Human herpesvirus 7 infection

INTRODUCTION — Human herpesvirus 7 (HHV-7) was first isolated in 1990 from the CD4 T cells of a healthy individual whose activated cells in culture showed cytopathic effects [1]. Although its structure has been well characterized, its role in human disease has yet to be defined.

VIROLOGY AND PATHOGENESIS — HHV-7 belongs to the Roseolovirus genus of the herpesvirus subfamily. Its linear, double-stranded DNA genome of about 145 kb shows homologies to human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV). Mature HHV-7 particles measure 170 nm in diameter, with nucleocapsids of 90 to 95 nm and a tegument of approximately 30 nm [2]. Its DNA codes for 84 different proteins, including two major capsid proteins [3,4]. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection".)

Viral genes — The HHV-7 genome is colinear with the HHV-6 genome and approximately 10 percent shorter. The overall arrangement of the genomes is similar for the two viruses. The primary divergences from HHV-6 are:

●Absence of the adeno-associated virus type 2 (AAV-2) rep gene homologue found in HHV-6 (open reading frame [ORF] U94), which is associated with the viral origin of DNA replication [3].

●Divergent binding properties between the respective origin binding proteins [5].

●Lack of two spliced exons (ORFs U96 and U97) that encode portions of the major HHV-6 virion glycoprotein (gp) 105.

●The inclusion of genes encoding putative viral transactivator proteins and the DR element, which specify ORFs of different coding capacities than HHV-6 [3].

The significance of these differences for viral DNA replication is unknown.

In common with HHV-6, HHV-7 contains two ORFs (U12, U51) that encode putative G protein-coupled receptors. Further analysis demonstrates that they encode functional calcium-mobilizing receptors for beta-chemokines, which include thymus and activation-regulated chemokine, macrophage-derived chemokine, EBI1-ligand chemokine, and secondary lymphoid-tissue chemokine [6].

These ORFs encode a transmembrane glycoprotein (gB), which is thought to represent one of the HHV-7 envelope proteins involved in the adsorption of virus-to-cell surface proteoglycans [7]. These ORFs also encode two other glycoproteins (gH and gL) [8], a phosphotransferase/ganciclovir kinase, a ribonucleotide reductase, a protease, and a heparin-binding gp 65 that may contribute to viral attachment [9,10]. Some genetic diversity in gB and gH has been observed, suggesting possible use in the classification of HHV-7 isolates [11,12]. HHV-7 ORF U47 encodes gO-gH complex, which may have similar function to that in human cytomegalovirus and HHV-6, such as cell-to-cell fusion in viral infection [13].

HHV-7 ORF U12 activates distinct transmembrane signaling pathways that may mediate biologic functions by binding with a beta-chemokine [14]. In addition, an HHV-7 glycoprotein U21 is an immunoevasin that binds to class I major histocompatibility complex molecules and diverts them to a lysosomal compartment [15-18]. U24, a protein common to roseola viruses that is known to downregulate the T cell receptor, has also been shown to downregulate a transferrin receptor, blocking early endosomal recycling [19], which may play a role in perturbing the levels of proteins such as Nedd4 family E3 ubiquitin ligase, proteins that play a crucial role in dendrite outgrowth in the central nervous system [20].

Human antibodies raised in response to HHV-7 are directed against the immunodominant protein pp85 encoded by ORF (U14) [21].

Cell tropism — HHV-7 is a lymphotropic virus that replicates in CD4 T lymphocytes. It can be induced from latency within T cells by cell activation [22]. It can also be cultured in a CD4 lymphoblastic cell line (SupT1) [2,23], in cord blood mononuclear cells, and macrophages [24]. Its in vitro host-cell range is narrower than HHV-6. It does not infect certain CD4 cell lines such as Jurkat and H-9 HeLa-CD4 [25] but may be able to infect CD4-positive hematopoietic precursor cells [26,27]. HHV-7 has been detected in CD68+ monocyte/macrophage associated with Kaposi sarcoma [28].

Viral entry — HHV-7, unlike HHV-6, utilizes CD4 as a cellular receptor for entry into cells [29,30]. CD4 expression is necessary, but not sufficient, for infection of T cells, as evidenced by its inability to penetrate many cell lines expressing CD4 such as HeLa-CD4 or Jurkat.

