Human Herpesvirus-6
Authors: Nina Singh, M.D., Donald R. Carrigan, Ph.D.
VIROLOGY
In 1986, a novel human herpesvirus was isolated from the peripheral blood of six patients with lymphoproliferative disorders; two of these patients were infected with the human immunodeficiency virus (HIV) (32). The herpesvirus was originally designated "human B-lymphotropic virus." Subsequent studies, however, established that the virus was primarily T-cell lymphotropic; it was therefore renamed "human herpesvirus-6". Human herpesvirus-6 is an enveloped virion with an icosahedral nucleocapsid of 162 capsomers, and it contains a large double-stranded DNA genome. Human herpesvirus-6 is antigenically distinct from other human herpesviruses, such as cytomegalovirus, herpes simplex virus types 1 and 2, varicella zoster virus, and Epstein-Barr virus (21). Its closest phylogenetic relative is cytomegalovirus; nucleotide sequencing has shown 66% DNA sequence homology between cytomegalovirus and human herpesvirus-6 (21).
On the basis of genomic DNA sequences, cell tropism and protein expression, two distinct variants of HHV-6 designated as the A (HHV-6A) and B (HHV-6B) variants have been described. The two variants also differ in a number of their biologic properties including antiviral susceptibilities. HHV-6A is a potent inducer of TNF-alpha and other proinflammatory cytokines (14,15). HHV-6A strains appear to be more susceptible to acyclovir than HHV-6B strains.
EPIDEMIOLOGY
As with other herpesviruses, HHV-6 persists in the host in a latent form. Seroprevalence in general population exceeds 90%. Primary infection is acquired during the first two years of life; saliva being the most likely mode of transmission.
CLINICAL MANIFESTATIONS
Primary HHV-6 infection has been shown to be the cause of roseola or exanthem subitum, a febrile illness of early childhood. In immunocompetent adults, the virus has been associated with EBV-like mononucleosis syndrome, autoimmune disorders (e.g., Sjogern's disease), non-Hodgkins and Hodgkins lymphomas, necrotizing lymphadenitis and encephalitis (3, 20, 24). Recent evidence suggests that HHV-6 may also play an important role in the pathogenesis of multiple sclerosis; active HHV-6 infection has been detected in association with plaques that are a characteristic pathologic feature of multiple sclerosis (8, 9,17).
In organ transplant recipients, a non-specific febrile syndrome occurring in the early post-transplant period is the most frequently observed clinical manifestation of HHV-6 infection. Unexplained fever was documented in 87% of the liver transplant recipients with HHV-6 infection compared to 20% of those without it (p < 0.01) (41). Less commonly, HHV-6 has been associated with idiopathic marrow suppression, interstitial pneumonitis and fatal encephalitis (34). HHV-6 is a strongly neurotrophic virus and its propensity to cause central nervous system disease has been noted both in bone marrow and solid organ transplant recipients (13, 18,24). Mental status changes, ranging from confusion to coma, seizure and headache are the predominant clinical manifestation of HHV-6 encephalitis. Focal neurologic findings are rare. CSF pleocytosis ranging from 6 to 53 cells/mm3 was present in 50% of the patients with HHV-6 encephalitis in a review (37). Neuroimaging abnormalities on MRI were present in 2 of 8 patients in one report (37). These included multiple, nonenhancing, low attenuation lesions in the gray matter.
LABORATORY DIAGNOSIS
Serologic, virologic, and in situ immunohistochemistry assays have been utilized for the diagnosis of HHV-6. For the serologic diagnosis of HHV-6, enzyme immunoassays have proven more sensitive than the fluorescence assays.
HHV-6 induces a characteristic cytopathic effect in primary lymphocyte culture with "large ballooning" refractile cells and loss of normal lymphocyte clumping. Confirmation of HHV-6 in cell culture, however, must be performed by HHV-6 specific reagents and not merely by the cytopathic effect. HHV-6 isolation in cell culture is labor intensive and requires 5-21 days for detection.
Qualitative PCR for the diagnosis of HHV-6 is limited by the fact that it can detect latent virus. Latently infected peripheral blood mononuclear cells, however, contain fewer than 10 HHV-6 genomes per 106 cells. Nevertheless, PCR has other advantages; PCR positivity in cell free specimens can be diagnostically useful. Furthermore, HHV-6 variant discrimination can be readily accomplished by PCR. Immunohistochemical staining of tissues with murine monoclonal antibody reactive against the structural protein p101 of variant B and structural protein gp82 of variant A, detects cells productively and not latently infected with human herpesvirus-6.
