World J Gastroenterol. 2009 June 7; 15(21): 2561-2569.
Published online 2009 June 7. doi: 10.3748/wjg.15.2561.
©2009 The WJG Press and Baishideng. All rights reserved.
Human herpesvirus 6 infections after liver transplantation
Rima Camille Abdel Massih, Raymund R Razonable, Division of Infectious Diseases, Department of Medicine, and the William J von Liebig Transplant Center, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, United States
Received March 26, 2009; Revised April 11, 2009; Accepted April 18, 2009;
Human herpesvirus 6 (HHV-6) infections occur in > 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection (reactivation in the transplanted organ). In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus (CMV), hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.
Keywords: Immunocompromised, Antivirals, Human herpesvirus 6, Liver transplantation, Opportunistic infections
Human herpesvirus 6 (HHV-6), a member of the β-Herpesviridae subfamily of human herpesviruses, is a ubiquitous virus that was first isolated from peripheral blood leukocytes in 1986[1
]. The virus was not associated with any clinical illness until 2 years later, when HHV-6 was isolated from the peripheral blood of patients with roseola infantum (also known as exanthem subitum or sixth disease), which is a common febrile illness in children[2
]. Since then, there have been large-scale epidemiologic studies that have established the natural history of HHV-6 infections in humans. Primary infection with HHV-6 occurs most commonly during the first 2 years of life, with a peak incidence between 6 and 12 mo after birth. By 2 years, more than 90% of individuals have been infected, as evidenced by a positive HHV-6 antibody. Primary HHV-6 infections may present as an asymptomatic illness or as a febrile syndrome accompanied later on by a maculopapular rash (exanthem subitum). In addition, primary HHV-6 infection has been associated with otitis, gastrointestinal symptoms, respiratory distress, and seizures[34
There are two variants of HHV-6, variant A and variant B (HHV-6A and HHV-6B, respectively). These variants share certain biological properties and have a high level of sequence homology, differing from one another only by up to 8% at the nucleotide level[56
]. However, the two HHV-6 variants differ epidemiologically and clinically. HHV-6B is implicated in the majority of primary HHV-6 infections during the first 2 years of life. HHV-6B replicates in the salivary glands[7
] and hence, the mechanism of transmission between humans is thought to be via salivary secretions. In contrast, HHV-6A seems to be more neurotropic and has been implicated in neurologic diseases[89
]. HHV-6A is also more frequently detected among patients with acquired immunodeficiency syndrome[10
]. The age of acquisition of HHV-6A remains undetermined and, unlike HHV-6B, it does not seem to replicate in salivary glands and thus, the mode of transmission is not known.
HHV-6 infects mainly CD4+ T lymphocytes, and to a lesser extent, CD8+ T lymphocytes and natural killer cells[11
]. HHV-6 binds to the CD46 receptor[14
] that is located on what is called a “lipid raft,” which then carries the virus inside the cell. The HHV-6 envelope fuses to the cell membrane, and the viral nucleocapsid is transported into the nucleoplasm where the viral DNA genome is released[15
]. The virus then replicates, assembles, and exits the infected cell to infect other cells. The first proteins synthesized during viral replication are the immediate-early (IE) proteins[16
]. It was recently reported that two proteins, IE1 and IE2, distinguish the variants, HHV-6A and HHV-6B, respectively (L. Flamand, abstract 3-2, 6th International Conference on HHV6 & 7, 2008). However, the exact mechanism of HHV-6 replication and assembly is not clear, although viral assembly occurs inside multivesicular bodies which are subsequently transported toward the cell surface to facilitate virus exit from the cell.
One of the mechanisms postulated to explain the ability of HHV-6 to escape the immune system and establish latency is its property of immunomodulation. HHV-6 infection results in altered cytokine responses resulting in the selective suppression of interferon-γ[17
] and up-regulation of tumor necrosis factor-α production[19
]. In addition, HHV6 down-regulates the expression of its CD46 receptor[1214
], which functions as a regulator of complement activation[20
] and an important link between the innate and adaptive arms of the immune system. Finally, HHV-6 has been demonstrated to enhance apoptosis in vitro
LATENCY AND CHROMOSOMALLY-INTEGRATED HHV-6
After primary infection, HHV-6 establishes a state of subclinical persistence or latency. This is a property that it shares with the other members of the human herpes