Among other cofactors that might allow HHV-7 entry are cell-surface proteoglycans, which are capable of binding to HHV-7 glycoprotein B (gB) and are present on SupT1 cells but not on other CD4 T cell lines resistant to HHV-7 infection [7]. HHV-7 induces a profound downregulation of CD4 expression, which occurs six to nine days after infection [31,32] through a suppressive effect on CD4 transcription [33]. Thus, HHV-7 infection interferes with HIV-1 infection [29,34]. HHV-7 does not require CXCR4 for entry [35] but may downregulate its expression with potential implications for HIV-1 coinfection [35,36]. HHV-7 infection may also reactivate HHV-6 [22,37].

Effects on cells — HHV-7 has a variety of effects on cells:

●HHV-7 is more cell associated, less cytopathic, and grows with slower kinetics in culture than HHV-6 [38].

●Similar to HIV-1 and HHV-6, the cytopathic effect (CPE) of HHV-7 is characterized by membrane blebbing and the presence of multinucleated giant cells (syncytia) that eventually undergo necrotic lysis [1,39].

●HHV-7 can induce apoptosis in a number of cell types [33,40,41], an effect that may be mediated via the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) pathway [42].

●HHV-7 can also support latent infection, as evidenced by the absence of viral transcripts in the peripheral blood mononuclear cells of healthy donors infected with HHV-7 [43].

●Immunomodulatory effects on cytokines have been described in vitro, such as increases in tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, and interleukin (IL-)15 and a decrease in IL-2 [44,45]. No effect has been observed on IL-4 and IL-6. Recent ex vivo and in vivo experiments have demonstrated that HHV-7 down-modulates expression of human leukocyte antigen (HLA) and beta-2 microglobulin. HHV-7 immunoevasin U21, a class I major histocompatibility complex (MHC)-like protein, binds with high affinity to class I MHC molecules as a tetramer and escorts them to lysosomes, where they are degraded [46]. This could help viral escape from host immune pressure and partly explain HHV-7 persistence in infected cells [47].

●A possible case of germline HHV-7 integration has been identified using primers against the U90 ORF of HHV-7, suggesting that HHV-7 may behave like HHV-6 in this regard [48]. This finding requires confirmation.

●The protein tyrosine phosphatase CD45, which is essential for signaling through the T cell receptor and development of a fully functional immune response, is downregulated in T cells infected with HHV-7 [49].

EPIDEMIOLOGY — HHV-7 is ubiquitous. More than 95 percent of adults are seropositive [50]. Infection with HHV-7 generally occurs during childhood but peaks at a later age than infection with human herpesvirus 6 (HHV-6), usually around three years of age [50,51]. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection".)

HHV-7 appears to be shed throughout life in saliva, and 75 percent of healthy adults secrete HHV-7 in saliva at some time [34,52-55]. Intrafamilial transmission has been documented using restriction analyses of HHV-7 genome from virus recovered from saliva of individuals within a family [54]. The average number of genome copies is higher than that of HHV-6, and this amount is stable over time [56].

HHV-7 DNA has been detected in breast milk in 3 of 29 samples studied, suggesting that breastfeeding could be one route of transmission [57]. It has also been isolated from cervical secretions [58]. HHV-7 DNA can be detected in the peripheral blood mononuclear cells (PBMCs) of most healthy adults at a level of approximately 300 copies per million cells [59], but infectious virus cannot be isolated from unstimulated PBMC cultures [1,22]. HHV-7 DNA has also been detected in 50 percent of bone marrow samples from 18 healthy patients who had undergone hip arthroplasty [60] and in bronchoalveolar lavage fluid of 32 percent and 21 percent of hospitalized adult transplant and nontransplant patients, respectively [61].

In one study seeking to identify risk factors for HHV-7 infection, seasonal factors and Black race were associated with a higher prevalence of HHV-7 infection among children [62]. A history of ever having been breastfed seemed to have a protective effect. A study performed in children admitted to hospital in sub-Saharan Africa (a region with high HIV prevalence) showed no association between HHV-7 DNAemia and HIV infection, being underweight, or with the admission diagnosis [63].

CLINICAL MANIFESTATIONS — HHV-7 infection is generally asymptomatic.

Primary infection — Some studies suggest that HHV-7 shares similar clinical features with human herpesvirus 6 (HHV-6). In one prospective study, 15 of 71 infants and children (21 percent) who presented for acute febrile respiratory illness with or without skin rash were infected with HHV-7. Fever was observed in all 15, which persisted for 2.9 days. A papular, macular, or maculopapular rash was observed in 14, appearing on the face, trunk, and extremities as fever subsided and lasting for 2.7 days. A simultaneous increase in antibody titers to HHV-6 was observed in 8 of the 15 (53 percent) during primary HHV-7 infection [64]. In another study, 8 of 250 (3 percent) children with acute febrile illness or seizure were HHV-7 infected compared with 29 out of 250 (12 percent) who were infected with HHV-6 [65]. Low lymphocyte counts, rash, vomiting, and diarrhea were present.

