Diseases of blood vessels

Replicative and latent infection of vascular endothelium by HHV-6 was repeatedly shown in vivo and in vitro using immunohistochemical and molecular techniques (Wu and Shanley, 1998; Rotola et al., 2000; Caruso et al., 2003). In vitro infection of human umbilical vein endothelium (HUVEC) with HHV-6 was followed by the expression of early and late viral antigens in 37.6 and 6.5% of HUVEC, respectively, with persistence of the antigens for up to 27 days. Although virus was not obviously released from these cells, it could be recovered by cocultivation (Wu and Shanley, 1998). Endothelial cells obtained from the aorta, vasa vasorum, or from cardiac microvessels of immunocompetent patients with aortic insufficiency or aneurysm revealed HHV-6 by nested polymerase chain reaction (PCR) even in cases where viral DNA was not recovered from peripheral blood mononuclear cells (Rotola et al., 2000). Viral transcripts from immediate-early (U91, U42) and late (U22) genes were detected in aortic endothelial cells by nested reverse transcription PCR. Since no p41 early antigen was demonstrable by immunohistochemistry, the authors think that there exists only a low-level viral replication at these sites thus confirming the earlier data.

Both in vitro and in vivo infections by HHV-6 can occur without causing visible cytopathic effects, yet the increase in factors such as thrombomodulin, plasminogen activator-inhibitor-1, and cyclic GMP in infected persons may signal vascular injury (Takatsuka et al., 2003). In addition, HHV-6 upregulates monocyte chemo-attractant protein-1 (MCP-1) and interleukin-8 (IL-8) and induces the de novo synthesis of RANTES CC chemokine (Caruso et al., 2002, 2003). HHV-6-infected endothelial cells, thus, may well support the attraction of immunocompetent cells and the initiation of an inflammatory reaction.

In contrast to the frequent demonstration of HHV-6 DNA and antigen in vascular endothelial cells stands its rather infrequent association with vascular disease. We have observed increased levels of HHV-6A antigens and DNA in various endothelial cells of patients with HHV-6 reactivation (Fig. 1; unpublished data). In no case, there was any evidence of "endothelitis" or of other forms of vascular inflammation. Okano and coworkers (1989) found 81% of patients with Kawasaki's disease to have elevated IgM and IgG antibodies to HHV-6 and theorized that the virus may add to the immunologic alterations of this disease.

In another study, however, the etiologic role of HHV-6 for Kawasaki's syndrome was not confirmed (Marchette et al., 1990). Both of these studies use only serologic investigations for determining any possible association of the virus with the vasculitis and thus remain inconclusive. Toyabe and collaborators (2002) reported on a 9-month-old boy with large vessel arteritis and active HHV-6 infection. IgM and IgG antibodies to HHV-6 were elevated in the patient's serum and viral DNA was isolated from the peripheral blood and from blood mononuclear cells. No attempts were made, though, to show viral components in the inflamed vessel itself. Three other studies using PCR and real-time PCR on vascular biopsies were unable to prove an association of HHV-6 and giant cell arteritis (Helweg-Larsen et al., 2002; Rodriguez-Pla et al., 2004; Alvarez-Lafuente et al., 2005).

Fig. 1 HHV-6 infection of vascular endothelial cells. Top: Splenic sinusoidal endothelial cells containing HHV-6 late antigens (red-stained cells; APAAP reaction using HAR 1-3 antibody). Bottom: HHV-6 DNA in endothelial cells of cardiac arteriole in an AIDS patient (left) and of a brain venule (right) in a case of necrotizing encephalitis in a child with active HHV-6 infection (black cells; in situ hybridization with pZVH14 probe). (for colour version: see colour section on page 357).

Fig. 1 HHV-6 infection of vascular endothelial cells. Top: Splenic sinusoidal endothelial cells containing HHV-6 late antigens (red-stained cells; APAAP reaction using HAR 1-3 antibody). Bottom: HHV-6 DNA in endothelial cells of cardiac arteriole in an AIDS patient (left) and of a brain venule (right) in a case of necrotizing encephalitis in a child with active HHV-6 infection (black cells; in situ hybridization with pZVH14 probe). (for colour version: see colour section on page 357).

Matsuda and coworkers (1999) reported a case of thrombotic microangiopathy in a patient with high-dose chemotherapy, bone marrow transplantation, and HHV-6 reactivation. Although HHV-6 may theoretically have contributed to the pathogenesis of this disorder, there are many other "pathogens" in the patient's history that must be considered, such as cyclosporine A or other chemotherapy, graft-versus-host reaction, and irradiation. All are known to damage vascular en-dothelium, and thus be able to initiate some kind of microangiopathy.

Infectious agents, including herpesviruses and Chlamydia pneumoniae, have been identified with some frequency in atherosclerotic lesions. Although the primary role of these agents in the pathogenesis of atherosclerosis has not been determined, infectious agents have the potential to participate as promoters of inflammation, which is important in the progression of atherosclerosis (Kol and

Libby, 1998; Anderson, 2005). As discussed above, HHV-6 infection of endothelial cells has the potential of triggering an inflammatory reaction. However, the prevalence of HHV-6 in atherosclerotic lesions is not known, and there is no evidence to support the role of HHV-6 in atherogenesis.

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