Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection

INTRODUCTION — Human herpesvirus 6 (HHV-6) was first isolated and characterized from patients with lymphoproliferative disorders [1] and was originally named human B-lymphotropic virus. Its name was changed to human herpesvirus 6 as its tropism was further characterized [2].

The virology, pathogenesis, and epidemiology of HHV-6 infection will be discussed here. The clinical manifestations, diagnosis, and treatment in adults and children are presented separately; HHV-6 infection in hematopoietic cell transplant recipients is also discussed elsewhere. (See "Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults" and "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)

TAXONOMY — HHV-6 is a member of the Herpesviridae family. Its genetic and biologic similarities to human cytomegalovirus (CMV) have prompted its classification in the beta herpesvirus subfamily (genus Roseolovirus, along with human herpesvirus 7) [3]. There are two HHV-6 variants, HHV-6A and HHV-6B. Based on their distinctive biological properties and genome sequences, HHV-6A and HHV-6B are classified as two distinct herpesvirus species [4]. HHV-6A and HHV-6B also differ in epidemiology, growth properties, antigenic properties, and restriction endonuclease profiles [5-8]. The nucleotide sequence identity between the two variants ranges from 75 to 95 percent depending upon which gene is compared.

VIROLOGY AND PATHOGENESIS — As with other herpes viruses, mature HHV-6 virions are double-stranded deoxyribonucleic acid (DNA) viruses, approximately 200 nm in diameter and are composed of four main structural elements: an electron-dense core, a capsid with icosahedral symmetry, a tegument, and an outer envelope.

Cell tropism — HHV-6 replicates most efficiently in vitro in activated primary T cells as well as in continuous T cell lines. However, the virus can also replicate with varying efficiency in a wide array of host cell types including monocytes/macrophages, natural killer cells, astrocytes, megakaryocytes, and glial cell lineages [2,9-12]. HHV-6 can also be recovered in vivo from a broad range of tissues such as lymph nodes, peripheral blood mononuclear cells (PBMCs), renal tubular cells, salivary glands, and the central nervous system [13-19]. HHV-6 has also been identified in astrocytes from gliomas, suggesting a potential role in tumorigenesis [20,21].

During acute HHV-6 infection, monocytes/macrophages harbor more replication-competent HHV-6 than CD4+ T cells [22]. Hematopoietic differentiation can also lead to HHV-6 reactivation from infected peripheral blood progenitor cells [23].

Viral replication — CD46, an immunomodulatory protein that is also called membrane cofactor protein, is a cellular receptor for HHV-6A and HHV-6B [24]. The following observations have been made concerning this relationship:

●Both acute infection and cell fusion mediated by HHV-6 are specifically inhibited by antibodies against CD46, while fusion can be blocked competitively by soluble CD46 [24].

●Nonhuman cells that are resistant to HHV-6 fusion and entry become susceptible upon expression of recombinant human CD46 [24].

●Three HHV-6 glycoproteins form a heterotrimeric complex on the viral envelope that is a viral ligand for human CD46 [25].

●CD46 isoforms may affect susceptibility of T cells to infection with HHV-6A and HHV-6B [26]. Whether binding to CD46 plays a role in the immune dysfunction observed after HHV-6 infection remains to be determined. HHV-6 downregulates interleukin (IL)-12 production [27], an effect that may be mediated by crosslinking of CD46 [28]. It has also been shown that HHV-6 infection results in a reduction of CD45 on the surface of infected T cells and impaired activation in response to T cell receptor stimulation [29].

CD134, a member of the tumor necrosis factor (TNF) receptor superfamily, has been identified as a receptor for HHV-6B entry [30,31]. It has been suggested that nectin-2 may act as an HHV-6B entry-mediated protein [32].

U27 increases the in vitro DNA synthesis activity of HHV-6A DNA polymerase and plays an essential role in viral replication as demonstrated in a U27-deficient mutant model [33].

HHV-6 integrates into the human genome and can integrate into germline cells; several different chromosomal sites of integration have been identified [34]. Inherited chromosomally integrated HHV-6 (iciHHV-6) can cause a confusing clinical picture in the setting of allogeneic hematopoietic cell transplantation. Because patients with inherited HHV-6 have at least one copy of the viral genome in each cell of their body, they have unusually high levels of HHV-6 DNA in blood, cerebrospinal fluid, and tissues. This is discussed in greater detail separately. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Detecting inherited chromosomal integration'.)

Mature HHV-6 virions are found within multivesicular bodies and are released from the host cell via the exosomal pathway [35].

Effect on the immune system — CD4+ T cells constitute the major population of cells permissive to HHV-6 replication even though HHV-6 does not bind directly to the CD4 molecule [36]. Once HHV-6 enters a permissive host cell, viral replication occurs relatively slowly. Within 24 hours after infection, the rate of cellular protein synthesis is high; by 65 hours after infection, host cell DNA synthesis is shut off and viral DNA synthesis is underway [37]. Cytopathic effects can be seen within three to five days after infection. The net effect is a significant impairment in immune function [27], which may be mediated in part by downregulation of cell surface CD3 expression [38] or via induction of cytokines, such as TNF-alpha, interferon-gamma, and IL-1 beta [39]. Other cytokines have been shown to be upregulated including the interferon-inducible CXCL11 [40].

