Homologies are Red blocks represent the herpesvirus core genes, numbered from I to VII. Yellow blocks represent HHV-6A genomes are kbp to kbp long.
As sequenced, the genome of U strain is kbp long 14 ; the HHV-6B genome has been sequenced only partially. Seven gene blocks in the central region I-VII designated as herpesvirus core genes are common to all Herpesviridae. Amino acid similarity to HHV-7 is Few gene products have been characterized so far.
They include the immediate-early gene IE-A, which together with IE-B constitutes the IE locus, a highly spliced region with an arrangement similar to that of HCMV 18 ; the U3 gene, a homolog of the HCMV U L 24 gene, with transactivating activity 19 ; the origin binding protein 20 , the U53 protease 21 ; and p, also designated p, highly immunogenic, and most probably a constituent of the tegument 22 , In addition, HHV-6 but not HHV-7 carries a homolog of the adenoassociated type 2 parvovirus rep gene 24 , which is transcribed in latently infected cells A major focus has been in the glycoprotein field.
Five glycoproteins were identified: gB U39, gp 27 - 30 , gH U48, gp 31 , and gL U82, gp80 , which form at least a heterodimer, gM U72 , and gp U 29 , 30 , 32 , The HHV-6 genome sequence predicts a locus of glycoproteins UU24 and U85 that are specific to the Roseolovirus genus 14 , but the proteins have not yet been identified.
U20 and U85 have a predicted immunoglobulin structure. Frenkel and co-workers 34 , Ablashi et al. All the strains derived so far segregate into two groups, variant A and variant B, whose genome organization appears to be overlapping.
Viruses belonging to the two variants differ with respect to several properties. Differences in restriction endonuclease cleavage sites are scattered throughout the entire genomes. Major differences in biologic properties concern the in vitro cell tropism, regulation of transcription and splicing patterns, reactivity to some MAbs directed to variant-specific epitopes 29 , 34 , Typically, variant A viruses replicate in HSB-2 cells, whereas the variant B viruses grow in the less differentiated Molt3 T-cell lines.
Variant B viruses grow to higher yields than variant A viruses in primary human fetal astrocytes and require IL and phytohemagglutinin-activated PBMCs. The differences relative to infection in humans epidemiology, correlation with pathologic features, tissue tropism are detailed below and in the table. All strains fall into one or the other variant group. There is no evidence of recombination or a genetic gradient, which suggests that in vivo the two groups of viruses occupy different ecologic niches.
Any isolate characterized for more than one marker has been unambiguously assigned to one or the other variant group. The designation of the two groups as variants has been highly debated and controversial A key question is whether the two variants fulfill the criteria defined by the International Committee on Taxonomy of Viruses for classification as different species In our opinion, the information summarized above indicates that the two variant groups may be different species; therefore, the issue of nomenclature should be reconsidered.
Exceptions, if confirmed, are represented by countries e. Antibody titers are high in newborn children, drop at 3 to 9 months after birth, rise again briefly thereafter, and remain elevated until the age of 60 or older.
This pattern indicates that newborns carry maternal antibodies and primary infection occurs in the first 3 years of life, most frequently the first year. Transplacental infections are very infrequent but may contribute to HHV-6 seropositivity in newborns Figure 2. Stages of the natural history of HHV-6 infection: I. Primary infection occurs in infants, may result in exanthem subitum rash on the child's chest , and spreads to organs. Question marks denote Three stages can be recognized in the natural history of HHV-6 infection Figure 2.
The first is represented by acute primary infection in infants. The second occurs in healthy children and adults; the virus replicates in the salivary glands and is secreted in saliva for HHV-6B without inducing any obvious pathology, remains latent at least in lymphocytes and monocytes, and persists in various tissues, possibly with a low-level replication.
The third stage occurs infrequently, typically in immunocompromised persons, and is linked to reactivation of virus from latency or reinfection. The unequivocal demonstration that primary infection with HHV-6B causes roseola infantum was provided by Yamanishi et al.