PATHOGENESIS
The primary target cell for HHV-6 is CD4+ T lymphocytes, a characteristic that it shares with HIV (8, 12). The propensity to preferentially infect CD4+ T cells differentiates HHV-6 from other DNA viruses. The virus uses CD46 as a cellular receptor. HHV-6 and HIV can coinfect and simultaneously replicate within the same CD4+ T cells. Indeed, HHV-6 has been proposed as a cofactor in the acceleration of HIV infection (8, 13). HHV-6 can upregulate CD4 expression and induce CD4 receptors on CD8+T cells and NK cells, thus making these cells susceptible to infection with HIV (13). Although HHV-6 most efficiently replicates in CD4+T cells, its cellular host range is broad and includes CD8 + T lymphocytes, natural killer cells, macrophages, megakaryocytes, glial cells, and epithelial cells.
Besides direct infection of the cells, HHV-6 particularly variant A is a powerful inducer of cytokines, e.g., tumor necrosis factor-alpha, interferon-gamma, and interleukin-1 beta (13, 14). It has been proposed that the immunomodulatory and marrow suppressive effect of HHV-6 may partly be due to the production of these cytokines (29). HHV-6 is also proposed to be a cofactor in the pathogenesis of AIDS; HIV and HHV-6 can coinfect the same CD4+ lymphocytes (19, 22). HHV-6 can upregulate CD4 receptors on CD8+ T lymphocytes and natural killer cells, thus rendering these cells more susceptible to infection with HIV (22).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Antiviral susceptibilities to HHV-6 are determined using tissue culture systems. Only limited data on in vitro sensitivities of HHV-6 exists in the literature and it must be interpreted in context of variations in cell culture assays and HHV-6 strains used for susceptibility testing. For e.g., there are fewer than 10 independently obtained strains of HHV-6A worldwide to our knowledge, and two of these, HHV-6AGs and HHV-6AU1102 have been passaged innumerable times in T leukemia cell lines in culture. Such passaging can introduce cell culture artifacts that tend to make the virus strain less representative of wild-type strains of the virus. Such artifacts may also be responsible for the reported resistance of HHV-6AGs to most antiviral agents (4, 7). Clinical isolates that have received few or no cell passage would be optimal for screening antiviral agents. The type of cell employed in the cell culture system may also influence the susceptibility results. For e.g., most of the testing for HHV-6A stains has involved the use of T cell leukemia lines which are frequently susceptible to drug toxicity and may have abnormal nucleotide kinase expression.
HHV-6 resemble, in general, CMV, i.e., it is very sensitive to ganciclovir and foscarnet and less so to acyclovir.
Acyclovir
HHV-6A and HHV-6B have differential sensitivities to acyclovir; HHV-6A strains being more susceptible to acyclovir than the HHV-6B strains. The mean inhibitory concentrations 50% (IC50) of HHV-6A strains in the reported studies was approximately 20 uM with some strains demonstrating an even higher degree of sensitivity (3, 7). Strains of HHV-B are less sensitive to acyclovir, the mean IC50 of such isolates in the reported studies being 37 um (6, 12, 31). Serum acyclovir levels (1.8 to 3.6 ug/ml) following low-dose oral acyclovir (200 mg) are inadequate to suppress HHV-6. However, high dose oral acyclovir (800 mg) can achieve plasma concentrations of approximately 1.6 ug/ml, which may be at least partially suppressive for HHV-6A strains. While these concentrations would appear to be ineffective at suppressing HHV-6B, some strains of HHV-6B may also be sensitive to acyclovir (e.g., IC50 of 4.4 uM for HHV6Boc) (16).
Ganciclovir
Ganciclovir is highly active against HHV-6A and B in vitro. Peak serum concentrations following intravenous ganciclovir (5 mg/kg) average 31-43 uM and should be adequate to suppress HHV-6. The IC50 of ganciclovir of HHV-6A strains ranged between 1.1 to 25 uM (Table 1). The IC50 of HHV-6 for ganciclovir ranges between 1.0 to 2.5 uM (2, 6, 33).
Ganciclovir resistance has been documented in vitro, and anecdotally in clinical setting. A mutant HHV-6 virus after serial passaging under increasing ganciclovir pressure was shown to be resistant to ganciclovir and cidofovir, with 24-fold and 22-fold decrease in sensitivities, respectively (23). HHV-6 infected peripheral blood mononuclear cells from an HIV infected patient who had received prolonged ganciclovir therapy, yielded a mutant strain with M318V mutations that are analogous to M460V/I/L substitutions in HCMV pUL97 (10).
