In chronic persistent HHV-6 infection, viral DNA load and cellular changes show certain cyclic changes, suggesting some fluctuation in viral replication (Krueger et al., 2001). In about 6%, heterophile-negative infectious mononucleosis is caused by HHV-6A or B infection (Steeper et al., 1990; Horwitz et al., 1992; Akashi et al., 1993). More frequent is the reactivation of latent HHV-6 in patients with classical EBV-induced infectious mononucleosis resulting in a more protracted course of the disease with elevated liver enzymes (Bertram et al., 1991). Occasionally caused by HHV-6, preferentially variant B, are angioimmunoblastic lymphadenopathy (Luppi et al., 1993; Daibata et al., 1997), hemophagocytic syndromes (Sugita et al., 1995; Tanaka et al., 2000) and Langerhans cell histiocytosis (Leahy et al., 1993).
HHV-6 (preferentially subtype A) and/or increased viral DNA loads were found in certain malignant lymphomas, including subtypes of Hodgkin's disease (Krueger et al., 1989; Torelli et al., 1991; Di Luca et al., 1994; Braun et al., 1995; Hallas et al., 1996; Razzaque et al., 1996; Bandobashi et al., 1997; Luppi et al., 1998; Lin et al., 1999; Hermouet et al., 2003) as well as in a number of pre-lymphomatous atypical polyclonal lymphoproliferations including Canale-Smith syndrome (Krueger et al., 2002). Since oncogenic effects of the HHV-6 genome (Razzaque, 1990; Thompson et al., 1994) have not been proven, other mechanisms may account for a typical lymphoproliferation (Krueger and Ferrer-Argote, 1994), such as persistent antigenic stimulation or immune dysfunction (Kakimoto et al., 2002).
Both subtypes infect hematopoietic stem cells suppressing their engraftment in transplant recipients (Carrigan and Knox, 1994; Rosenfeld et al., 1995; Herbein et al., 1996; Singh and Carrigan, 1996; Isomura et al., 1997; Penchansky and Jordan, 1997; Lau et al., 1998; Wang et al., 1999). Frequent HHV-6 infections with high virus load were reported in bone marrow and stem cell transplant recipients (Clark, 2002; Ihara et al., 2002; Sashihara et al., 2002; Boutolleau et al., 2003). Besides failure of engraftment, lymphocytopenia, suppression of myelopoiesis or er-ythrocytopenia may ensue HHV-6 reactivation, and the virus can be even transmitted by the graft itself (Lau et al., 1998).
HHV-6 reactivates frequently in patients with renal and hepatic allografts, yet pathologic sequelae usually arise from coincident cytomegalovirus infections
(Kaden et al., 1997; Clark et al., 2003; Feldstein et al., 2003; Yoshikawa, 2003). HHV-6 antigen was found in bone marrow cells of patients with myelodysplasia and certain chronic myeloproliferative disorders (Krueger et al., 1994b; Rojo et al., 2000). Since this pertains equally well to EBV and HHV-7, a deficient clearance of virus may be responsible for this phenomenon rather than indicating some etiologic relationships.
Persistent HHV-6 may cause functional disturbances of the immune system as indicated by elevated antibody titers against HHV-6 in allergies, drug-induced hypersensitivity reactions and in systemic lupus erythematosus, Sjogren's syndrome and progressive systemic sclerosis (Krueger et al., 1991, 1994b De Clerck et al., 1992; Klueppelberg, 1994; Lasch et al., 1996; Descamps et al., 1997, 2001; Toh-yama et al., 1998; Conilleau et al., 1999). Virus persistence may constitute a risk factor for additional immune dysregulation and for increasing the severity of adverse reactions (Suzuki et al., 1998).
Central nervous system (see also chapter 16)
HHV-6 replicates with low efficiency in neuroglial cells (Luppi et al., 1995). Viral DNA and antigen have been successfully demonstrated in human brain tissue, both in healthy organs and in diseased tissues, with subtype A being about three times more frequent than subtype B (Fig. 2; Luppi et al., 1995; Hall et al., 1998; Cuomo et al., 2001). There are increasing reports of HHV-6-associated meningitis, encephalitis in children with febrile seizures (Caserta et al., 1994; Wilborn et al., 1994; Knox and Carrigan, 1995; Bonthius and Karacay, 2002; Eeg-Olofsson, 2003), acute necrotizing or hemorrhagic encephalitis and demyelinating brain diseases in immune-deficient patients and in persons suffering from multiple sclerosis (Challoner et al., 1995; Wagner et al., 1997; Solldan et al., 2000; An et al., 2002; Cirone et al., 2002; Chapenko et al., 2003; Tejada-Simon et al., 2003). CNS infections with HHV-6 appear more frequent in patients with T-cell immune deficiency (Pruitt, 2003).
Cardiovascular system (see also chapter 17)
HHV-6 infects endothelial cells of the aorta, umbilical vein and capillaries (Wu and Shanley, 1998; Rotola et al., 2000; Takatsuka et al., 2003). It may induce thrombotic microangiopathy or large vessel arteritis (Wu and Shanley, 1998; Toyabe et al., 2002; Takatsuka et al., 2003). There are single reports relating HHV-6 infection to leukocytoclastic vasculitis and to Kawasaki's disease (Hagiwara et al., 1993; Luka et al., 1995; Drago et al., 1999; Yoshikawa et al., 2003). HHV-6 genomic material was found in coronary arteries of heart allografts suggesting virus reactivation at this site. Finally, a case of fulminant myocarditis was described in a patient receiving steroid therapy for hepatitis. HHV-6 antibodies showed a fourfold increase in this patient, and HHV-6 DNA was demonstrated by PCR in liver and heart tissue (Fukae et al., 2000).
Other organs and tissues (see also chapters 13 and 18)
Other diseases described in association with active HHV-6 infection were interstitial pneumonitis (Cone et al., 1993; Know et al., 1995) and fulminant hepatic failure with HHV-6 present in liver tissue and in portal vein endothelium (Aita et al., 2001; Ishikawa et al., 2002). Some recipients of stem cell transplants, which suffered from severe posttransplant diarrhea showed HHV-6B DNA and antigens in their peripheral blood cells and in intestinal epithelia (Amo et al., 2003).
Finally, it is important to notice that HHV-6 can apparently activate other viral infections, e.g. those induced by EBV, CMV, HIV-1, measles, apparently also papillomavirus and parvovirus. HHV-6 may thus contribute to the pathologic effects of these viruses (Lusso et al., 1992, 1995; Flamand et al., 1993; al-Kaldi et al., 1994; Chen et al., 1994; Ablashi et al., 1995; Como et al., 1998; Singh et al., 1998). Dual active infections appear especially frequently with other herpesviruses (CMV, EBV, HHV-7) as well as with HIV-1.
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