In addition to febrile seizures, other central nervous system (CNS) manifestations have been described, as discussed below. (See 'CNS manifestations including febrile seizures' below.)

HHV-7 has been identified as one of the viruses causing exanthem subitum (ES; roseola), although HHV-6 is more common. One study demonstrated seroconversion to HHV-7 in five of seven infants immediately after exhibiting typical signs and symptoms of ES [66]. (See "Roseola infantum (exanthem subitum)".)

Hepatitis has been reported during HHV-7 infection [67], and a mononucleosis-like syndrome has been associated with HHV-7 with or without concurrent Epstein-Barr virus infection [68,69].

In children ≤24 months of age, HHV-7 infections occur less often than HHV-6 infections. In one study, of 2806 samples from 2365 children ≤10 years old, 30 (1 percent) showed evidence of HHV-7 viremia; 23 (77 percent) of these were primary and 7 (23 percent) were reactivated HHV-7 infections [70]. Four (13 percent) showed concurrent HHV-6 viremia, and two were associated with primary HHV-7 infections. The clinical manifestations of primary and reactivated HHV-7 infections were similar, except that seizures occurred more frequently in reactivated infections.

CNS manifestations including febrile seizures — Several reports describe an association between HHV-7 and febrile seizures [65,71-74]. As noted above, HHV-7 isolation has been described from infants with ES, including a report of two cases of seizures and acute hemiplegia complicating this entity [75-77]. Whether this syndrome can be attributed to HHV-7 infection itself or to its ability to reactivate HHV-6 var B from latency [22] remains unknown, although some findings such as rising anti-HHV-6 antibody titers in sera from convalescing infants or excretion of HHV-6 DNA in saliva [78,79] suggest that coinfection plays a role in pathogenesis.

Isolated cases of encephalopathy [80,81] and hemiconvulsion and hemiplegia syndrome [82] have been reported during HHV-7 infection. Rare cases of acute myeloradiculoneuropathy associated with HHV-7 have been reported [83,84].

In three adolescents, two of whom had encephalitis and one of whom had Guillain-Barré syndrome, primary HHV-7 infection was confirmed as the cause of the neurologic disease syndrome [85]. One immunocompetent adolescent presented with limbic encephalitis; HHV-7 was the only pathogen detected in the cerebrospinal fluid (CSF) by a metagenomic panel [86]. A case of hemorrhagic brainstem encephalitis has been described in an otherwise healthy child [87]. After extensive investigation, only HHV-7 DNA was found in his CSF.

Cases of acute encephalitis occur rarely in immunocompetent adults. One patient with involvement of the nucleus of cranial nerve VI had only HHV-7 DNA found in the CSF [88]. A second patient had ophthalmoplegia, HHV-7 DNA in the CSF, and increased HHV-7 antibody titers, although an antibody avidity assay was not performed [89]. A third patient had limbic encephalitis with HHV-7 DNA in the CSF and an increase in HHV-7 IgG titers, believed to be due to HHV-7 reactivation [90].

HHV-7 has been found in CSF of documented anti-NDMAR encephalitis. The contribution of this finding is unknown [81,91].

Two cases of HHV-7 associated meningitis were described, one was in a 53-year-old immunocompetent woman who died one month after diagnosis, the second was in an adolescent girl. In both cases, the CSF was compatible with viral meningitis and HHV-7 was the only pathogen recovered [92,93].

Pityriasis rosea and lichen planus — An association of HHV-7 with pityriasis rosea (PR) has been suggested by the presence of HHV-7 DNA in cell-free plasma, seroconversion to the virus [94-96], and viral particles suggestive of HHV-7 on electron microscopy [97]. In contrast with these observations, one study failed to detect HHV-7 DNA sequences or antigens in skin lesions from PR patients [98]. A persistent form of PR was described in 12 patients presenting with severe systemic symptoms and oral lesions [99,100]. This was associated with persistent reactivation of HHV-6 or HHV-7.