Foscarnet
The IC50 of foscarnet for HHV-6 ranges between 49 to 67 uM (6, 33). For 14 clinical isolates of HHV-6B tested, the IC50 was 67uM ± 22 uM (range 21 um to 117 uM), (Carrigan unpublished observation). Following an infusion of 90 mg/kg/d of foscarnet, the peak serum concentrations range between 240 - 650 uM and therefore exceed the IC50 of all but a rare isolate of HHV-6 (Table 2). Furthermore, foscarnet does not possess the potential marrow toxicity associated with ganciclovir.
Other Antiviral Agents
The L-valine ester of acyclovir, valaciclovir upon oral administration is rapidly and nearly completely converted to acyclovir, achieving peak plasma level of 22 uM and 38 uM after 100 and 200 mg of valaciclovir respectively. These levels of acyclovir would be effective against most strains of HHV-6A. Other drugs with in vitro activity against HHV-6 are guanosine analogue (9-[-4 hydroxy-2-(hydroxymethyl)butyl] guanine, ampligen and kutapressin (1, 4).
Cidofovir exhibits excellent in vitro activity against HHV-6 and is one of the most active antiviral agents available (27). As foscarnet, cidofovir has selectively higher affinity for viral compared to cellular DNA polymerases.
A benzamidazole derivative, maribavir, is currently undergoing clinical trials for the prevention of CMV infection. This agent inhibits viral DNA assembly and egress of viral capsids from the nucleus of infected cells and is highly active against CMV in vitro(40). Maribavir, however, is inactive against HHV-6.
ANTIVIRAL THERAPY
The efficacy of antiviral therapy for HHV-6 has largely been documented in case series or case reports. No clinical trials of antiviral therapy for HHV-6 exist. Four bone marrow transplant recipients with marrow suppression and viremia due to HHV-6 who were treated with ganciclovir or foscarnet (13). Viremia and neutropenia resolved in all patients, however HHV-6 infection recurred in one patient who eventually died (13). A case of a liver transplant recipient with disseminated invasive HHV-6 infection successfully treated with ganciclovir has been reported (36). Foscarnet in 2 liver transplant recipients with marrow suppression led to resolution of cytopenia (35). Late graft failure and aplastic marrow was successfully treated with foscarnet and retransplantation in a bone marrow transplant recipient (30). Antiviral therapy may be clinically efficacious in HHV-6 encephalitis (38). In a review on HHV-6 encephalitis in transplant recipients, cure was documented in 88% (7/8) of the patients who received ganciclovir or foscarnet for >7 days compared to 0% of those who did not receive these drugs or received them for ≤ 7 days (37). Of 11 hematopoietic stem cell transplant recipients with HHV-6 DNA detected by PCR in the cerebrospinal fluid, 8 had central nervous system dysfunction of unclear etiology (43). Antiviral therapy with ganciclovir and/or foscarnet was associated with a median log decrease in HHV-6-DNA in the serum from 2.0 to 0 copies/mL and in the cerebrospinal fluid from 4.4 to 2.0 copies/mL (42).
Drug of Choice
Transplant Recipients
Because of the latent and ubiquitous nature of HHV-6, the criteria for initiating treatment should include documentation of active or replicative infection, and presence of symptoms or signs attributable to HHV-6 pathogenicity. The superiority of either ganciclovir or foscarnet over the other has not been established in clinical studies. However, of 20 bone marrow transplant recipients with CMV viremia, 7 also had HHV-6 detectable in the peripheral blood mononuclear cells by PCR; all 3 patients who received foscarnet as compared to only one of 4 who received ganciclovir became HHV-6 negative (39). Other clinical circumstances such as renal failure or degree of marrow suppression may also dictate whether ganciclovir or foscarnet is employed as therapy for HHV-6. For e.g., ganciclovir may be preferable in patients with renal dysfunction since foscarnet is a potentially nephrotoxic drugs. On the other hand, foscarnet may be preferable in patients with marrow suppression because it does not possess the myelosuppressive effect of ganciclovir (26).
Other Patients
HHV-6 is generally a self-limited infection in children with E. subitum, and therapy is not recommended. In immunocompetent individual with encephalitis due to HHV-6, successful outcomes have been documented with ganciclovir (5, 11). A combination of ganciclovir and foscarnet has also been successfully employed in HHV-6 meningoencephalitis after suboptimal response with either agent as monotherapy (28). Treatment with cidofovir in an immunocompetent patient with HHV-6 encephalomyelitis led to undetectable viral DNA in the cerebrospinal fluid after 6 days (11). However, an adverse reaction to probenecid employed in conjunction with cidofovir necessitated a switch to ganciclovir which was associated with a successful outcome (11).