HHV-6 differentially influences the functions of naïve T cells and different subsets of memory CD4+ and CD8+ T cells, which may be due in part to differential susceptibility to HHV-6A–induced apoptosis [41]. HHV-6 can be transmitted from monocyte-derived dendritic cells to stimulated CD4+ T cells in vitro. Thus, dendritic cells may be the first cell population targeted by HHV-6, and they could play an important role in the virus' transmission to T cells, which leads to further virus propagation [42].

HHV-6 can induce expression of a superantigen, which may lead to further dysregulation of the immune system [43]. On the other hand, HHV-6 increases the activity of natural killer (NK) cells via activation of IL-15 [44]. The increase in NK cell activity may represent a natural antiviral defense mechanism that promotes elimination of virus-infected cells.

HHV-6 may also establish a latent state in monocytes, capable of later reactivation [15,45].

Viral genes — The genome of the U1102 strain of HHV-6A has been completely sequenced [46,47].

HHV-6 replication genes encode a number of viral proteins including:

●U38, a viral DNA polymerase.

●U27, a polymerase accessory/processivity protein.

●U41, a single-stranded DNA-binding protein.

●U43, U74, U77, which are three helicase-primase proteins.

●U14, the tegument protein, constitutes the viral structure and is essential for viral replication; its crystal structure has been characterized [48].

●U94, indispensable for HHV-6 chromosomal integration [49,50].

●U14, U11, which are important for HHV-6A maturation and propagation [51,52].

●HHV-6A U4 inhibits amyloid precursor protein degradation by interacting with cullin-RING E3 ubiquitin-protein ligases [53].

●U12 and U51 encode putative homologues of human G-protein-coupled receptors like CCR1, CCR3, and CCR5 [54].

HHV-6 also encodes three homologues of herpes simplex virus (HSV)-1 glycoproteins important in viral entry: gB [55], gH, and gL [46]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Pathogenesis of infection'.)

Another candidate for a potential receptor-binding protein is gp82-105, which is a major component of virions and is a target for neutralizing antibodies [56].

HHV-6 also encodes gene products that are able to transactivate human immunodeficiency virus (HIV)-1 long terminal repeat (LTR)-directed gene expression [57]. This is particularly relevant because both HHV-6 and HIV-1 can infect CD4+ T lymphocytes [58] and HHV-6 induces CD4 expression in otherwise CD4-negative subpopulations of lymphocytes and natural killer cells, making them susceptible to HIV infection [59].

A study analyzing complete genomes from 61 isolates of HHV-6B from patients with active infections and 64 strains of iciHHV-6B led to altered annotations for more than 10 percent of existing genes [60]. Multiple iciHHV-6B sequences from unrelated individuals were identical. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. These results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Integration of HHV-6B is discussed in greater detail above. (See 'Viral replication' above.)

EPIDEMIOLOGY — HHV-6 seroprevalence rates vary from 20 percent among pregnant women in Morocco [61] to 100 percent among asymptomatic Chinese adults [62]. In industrialized nations such as the United States and Japan, rates of seroprevalence range from 72 to 95 percent [63,64].

HHV-6 is frequently acquired by an early age. This is illustrated by the following observations:

●In a study of 2235 infants and children under the age of three who presented to the emergency department with an acute illness, HHV-6 DNA was detected in 10 percent of infants less than one month of age, consistent with perinatal transmission, compared with 66 percent at one year (figure 1) [45]. The rate of seroconversion was highest between 6 and 12 months of age.

●Similar findings were noted in a prospective study of 277 children in which saliva was tested weekly for HHV-6 DNA with the use of polymerase chain reaction (PCR) during the first two years of life [65]. Primary HHV-6 infection occurred in 130 children; 40 percent of infections occurred by 12 months of age and 77 percent by 24 months.

Distribution of HHV-6A and HHV-6B — Molecular techniques have been used to determine whether the distribution of the two HHV-6 species differs based upon geography. Among young children with an acute febrile illness, the proportion of cases in which HHV-6A is detected in peripheral blood mononuclear cells (PBMCs) has varied from less than 3 percent in the United States to 44 percent of infants from central Africa [66,67].

The vast majority of isolates from otherwise healthy children or adults are HHV-6B [45]. In contrast, both HHV-6A and -6B have been recovered from PBMCs of patients who are immunocompromised or chronically ill. In one study, for example, HHV-6A was the predominant species in lymph nodes from HIV-1 infected adults [68]. HHV-6A may also have greater neurotropism and neurovirulence [69,70].

Incubation period and transmission — Although there are few data regarding the incubation period of HHV-6 infection, the mean incubation period is thought to be approximately 9 to 10 days [71].