Fever lasts for a few days and is sometimes followed by a maculopapular rash that resolves spontaneously. Primary infection may be asymptomatic or may cause clinical manifestations other than classic exanthem subitum.
Other than rash, symptoms included otitis, gastrointestinal or respiratory distress, and seizures 41 - Complications of primary HHV-6 infections are uncommon and rarely fatal; they were described mainly as case reports and include invasion of the central nervous system CNS with seizures, hyperpyrexia, vomiting, diarrhea, cough, emophagocytic syndrome, fulminant hepatitis, disseminated infection, and hepatosplenomegaly. These complications suggest that the virus may spread to a number of organs, which may represent potential sites of virus persistence or latency and subsequently reactivation.
For example, seizures and other CNS complications are clear indications of invasion of this organ and correlate well with neurotropism of HHV HHV-6B is not the only causative agent of exanthem subitum. Occasionally, HHV-7 may also cause fever with or without rash. Virus replicated in the salivary glands and secreted in saliva is the epidemiologically proven source of transmission. Other routes of transmission have been suggested but remain to be proven.
HHV-6B DNA was recovered from cervical tissues and secretions 47 - 49 , but children born to mothers with positive cervical swabs did not acquire the infection.
Intrauterine transmission was suggested by polymerase chain reaction PCR positivity of uncultured cord blood mononuclear cells CBMCs in 1. Integration of the HHV-6 genome in lymphoblasts from a leukemic patient and his offspring raised the possibility of genetic transmission. As vertical transmission was not observed in other cases of genome integration, the presence of HHV-6 DNA in offspring was alternatively interpreted as a tendency of HHV-6 to integrate at specific chromosomal loci 51 , With the exception of a strong association of HHV-6A with febrile syndromes in Zambian children 43 , which could reflect an endemic variant A hot spot, HHV-6A has rarely been isolated or detected in children with primary HHV-6 infection 53 , The age at which primary HHV-6A infection occurs and the diseases clearly linked to it have not been determined.
The second stage of HHV-6 infection occurs in healthy children and adults, in whom the virus actively replicates in the salivary glands, is latent in at least lymphocytes and monocytes, and persists in various tissues. Replication in salivary glands—observed for HHV-6B but not HHV-6A 9 , 10 , 47 —accounts for the route of transmission and for the high frequency of detection and isolation of virus in saliva.
Additional sites of latency likely exist since the virus or viral sequences can be readily detected in a number of tissues. A form of latent infection is represented by integration of the HHV-6 genome in the host chromosomes 51 , A missing link in our understanding of the natural history of HHV-6 infection is the source of the virus that spreads to organs. Monocytes have a short half-life; they may be vehicles of virus spread to organs, but they themselves need to be infected. A possible source may be virus produced in the salivary glands.
In one case, early bone marrow progenitor cells were found to be latently infected in vivo 56 , which raises the possibility that they may represent a site of latency, and by corollary, upon viral reactivation from latency, an alternative source by which virus spreads to tissues.
In immunocompetent adults, infection or reactivation of HHV-6 at sites other than the salivary glands is rare. Occasionally, infection results in lymphoadenopathy, fulminant hepatitis, mononucleosislike syndrome, or generalized infection. The third stage of HHV-6 infection, which occurs in the immunosuppressed, is responsible for the most serious clinical manifestations associated with HHV-6 infection or reactivation.
Persons at risk are recipients of bone marrow, kidney, and liver transplants, in whom immunosuppression is induced for therapeutic reasons.
In these patients, HHV-6 infection or reactivation may result in bone marrow suppression, pneumonitis, encephalitis, encephalopathy, hepatitis, fever, and skin rash or may complicate engraftment of the transplanted organ and culminate in rejection and death. As the number of persons undergoing organ transplantation and, consequently, subjected to therapeutic immunosuppression increases, the number of persons at risk is increasing. Assessment of the contribution of HHV-6 to posttransplant complications is made more difficult by the presence of other opportunistic viruses and by the scarcity of thorough studies on all the viruses present in these organs.