ADJUNCTIVE THERAPY
Supportive therapy in the form of packed red blood cell transfusions (for anemia) and colony stimulating factors (for leukopenia) may be employed in patients with HHV-6 associated bone marrow suppression. The role of intravenous immunoglobulin (IVIG) for HHV-6 has not been defined. Although IVIG preparations are likely to have high HHV-6 antibody titers, their efficacy in treating HHV-6 infections has not been discerned.
ENDPOINTS FOR MONITORING
The viral load for HHV-6 has been shown to decline after antiviral therapy (25, 43). However, the duration of therapy should be decided based on clinical and not virologic response.
VACCINES
There are no vaccines for HHV-6.
PROPHYLAXIS
Since HHV-6 is associated with considerable morbidity and even mortality in transplant recipients (particularly bone marrow transplant recipients), prophylaxis for HHV-6 is a reasonable goal in the transplant setting. The optimal approach toward timing of initiation of, duration of, and efficacy of prophylaxis for HHV-6 infection after transplantation remains to be defined. Intravenous ganciclovir, oral valganciclovir, and foscarnet could clearly achieve serum concentrations high enough to provide effective prophylaxis against HHV-6. The role of oral ganciclovir remains undetermined. Administration of 1000 mg ganciclovir orally three times daily resulted in a maximum serum concentration of 4.7 uM (Product monograph, Cytovene, Roche Laboratories, Palo Alto, CA). While these levels may suppress some strains of HHV-6, they may not be adequate for all strains. High-dose acyclovir was associated with a significantly lower incidence of HHV-6 in a study in bone marrow transplant recipients (39). Other studies have documented active HHV-6 infection despite high dose acyclovir (13).
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Table 1: Susceptibility of HHV-6A to Inhibition by Currently Available Antiviral Compounds
| Antiviral Compound | 50% Inhibitory Concentration (IC50) | Virus Strain |
|---|---|---|
Acyclovir |
59 uM |
HHV-6AGS |
Acyclovir |
27 uM |
HHV-6ASIE |
Acyclovir |
30 UM |
HHV-6ASIE |
Acyclovir |
7 uM |
HHV-6U1102 |
Ganciclovir |
25 uM |
HHV-6AGS |
Ganciclovir |
1.1 uM |
HHV-6ASIE |
Ganciclovir |
2 uM |
HHV-6ASIE |
Ganciclovir |
2 uM |
HHV-6AU1102 |
Ganciclovir |
14 uM |
HHV-6AGS |
Foscarnet |
49 uM |
HHV-6AGS |
Foscarnet |
2.7 ug/ml |
HHV-6ASIE |
Foscarnet |
8.7 uM |
HHV-6ASIE |
Foscarnet |
25 uM |
HHV-6AU1102 |
Foscarnet |
> 150 uM |
HHV-6AGS |
Alpha Interferon |
40 IU/ml |
HHV-6AU1102 |
Beta Interferon |
16 IU/ml |
HHV-6AU1102 |
Zidovudine |
> 200 uM |
HHV-6AGS |
Zidovudine |
> 8 uM |
HHV-6ASIE |
Data from Akesson-Johasson 91, Agut 91, Agut 89 and Carrigan 96a and 96b.
Table 2: Susceptibility of HHV-6B to Inhibition by Antiviral Agents
| Antiviral Agent | IC50 (50% inhibitory concentration) |
|---|---|
Acyclovir |
37 uM (mean) |
Ganciclovir |
5.9 uM (mean)* |
Ganciclovir |
1.0-2.5 uM** |
Foscarnet |
21-117 uM* |
Foscarnet |
49-67 uM** |
* Data from Carrigan, 96 (unpublished observation)
** Data from Burns 90, Russler 89, DiLuca 90 , Agut 90 , Shiraki 89.
What's New
Potenza et al. HHV-6A in Syncytial Giant-Cell Hepatitis. N Engl J Med. 2008 Aug 7;359(6):593-602.
GUIDED MEDLINE SEARCH FOR
Reviews
Zerr DM, Razonable RR. Human Herpesvirus 6 in Transplant Recipients
Sun HY, et al. Pharmacotherapy of post-transplant viral infections. Expert Opin Pharmacother 2008;9(14):2409-2421.
Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infectious Diseases 2007;7:460-472.
GUIDED MEDLINE SEARCH FOR RECENT REVIEWS
History
Berger S. Emergence of Infectious Diseases into the 21st Century, 2008.
Altschuler EL. Oldest description of roseola and implications for the antiquity of human herpesvirus 6. Pediatr Infect Dis J 2000;19:903.