Biology Reference
In-Depth Information
mechanisms, including its reported capacity to inhibit the function of tumor sup-
pressor genes, induce chromosome breaks and possibly as a promoter of neoang-
iogenesis could contribute indirectly to the malignant phenotype of transformed
cells (Cinatl et al. 1996, 1999; Moreno et al. 1997; Shen et al. 1997; Fortunato
and Spector 1998; Zhu et al. 1998). HCMV infections have been previously impli-
cated as a cause or co-factor of other diseases, including rheumatologic disorders
such as rheumatoid arthritis and some rare autoimmune diseases; however, we
will limit this brief overview to possible pathogenic mechanisms of vascular dis-
ease associated with HCMV infection and chronic allograft rejection because
these groups of diseases have provided the most compelling evidence linking
HCMV infection to disease.
Chronic Vascular Disease in the Normal Host
The association of a herpesvirus infection and vascular disease was made nearly 30
years ago when Marek's disease virus, an avian herpesvirus was shown to induce
atherosclerotic disease in chickens (Fabricant et al. 1978; Fabricant and Fabricant
1999). Herpesviruses were detected in arterial endothelial cells and smooth muscle
cells from patients with atherosclerotic heart disease and HCMV has been shown to
replicate in arterial smooth muscle cells (Gyorkey et al. 1984; Tumilowicz et al.
1985; Hendrix et al. 1989, 1991; Wu et al. 1992; Melnick et al. 1993; Shi and
Tokunaga 2002). More recently, findings in patients undergoing coronary artery
angioplasty for atherosclerotic heart disease and studies using in vitro models of
HCMV infection of endothelial and smooth muscle cells have provided additional
evidence for the role of HCMV infection in vascular disease (Muhlestein et al. 2000;
Mueller et al. 2003; Nerheim et al. 2004; Westphal et al. 2006). Epidemiological
studies, including some with prospective study design, have suggested that individu-
als with serological reactivity to HCMV are at increased relative risk for coronary
atherosclerotic disease as well as increased risk for arteriosclerotic disease (Nieto
et al. 1996; Zhou et al. 1996, 2001; Drover et al. 1998; Sorlie et al. 2000; Grahame-
Clarke et al. 2003; Horne et al. 2003; Mueller et al. 2003). In several of these studies,
the risk for atherosclerotic disease attributable to HCMV infection was less than well-
accepted risk factors such as serum lipid concentration, yet infection was consistently
associated with atherosclerotic vascular disease. Infections with other herpesviruses
such as HSV were not associated with a definable risk. Finally, animal models of
atherosclerosis have demonstrated accelerated disease development following
infection with CMV (Hsich et al. 2001; Vliegen et al. 2004). Overall there appears
to be a body of provocative evidence implicating CMV infection as a contributor to
atherosclerotic vascular disease in the normal host. This disease association is even
more plausible when viewed together with the proposed role of this virus in the
accelerated vascular disease observed in allograft recipients.
The presence of herpes virus-like particles in inflammatory cells from atheromatous
plaques from patients with coronary artery disease initially suggested that the virus