Thus, most of the reports on the presence of HHV-6 did not deal with the fact that HCMV reactivation is frequent in transplant recipients particularly kidney and may occur together with HHV-6 reactivation.
Each of these viruses is a pathogen in its own right, and in combination with the other, may produce disease far more serious in outcome and clinical manifestations than it would alone.
In many studies, no effort was made to identify the HHV-6 variant. When the variants were characterized, a rather heterogeneous pattern emerged. In PBMCs, brain and lungs variant B strains were predominant 60 - 62 , whereas in spinal fluid and serum, variant A strains were prevalent 63 , The overall incidence of these infections has decreased substantially after the introduction of highly active antiretroviral therapy.
In addition to coinfection, observed in vivo and in vitro, HHV-6 promotes HIV replication through upregulation of cytokines e. This led to the initial definition of HHV-6 as a lymphotropic virus. Furthermore, productive infection has been monitored in some cases by immunohistochemistry e. Despite the wealth of research on the presence of HHV-6 in humans, our knowledge is fragmentary.
By immunohistochemical staining, active HHV-6 infection was detected in various cells e. Since in numerous studies detection was performed by PCR, latent, persistent, or productive infections were not differentiated, nor was the nature of the infected cells defined. Variant A viruses appear predominant in skin and can replicate in primary fibroblast cultures, suggesting a preferential tropism for skin In addition to primary T lymphocytes, T-lymphocytic lines e.
Viruses of the two variants display different host range, as variant A strains generally do not replicate in Molt3 cells, whereas variant B strains do not replicate in HSB-2 cells.
Permissive cells of lineages other than T lymphocytes are the liver cell line HepG2 74 and a number of human and nonhuman cell lines in which the virus generally grows at very low yields e. Altogether, in cell cultures as well as in vivo, HHV-6 appears to have a host range wider than initially recognized, extending beyond T lymphocytes.
While this is meaningful with respect to studies on the natural history of the infection, the practical use of these cells in the laboratory is hampered by the very low virus yields.
In our experience, CBMC cultures, the most productive cell type, do not yield more that 10 4 infectious units per ml, whereas the titer of a herpes simplex virus type 1 stock is generally as high as 10 9 - 10 10 plaque-forming units per ml. HHV-6 is probably the most neurotropic virus known. Neuroinvasion has been documented in infants with primary infection, in focal encephalitis, in children and adults with AIDS, in recipients of bone marrow transplants, as well as in immunologically competent children and adults.
Challoner et al. Astrocytes were confirmed as a susceptible cell population, although in a subsequent study only samples from AIDS patients were positive Both variant viruses were detected in the brain of patients who died of causes related or unrelated to HHV-6, which demonstrates that both variant viruses can invade and be harbored in the brain 61 , 78 - Although studies on the differential distribution of the two variant groups provided conflicting results 78 , 83 , for HHV-6B, CNS invasion has been documented at primary infection.
A possible correlation between active HHV-6 infection and multiple sclerosis has been the focus of much attention in the past few years. Multiple sclerosis is a severe CNS disease of young adults, characterized by the progressive demyelination of nerves that leads to progressive paralysis and eventually death. The disease appears to be an autoimmune reaction to myelin, the coating of nerve fibers.
Viruses have long been suggested as etiologic agents of myelopathies, and DNA sequences from a number of viruses, particularly herpesviruses, have been detected, although not consistently.
In addition, since multiple sclerosis is accompanied by a characteristic increase in IgG titer in serum and spinal fluid, antibodies to various viruses including HHV-6 have been frequently searched for.
Our Mission. Find a Pediatrician. Text Size. Human Herpes Virus 6. Page Content. The information contained on this Web site should not be used as a substitute for the medical care and advice of your pediatrician.