Lichen planus (LP), a common inflammatory skin disease, has also been associated with HHV-7, as demonstrated by HHV-7 DNA through polymerase chain reaction (PCR) testing in LP lesions as compared with patients with psoriasis and healthy controls. A causal association, however, remains to be demonstrated [101,102].

HHV-7 and AIDS — Although in vitro studies have shown interference between HIV-1 and HHV-7, the clinical implications of these interactions are not fully understood [103]. In one study, HHV-7 DNA was detected less frequently in a group of patients with the acquired immunodeficiency syndrome (AIDS) than among 15 healthy controls [104]. However, in another study, detection and viral load of HHV-7 in saliva were found to be increased in HIV-1-infected subjects [105].

HHV-7 has also been demonstrated by immunohistochemistry in five out of seven lymph nodes of HIV-infected subjects compared with one out of five of HIV-uninfected subjects [106]. In a study comparing healthy blood donors with HIV-1-infected subjects with various degrees of disease progression, HHV-7 infection did not appear to be stimulated by HIV-1 infection nor interact with it. Rather, HHV-7 correlated with CD4 T-lymphocyte counts [107]. A case of HHV-7-associated myelitis was reported in a 40-year-old HIV-positive man with a CD4 cell count of 580/mm³ [108]. The investigation was negative except for HHV-7 DNA detected in the CSF. The patient responded to foscarnet therapy, and HHV-7 DNA was cleared from the CSF.

Transplant recipients — HHV-7 may be a cofactor for symptomatic cytomegalovirus (CMV) infection in renal transplant recipients. In several studies of such patients, those with symptomatic CMV disease were more likely to have prior and concurrent HHV-7 DNA in their peripheral blood lymphocytes than were patients with asymptomatic CMV infection [109-111]. In one study, renal transplant recipients with chronic allograft nephropathy had an increased incidence of HHV-6 and HHV-7 viremia compared with those without chronic allograft nephropathy [112].

There are conflicting reports about HHV-7 in hematopoietic cell transplant (HCT) recipients. In some studies, HHV-7 DNA in peripheral blood lymphocytes was associated with a longer time to neutrophil engraftment and with symptomatic CMV disease [113,114], whereas another study found only low levels of HHV-7 DNA in a minority of HCT recipients, which did not change over a six-month period [115]. One study, including 105 HCT recipients who underwent PCR testing for various viruses from before HCT to 42 days following HCT, showed that HHV-7 DNAemia was detected in 8.6 percent of patients; detection of HHV-7 peaked at 21 days following HCT [116]. In another study that included 69 allogeneic HCT recipients, HHV-7 DNAemia was associated with higher CMV loads, and HHV-7/CMV coinfection was associated with longer HHV-7 persistence [117].

Studies of HHV-7 infection in pediatric transplant patients have had conflicting results. In a prospective study of 59 pediatric patients followed 12 weeks after HCT, PCR revealed HHV-7 in blood samples in 56 percent [118]. The rate was higher in autologous compared with allogeneic grafts and there was no association with CMV, administration of colony-stimulating factor, or acute graft-versus-host disease (GVHD). In another study, prolonged reactivations appear to correlate with clinical manifestations such as fever, rash, and bone marrow suppression, but severe complications were rare [119]. However, another study found HHV-7 to be uncommon post-HCT (9 of 265), although it was associated with severe GVHD and sepsis [120]. The discrepancies among these results may be due to the sensitivity of the assay used and the design of the studies.

Isolated cases of acute myelitis, optic neuritis, meningitis, and encephalitis have been described after stem cell transplantation in association with HHV-7 [118,121-123]. In addition, HHV-7 may be a cofactor in HHV-6 reactivation [124].

In contrast with the above observations, no disease has been associated with HHV-7 following heart transplantation [125] or intestinal transplantation [126], and the role of HHV-7 in morbidity after hepatic transplantation is controversial [127,128]. In a study of 22 adult liver transplant recipients, 41 percent had HHV-7 viremia during a 90-day follow-up associated with either HHV-7-positive immunoglobulin (Ig)M or significant increases in IgG titers [129]. HHV-7 was shown to be prevalent in biliary fluid after liver transplant [130]. One small study in liver transplant recipients demonstrated that HHV-7 antigenemia usually occurred simultaneously with CMV antigenemia in patients with symptomatic CMV disease [131], whereas another showed that HHV-7 infection occurred independently of CMV in this patient population [132]. The clinical implications of these findings are unclear.

