Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice

Gobbi, A.; Stoddart, Cheryl A.; Malnati, Mauro S.; Locatelli, Giuseppe; Santoro, Fabio; Abbey, Nancy W.; Bare, Christopher; Linquist-Stepps, Valerie; Moreno, M B; Herndier, Brian; Lusso, Paolo; McCune, Joseph M.

doi:10.1084/jem.189.12.1953

Cited by 55 publications

(50 citation statements)

References 33 publications

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“…As a result of several in vitro analyses, HHV-6 has been demonstrated to have immunomodulatory effects such as impaired T cell activation, decreased cytokine synthesis, and impaired dendritic cell functions. [37][38][39][40] Although several investigators have suggested that HHV-6 infection is positively associated with CMV disease 15,17,18 and fungal infection 7 in liver transplant recipients, a definitive association between HHV-6 infection and these opportunistic infections remains unclear. This study showed no association between HHV-6 reactivation and CMV antigenemia or fungal infection.…”

Section: Discussionmentioning

confidence: 99%

Human herpesvirus 6 infection in adult living related liver transplant recipients

et al. 2007

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To analyze human herpesvirus 6 (HHV-6) infection in adult living related liver transplantation, we performed a virological analysis, including viral isolation, serological assay, and real-time polymerase chain reaction, of serially collected blood samples from 67 recipients. In addition, cytokine levels were measured to determine their role in viral reactivation. HHV-6 was isolated from only 4 recipients (6.0%), and viral DNA was detected in 15 (22.4%) of the 67 recipients. A significant increase in HHV-6 immunoglobulin G antibody titers was observed in 19 (28.4%) of the 67 recipients. Finally, 26 recipients (38.8%) had HHV-6 reactivation 2-6 weeks after transplantation. HHV-6 associated clinical features were analyzed in the 17 recipients presenting with either viremia or DNAemia. Two recipients with viremia and 3 recipients with DNAemia had unexplained fever at the time of viral infection. An increase in aminotransferase levels was observed in 2 recipients with viremia and 3 recipients with DNAemia. Recipients with liver cirrhosis caused by hepatitis B virus or hepatitis C virus infection as the underlying disease were more likely to have HHV-6 infection (P ϭ 0.025). Mortality at the last follow-up in recipients with HHV-6 reactivation was significantly higher than in those without viral reactivation (P ϭ 0.0118). Plasma interleukin-6 levels were significantly higher in the recipients with HHV-6 viremia than in the recipients without viremia at 4 weeks post-transplant (P ϭ 0.0411). Moreover, tumor necrosis factor ␣ levels were also higher in recipients with HHV-6 viremia (P Ͻ 0.0001) or reactivation (P ϭ 0.0011) than in recipients without viremia or reactivation 4 weeks post-transplant.

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Section: Discussionmentioning

confidence: 99%

Human herpesvirus 6 infection in adult living related liver transplant recipients

et al. 2007

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“…Models of HHV-6A and HHV-6B infection have been developed in marmosets and transgenic mice (46,47,54,55). Additionally, identification of naturally occurring herpesviruses related to human roseoloviruses has been reported by various groups, notably in pig-tailed macaques (56,57).…”

Section: Discussionmentioning

confidence: 99%

“…While we have not studied direct infection of T cells in vitro, our data strongly suggest that MRV has similar T-cell tropism. Furthermore, infection of humanized mice with HHV-6A showed severe loss of human CD4 ϩ cells in the thymus (45)(46)(47), and ex vivo infection of human lymphoid tissues decreased the CD4 ϩ T-cell number (48). The tissue tropism of human roseoloviruses may be very broad, involving a diverse array of organs and cell types (1).…”

Section: Discussionmentioning

confidence: 99%

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Patel

Zhao

Penna

et al. 2017

J Virol

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The human roseoloviruses human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 comprise the Roseolovirus genus of the human Betaherpesvirinae subfamily. Infections with these viruses have been implicated in many diseases; however, it has been challenging to establish infections with roseoloviruses as direct drivers of pathology, because they are nearly ubiquitous and display species-specific tropism. Furthermore, controlled study of infection has been hampered by the lack of experimental models, and until now, a mouse roseolovirus has not been identified. Herein we describe a virus that causes severe thymic necrosis in neonatal mice, characterized by a loss of CD4 ϩ T cells. These phenotypes resemble those caused by the previously described mouse thymic virus (MTV), a putative herpesvirus that has not been molecularly characterized. By next-generation sequencing of infected tissue homogenates, we assembled a contiguous 174-kb genome sequence containing 128 unique predicted open reading frames (ORFs), many of which were most closely related to herpesvirus genes. Moreover, the structure of the virus genome and phylogenetic analysis of multiple genes strongly suggested that this virus is a betaherpesvirus more closely related to the roseoloviruses, HHV-6A, HHV-6B, and HHV-7, than to another murine betaherpesvirus, mouse cytomegalovirus (MCMV). As such, we have named this virus murine roseolovirus (MRV) because these data strongly suggest that MRV is a mouse homolog of HHV-6A, HHV-6B, and HHV-7.IMPORTANCE Herein we describe the complete genome sequence of a novel murine herpesvirus. By sequence and phylogenetic analyses, we show that it is a betaherpesvirus most closely related to the roseoloviruses, human herpesviruses 6A, 6B, and 7. These data combined with physiological similarities with human roseoloviruses collectively suggest that this virus is a murine roseolovirus (MRV), the first definitively described rodent roseolovirus, to our knowledge. Many biological and clinical ramifications of roseolovirus infection in humans have been hypothesized, but studies showing definitive causative relationships between infection and disease susceptibility are lacking. Here we show that MRV infects the thymus and causes T-cell depletion, suggesting that other roseoloviruses may have similar properties.KEYWORDS herpesviruses, roseolovirus T he study of herpesviruses has been fruitful, not only revealing mechanisms that drive disease but also providing insight into diverse processes, including oncogenesis and immune regulation (1). The Herpesviridae family includes several highly prevalent human pathogens (1-3). While they are related, these viruses have diverse genomes,

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“…Besides this role as an opportunistic agent, however, several lines of clinical and experimental evidence support the concept that HHV-6 may also act as an immunosuppressive agent in its own right. Both HHV-6 subgroups were shown to induce severe thymocyte depletion in heterochimeric SCID-hu thy/liv mice, with a predominant tropism and cytopathicity for immature thymic precursor cells (8). Disseminated coinfection with HHV-6A and -6B was linked to progressive and ultimately fatal immunodeficiency in a human immunodeficiency virus (HIV)-negative child (13).…”

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confidence: 99%

Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo

Grivel

Santoro²,

Chen

et al. 2003

J Virol

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Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4؉ T lymphocytes expressing a nonnaive phenotype, while CD8 ؉ T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4؉ and CD8 ؉ T cells, whereas in HHV-6B-infected tissue CD4 ؉ T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodulation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.

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Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice

Cited by 55 publications

References 33 publications

Human herpesvirus 6 infection in adult living related liver transplant recipients

Human herpesvirus 6 infection in adult living related liver transplant recipients

A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion

Pathogenic Effects of Human Herpesvirus 6 in Human Lymphoid Tissue Ex Vivo

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