There may be variations in treatment that your pediatrician may recommend based on individual facts and circumstances. Follow Us. Back to Top. Chronic Conditions. Common Surgical Procedures. Developmental Disabilities. Emotional Problems. From Insects or Animals. Genitals and Urinary Tract. Learning Disabilities. The avidity index, measured according to the procedure described by Ward et al. HHV-6 PCR performed on peripheral blood mononuclear cells was positive, although it was negative in the serum samples.
The same woman was admitted to the emergency room 1 month after discharge because of dysethesia of the lower limbs, tonsillitis, asthenia, and low-grade fever. We assumed it could be a novel reactivation of the HHV-6 infection, but this was not confirmed.
It was, in fact, an EBV primary infection. One month later, neurologic manifestations had totally disappeared. Exanthem subitum complications, including seizures, hemiplegia, meningoencephalitis, or residual encephalopathy, illustrate HHV-6 neurotropism; HHV-6 commonly invades the brain during ES, even in cases of clinically asymptomatic infections. The virus then persists in brain tissues in a latent form 4. This case is, to our knowledge, the second of encephalomyelitis caused by HHV-6 in an immunocompetent patient.
HHV-6 is frequently reported to be implicated in encephalitis or meningoencephalitis in immunocompromised persons, such as HIV-positive patients or transplant recipients, but few reports have implicated HHV-6 in encephalitis in immunocompetent adults 5 — 7. Our patient was not immunocompromised by either drug therapy or disease. Serologic tests suggested HHV-6 viral reactivation: IgG were present even in the first serum samples, and the avidity index was high.
Symptoms observed were likely to result from a reactivated latent infection of virus in the brain. HHV-6 is known to reactivate frequently during acute infections with other viruses especially with other herpesviruses 9.
Although our patient had neither obvious immunosuppression nor any confirmed infection, she may have had a selective defect in her responses to HHV The virus can invade the central nervous system and, in some cases, cause acute or subacute encephalitis sometimes associated with diffuse or multifocal demyelinization 9.
In other cases of neurologic disease induced by HHV-6, such as encephalomyelitis 10 , meningoencephalitis 5 , 6 , or encephalitis 7 in immunocompetent adults, patients were treated with acyclovir. Three patients died 6 , 7 , 9 , and one recovered within 2 days, with small doses of acyclovir 5.
Data obtained in vitro indicate a greater susceptibility of HHV-6 to cidofovir than ganciclovir or acyclovir 11 , 12 ; acyclovir inhibited viral replication only at high concentrations, so our patient was given cidofovir. This regimen had clinical and virologic efficacy, as the patient started to recover and her CSF improved. The second injection was not possible because of a skin reaction to probenecid. The second treatment given to the patient was ganciclovir, which is known to be effective against HHV On this regimen, the patient completely recovered from HHV-6 encephalomyelitis.
Because this is a case report and not a controlled clinical trial, we cannot be certain that the antiviral drugs led to her recovery. She began to recover after starting ganciclovir therapy. As a result, we think that the antiherpesvirus drugs led to her recovery. Of interest is the EBV primary infection that occurred in this patient 1 month after discharge. The paresis observed during this episode was considered a reactivation of the episode during her HHV-6 infection, since paresis is not a classical manifestation accompanying EBV infection,.
In conclusion, the case reported here underlines the fact that HHV-6 may cause rapidly multifocal, demyelinating lesions in an immunocompetent adult, even in the case of viral reactivation.
Therefore, we think that HHV-6 should be considered in the differential diagnosis of acute demyelinating encephalomyelitis in immunocompetent adults. Denes works in the department of infectious diseases in the teaching hospital of Limoges, France, and cares for patients with all types of infections. He is particularly interested in neurologic manifestations of infectious diseases and in bone infections. Table of Contents — Volume 10, Number 4—April Please use the form below to submit correspondence to the authors or contact them at the following address:.
Highlight and copy the desired format. Data is collected weekly and does not include downloads and attachments. View data is from.
0コメント