;
Srivastava et al. 1999; Billstrom Schroeder and Worthen 2001; Froberg et al. 2001).
In addition, CMVs have recently been shown to induce expression of host genes
that promote host inflammatory responses such as Cox-2 or in the case of rhesus
CMV actually encode this enzymatic activity (Zhu 2002; Rue et al. 2004).
Interestingly, in a rat model of rat CMV accelerated graft loss, rat CMV has been
shown to induce Cox-2 expression in the allograft (Martelius et al. 2002). Together,
these pathways could create unregulated, autocrine and paracrine cascades in which
viral gene expression could lead to an increased host inflammatory response. In
turn, such a host response could promote virus replication and viral gene expression,
thus creating an autostimulatory loop. It should be noted that other investigators
have argued that the presence of virus-encoded chemokine receptors on infected
cells could also function as immune evasion molecules and act to scavenge extra-
cellular chemokines such as RANTES from areas of HCMV infection (Bodaghi
et al. 1998; Billstrom et al. 1999). Although this mechanism may be operative
during infection in vitro and possibly in normal hosts, it is likely that the outpouring
of cytokines and chemokines during an allograft rejection would quickly saturate
such functions.
α
Acknowledgements
The author would like to thank Drs. Michael Mach and Suresh Boppana for
helpful discussions about congenital HCMV infections and Drs. Michael Jarvis, Jay Nelson, and
Dan Streblow for their contributions to sections on chronic diseases associated with HCMV
infections.