Drug reaction with eosinophilia and systemic symptoms — Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as drug-induced hypersensitivity syndrome) has been associated with reactivation of HHV-7 [133] as well as HHV-6, Epstein-Barr virus, and cytomegalovirus [134-137], although a causal link between these viruses and DRESS has not been demonstrated. One hypothesis is that the rash could be mediated by increased activated CD8 T lymphocytes directed against these viruses [134]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Reactivation of Herpesviridae'.)

Other possible disease associations — Studies looking at a possible association of HHV-7 with Hodgkin lymphoma or non-Hodgkin lymphoma and T- and B-cell lymphoma have all been negative [138-140]. A suggested association of HHV-6 to multiple sclerosis has prompted studies to evaluate the role of HHV-7 in this syndrome, but no association has been found [141-144]. A case of venoocclusive disease in a patient with X-linked agammaglobulinemia and HHV-7 infection of the explanted liver after transplantation has been reported [145]. A study of 43 fibromyalgia patients found no association between A delta and C nerve fiber damage and HHV-7 [146]. Cases of anterior uveitis associated with the presence of HHV-7 DNA in aqueous humor have been described [147,148].

A case-control study of infants with cerebral palsy in Australia showed a 1.5 to 2.5 increased risk of developing cerebral palsy after perinatal exposure to herpes virus group B, as measured by PCR on dried blood spots. However, this does not prove causality [149]. CSF analysis of 62 Japanese children with encephalitis analyzed by multiplex PCR revealed 23 percent of HHV-6/7 infection, but again whether this indicates causality is unclear [150].

The possible role of HHV-7 in connective tissue diseases [151], periodontitis [152], Graves' disease [153], myocarditis [154], and Alzheimer disease [155], and myalgic encephalomyelitis/chronic fatigue syndrome [156] is also being evaluated.

In one meta-analysis, SARS CoV-2 infection has been associated with reactivation of several herpesviruses including HHV-7. The role of these reactivations in the severity of COVID disease is not clear [157].

DIAGNOSIS — Few clinical situations currently warrant the use of HHV-7 diagnostic assays, and they are currently used mainly for research purposes. Several serologic tests, including early versions of indirect immunofluorescence and enzyme-linked immunosorbent assay, have shown cross-reactivity with human herpesvirus 6 (HHV-6) [158,159]. Newer assays based upon an 89 kDa HHV-7 protein [160] or glycoprotein B [161] do not seem to cross-react with antibodies to HHV-6 [71].

Polymerase chain reaction (PCR) assays have been developed [162-164], and real-time PCR assays can quantify and differentiate herpesviruses [165-168]. Assays based on sequencing cell-free DNA are being developed to monitor a broad array of viral infections occurring in lung transplant recipients [169].

TREATMENT — No clinical settings in which treatment for HHV-7 infection is warranted have been identified. In vitro, foscarnet and cidofovir inhibit HHV-7 replication by achievable concentrations [170,171]. The virus is relatively resistant to acyclovir, penciclovir, and ganciclovir.

Small clinical studies suggest that HHV-7 is resistant to ganciclovir at levels that were effective for prevention and treatment of cytomegalovirus [172,173]. Sensitivity of HHV-7 to the guanine analogs was different from human herpesvirus 6, suggesting a difference in selectivity of specific viral enzymes [170].

SUMMARY AND RECOMMENDATIONS

●Unclear clinical significance – The role of human herpesvirus 7 (HHV-7) in human disease has yet to be clearly defined. (See 'Introduction' above.)

●Lymphotropic virus – HHV-7, which belongs to the herpesvirus subfamily, is a lymphotropic virus that replicates in CD4 T lymphocytes. (See 'Virology and pathogenesis' above.)

●High prevalence – More than 95 percent of adults are HHV-7 seropositive. Infection with HHV-7 generally occurs during childhood, peaking around three years of age. (See 'Epidemiology' above.)

●Clinical presentation

•HHV-7 infection is generally asymptomatic.

•Among children, HHV-7 has been associated with fever, rash, and febrile seizures. Among renal transplant recipients, HHV-7 may be a cofactor for symptomatic cytomegalovirus disease. Several reports describe an association between HHV-7 and febrile seizures.

•Other neurologic manifestations have been described in patients with HHV-7 infection, such as encephalitis and Guillain-Barré syndrome. (See 'Clinical manifestations' above.)

●Diagnosis – At present, diagnostic assays for HHV-7 are used primarily in research settings. (See 'Diagnosis' above.)

●No specific treatment – There are no clear indications for treating HHV-7 infection. (See 'Treatment' above.)