Characteristics and Acquisition of Human Herpesvirus (HHV)–7 Infections in Relation to Infection with HHV‐6

Hall, Caroline Breese; Caserta, Mary T.; Schnabel, Kenneth C.; McDermott, Michael P.; Lofthus, Geraldine; Carnahan, Jennifer; Gilbert, Lynne; Dewhurst, Stephen

doi:10.1086/503434

Cited by 101 publications

(68 citation statements)

References 27 publications

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“…Of them, HHV-6B colonizes nearly 100% of the human population, making it one of the most successful pathogens existing. In contrast, despite sharing >90% identity with HHV-6B, the A variant is encountered much less frequently in North America, Europe, and Japan (9,(21)(22)(23)(24)(25)(26). Previous reports have indicated that HHV-6 is sensitive to IFNs.…”

Section: Discussionmentioning

confidence: 99%

Divergent susceptibilities of human herpesvirus 6 variants to type I interferons

Jaworska

Gravel

Flamand

2010

Proc. Natl. Acad. Sci. U.S.A.

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Two distinct human herpesvirus 6 (HHV-6) variants infect humans. HHV-6B is the etiologic agent of roseola and is associated with lifethreatening neurological diseases, such as encephalitis, as well as organ transplant failure. The epidemiology and disease association for HHV-6A remain ill-defined. Specific anti-HHV-6 drugs do not exist and classic antiherpes drugs have secondary effects that are often problematic for transplant patients. Clinical trials using IFN were also performed with inconclusive results. We investigated the efficacy of type I IFN (α/β) in controlling HHV-6 infection. We report that cells infected with laboratory strains and primary isolates of HHV-6B are resistant to IFN-α/β antiviral actions as a result of improper IFN-stimulated gene (ISGs) expression. In contrast, HHV-6A-infected cells were responsive to IFN-α/β with pronounced antiviral effects observed. Type II IFN (γ)-signaling was unaltered in cells infected by either variant. The HHV-6B immediate-early 1 (IE1) physically interacts with STAT2 and sequestrates it to the nucleus. As a consequence, IE1B prevents the binding of ISGF3 to IFN-responsive gene promoters, resulting in ISG silencing. In comparison, HHV-6A and its associated IE1 protein displayed marginal ISG inhibitory activity relative to HHV-6B. The ISG inhibitory domain of IE1B mapped to a 41 amino acid region absent from IE1A. Transfer of this IE1B region resulted in a gain of function that conferred ISG inhibitory activity to IE1A. Our work is unique in demonstrating type I IFN signaling defects in HHV-6B-infected cells and highlights a major biological difference between HHV-6 variants.immediate-early 1 | interferon-stimulated genes | STAT2 S ecreted type 1 IFNs (α and β) bind to a receptor linked with Tyk2 and Jak1 tyrosine kinases (1, 2). Activated Jak1 and Tyk2 in turn phosphorylate STAT1 and STAT2, which assemble with IRF9 to form the IFN-stimulated gene factor 3 (ISGF3) complex that binds to IFN-stimulated response elements (ISRE) and promote transcription (3-6). Products of IFN-stimulated genes (ISGs) play essential roles in antiviral defense.Human herpesvirus 6 (HHV-6), isolated more than 20 years ago (7), is an increasingly recognized medically relevant pathogen. Two distinct HHV-6 variants (A and B) exist. These viruses have distinct biological properties and are associated with specific pathological conditions. The most common clinically defined disease associated with HHV-6B is roseola (8). HHV-6B reactivation is also common after hematopoietic stem cell transplantation and is responsible for severe complications (9). Much less is known regarding HHV-6A, but results suggest that this variant is more neurotropic than HHV-6B (10).In the present work, we studied the activation of ISGs during HHV-6 infection. Our results show a striking difference between HHV-6 variants, with HHV-6B effectively dwarfing ISGs activation and HHV-6A having only limited effects. Using RNA interference, we have identified that the immediate-early 1 (IE1) protein of HHV-6B is responsibl...

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Section: Discussionmentioning

confidence: 99%

Divergent susceptibilities of human herpesvirus 6 variants to type I interferons

Jaworska

Gravel

Flamand

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Primary infections with HHV-6A have been reported much less frequently, and it is generally assumed that HHV-6A is acquired after HHV-6B, through an asymptomatic infection. However, symptomatic primary infections with HHV-6A have been described for children in the United States as well as in sub-Saharan Africa (154)(155)(156).…”

Section: Clinical Impacts Of Hhv-6 Infections Primary Infectionsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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“…10,11 HHV-6 is the collective name for HHV-6A and HHV-6B, 12,13 two closely related beta-herpesviruses that establish primary infection in early childhood and maintain lifelong persistent infection with a combined seroprevalence of 490% in adults. [14][15][16][17] Of the two, HHV-6B is the variant implicated in nearly all documented cases of HHV-6 reactivation following HSCT, which typically occurs within 30 days of HSCT. 18 One of the most severe consequences of HHV-6 reactivation among post-transplant patients is infection of the central nervous system (CNS), which can lead to the development of HHV-6 encephalitis.…”

Section: Introductionmentioning

confidence: 99%

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

Scheurer

Pritchett

Amirian

et al. 2012

Bone Marrow Transplant

108

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Reactivation of human herpesvirus-6 (HHV-6) frequently occurs following hematopoietic SCT (HSCT), and has been associated with clinical consequences in many patient populations. HHV-6 reactivation and HHV-6 encephalitis seem to occur more frequently in patients undergoing HSCT with cord blood (CB) as the stem cell source. We have conducted a systematic literature review and meta-analysis to investigate the clinical significance of this correlation. A systematic review of publications indexed in PubMed was performed for HSCT studies published over the past 10 years that fit inclusion criteria. Data on prevalences of HHV-6 reactivation and HHV-6 encephalitis post HSCT were abstracted from 19 papers. Meta-analyses were conducted to calculate combined prevalence estimates. The prevalences of HHV-6 reactivation and encephalitis were compared among CB vs non-CB HSCT. Prevalences of HHV-6 reactivation and HHV-6 encephalitis were significantly higher in patients receiving CB as the stem cell source than in patients receiving another stem cell source (72.0% vs 37.4%, Po0.0001; 8.3% vs 0.50%, Po0.0001, respectively). HHV-6 reactivation and HHV-6 encephalitis are significant complications in the post-HSCT setting, particularly in patients receiving CB as the stem cell source. Thus, patients undergoing umbilical CB transplantation should be closely monitored for HHV-6 reactivation.

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Characteristics and Acquisition of Human Herpesvirus (HHV)–7 Infections in Relation to Infection with HHV‐6

Cited by 101 publications

References 27 publications

Divergent susceptibilities of human herpesvirus 6 variants to type I interferons

Divergent susceptibilities of human herpesvirus 6 variants to type I interferons

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

HHV-6 encephalitis in umbilical cord blood transplantation: a systematic review and meta-analysis

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