The most common route of HHV-6 transmission appears to be transfer via saliva from mother to infant. Early studies detected HHV-6 in the saliva of almost all subjects tested, although some of the positive results might have been due to cross-reactivity with human herpesvirus 7 [62,72], which is shed in saliva much more frequently [73]. The following observations have been made in later studies using PCR in healthy individuals, although cross-reactivity is still possible with some primers:

●HHV-6 has been isolated from saliva in 3 to 90 percent [14,73,74].

●HHV-6 has been found in 63 percent of salivary gland biopsies, which appears to act as a viral reservoir [73]. The tonsils may be another common site of latent infection [75].

Perinatal transmission is also possible. Most women of reproductive age have been infected with HHV-6, as indicated by serologic testing, and approximately 2 percent of pregnant women shed low levels of virus in genital secretions [76]. In addition, HHV-6 DNA has been detected in 41 to 44 percent of samples during pregnancy [77] but only 1 percent of cord blood samples [77,78].

In a study cited above of infants and young children presenting with an acute febrile syndrome, HHV-6 DNA was detected in 10 percent of infants less than one month of age, a finding that is consistent with perinatal transmission [45]. Intrauterine transmission has also been proposed in selected cases in which spontaneous abortion, fetal hydrops, and fulminant neonatal hepatitis were associated with HHV-6 infection [79-81].

The issue of congenital HHV-6 infection was addressed in a prospective study of 5638 children [78]. Congenital HHV-6 infections occurred in 1 percent of births, similar to the rate for cytomegalovirus infection and to the rate of isolation of HHV-6 in cord blood [77,78]. All of the children with congenital infection were asymptomatic. In contrast, postnatal infections were associated with acute febrile illness, which has also been noted by others [45].

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●Basics topic (see "Patient education: Roseola (The Basics)")

SUMMARY

●Virology − Human herpesvirus 6 (HHV-6) is a member of the Herpesviridae family. Its genetic and biologic similarities to human cytomegalovirus (CMV) have prompted its classification in the beta herpesvirus subfamily (genus Roseolovirus, along with human herpesvirus 7). As with other herpes viruses, mature HHV-6 virions are double-stranded DNA viruses, approximately 200 nm in diameter and are composed of four main structural elements: an electron-dense core, a capsid with icosahedral symmetry, a tegument, and an outer envelope. (See 'Virology and pathogenesis' above.)

●Taxonomy − Two HHV-6 species, HHV-6A and HHV-6B, differ in epidemiology, growth properties, nucleotide sequences, antigenic properties, and restriction endonuclease profiles. (See 'Taxonomy' above.)

●Cell tropism − HHV-6 replicates most efficiently in vitro in activated primary T cells as well as in continuous T cell lines. However, the virus can also replicate with varying efficiency in a wide array of host cell types including monocytes/macrophages, natural killer cells, astrocytes, megakaryocytes, and glial cell lineages. (See 'Cell tropism' above.)

●Cellular receptor − CD46, an immunomodulatory protein that is also called membrane cofactor protein, is a cellular receptor for HHV-6A and HHV-6B. HHV-6 integrates into the human genome; seven different chromosomal sites of integration have been identified. (See 'Viral replication' above.)

●Viral replication and effect on immune system − CD4+ T cells constitute the major population of cells permissive to HHV-6 replication even though HHV-6 does not bind directly to the CD4 molecule. Once HHV-6 enters a permissive host cell, viral replication occurs relatively slowly. Within 24 hours after infection, the rate of cellular protein synthesis is high; by 65 hours after infection, host cell DNA synthesis is shut off and viral DNA synthesis is underway. Cytopathic effects can be seen within three to five days after infection. The net effect is a significant impairment in immune function. (See 'Effect on the immune system' above.)

●Important viral proteins − HHV-6 replication genes encode a number of viral proteins including U38, a viral DNA polymerase; U27, a polymerase accessory/processivity protein; U41, a single-stranded DNA-binding protein; and U43, U74, U77, which are three helicase-primase proteins. (See 'Viral genes' above.)

●Seroprevalence − HHV-6 seroprevalence rates vary from 20 percent among pregnant women in Morocco to 100 percent among asymptomatic Chinese adults. In industrialized nations such as the United States and Japan, rates of seroprevalence range from 72 to 95 percent. HHV-6 is frequently acquired by an early age. (See 'Epidemiology' above.)

●Predominance of HHV-6B − The vast majority of isolates from otherwise healthy children or adults are HHV-6B. In contrast, both HHV-6A and -6B have been recovered from peripheral blood mononuclear cells of patients who are immunocompromised or chronically ill. (See 'Distribution of HHV-6A and HHV-6B' above.)

●Transmission − Although there are few data regarding the incubation period of HHV-6 infection, it is thought to be approximately 9 days (range 5 to 15 days). The most common route of HHV-6 transmission appears to be transfer via saliva from mother to infant. Perinatal transmission is also possible. (See 'Incubation period and transmission' above.)