Human herpesvirus 6: molecular biology and clinical features

Dockrell, David H.

doi:10.1099/jmm.0.05074-0

Cited by 98 publications

(62 citation statements)

References 177 publications

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“…Several lines of evidence suggest that HHV-6 may act as an immunosuppressive agent (8,20). However, the clinical observations are still limited, and the potential mechanisms of this immunosuppressive activity are still largely unknown.…”

Section: Discussionmentioning

confidence: 99%

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Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Smith

Paolucci

Lullo

et al. 2005

J Virol

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Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive CD4؉ -T-lymphotropic betaherpesvirus that causes severe human thymocyte depletion in heterochimeric SCID-hu thy/liv mice and has been implicated as a potential cofactor in the progression of AIDS. However, the mechanisms of HHV-6-mediated immunosuppression have not yet been fully elucidated. We investigated the phenotypic and functional alterations induced by HHV-6 on peripheral blood-derived human dendritic cells (DC). The infection of DC with HHV-6 A or B was nonproductive, as revealed by calibrated real-time PCR measuring the accumulation of viral genome equivalents over time. Nevertheless, preexposure to HHV-6 markedly impaired the maturation of DC driven by gamma interferon and lipopolysaccharide, as shown by the reduced surface expression of major histocompatibility complex class I molecules, HLA-DR, CD40, and CD80. Moreover, HHV-6, but not the closely related betaherpesvirus HHV-7, dramatically suppressed the secretion of interleukin-12 (IL-12) p70 by DC, while the production of other cytokines that influence DC maturation, i.e., IL-10 and tumor necrosis factor alpha, was not significantly modified. Likewise, the secretion of the CC chemokines macrophage inflammatory protein 1␤ and RANTES was unaltered. Functionally, a pretreatment with HHV-6 impaired the ability of DC to stimulate allogeneic T-cell proliferation. Altogether, these data identify interference with the functional maturation of DC as a potential mechanism of HHV-6-mediated immunosuppression.

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Section: Discussionmentioning

confidence: 99%

“…Like other herpesviruses, HHV-6 is able to induce latent infections and may persist indefinitely in the host. In immunocompromised patients, HHV-6 reactivation or reinfection may cause severe opportunistic diseases, including encephalitis, pneumonitis, hepatitis, and retinitis, as well as bone marrow graft failure (8).…”

mentioning

confidence: 99%

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Smith

Paolucci

Lullo

et al. 2005

J Virol

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“…Two subtypes of HHV-6 have been identified: variants A and B. Although these two variants are similar in sequence and genome organization, they are associated with different pathologies (8,10). HHV-6 variant B (HHV-6B) causes exanthem subitum (roseola infantum) in young children (43).…”

Section: Human Herpesvirus 6 (Hhv-6) Is a Ubiquitous Pathogen Of The mentioning

confidence: 99%

Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Sullivan

Coscoy

2008

J Virol

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We have performed a screen aimed at identifying human herpesvirus 6 (HHV-6)-encoded proteins that modulate immune recognition. Here we show that the U24 protein encoded by HHV-6 variant A downregulates cell surface expression of the T-cell receptor (TCR)/CD3 complex, a complex essential to T-cell activation and the generation of an immune adaptive response. In the presence of U24, the TCR/CD3 complex is endocytosed but is not recycled back to the plasma membrane. Instead, it accumulates in early and late endosomes. Interestingly, whereas CD3 downregulation from the cell surface is normally associated with T-cell activation, U24 downregulates CD3 independently of T-cell activation. Moreover, we found that U24-expressing T cells are resistant to activation by antigen-presenting cells. HHV-6 has evolved a unique mechanism of inhibition of T-cell activation that may impair the establishment of an adaptive immune response. Furthermore, lymphocyte activation creates an environment favorable to the reactivation and replication of lymphotropic herpesviruses. Thus, by inhibiting T-cell activation, HHV-6 might limit its reactivation and thus minimize immune recognition.

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“…perturb the cytokine network (4,6,7,9,16,27). Modulation of host immune factor expression is one mechanism of evading the immune response or creating an environment in which the virus can survive, but this strategy alone does not fully explain the persistence of latent HHV-6 infection.…”

mentioning

confidence: 99%

Human Herpesvirus‐6‐Specific Interleukin 10‐Producing CD4⁺ T Cells Suppress the CD4⁺ T‐Cell Response in Infected Individuals

Wang

Yao

Yin

et al. 2006

Microbiology and Immunology

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Human herpesvirus‐6 (HHV‐6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV‐6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4+ T cells and PBMCs but not CD8+ T cells from HHV‐6‐infected individuals was stimulated with HHV‐6‐infected cell lysates. Moreover, HHV‐6‐stimulated CD4+ T cells from HHV‐6‐infected individuals have suppressive activity on naïve CD4+ T and CD8+ T cells from HHV‐6‐uninfected individuals. However, no increased proportion of CD4+ CD25+ Treg cells from HHV‐6‐infected individuals contributed to the suppressive activity of the HHV‐6‐stimulated CD4+ T cells from HHV‐6‐infected individuals. Transwell experiments, ELISA and anti‐IL‐10 antibody blocking experiment demonstrated that IL‐10 may be the suppressive cytokine required for suppressive activity of CD4+ T cells from HHV‐6‐infected individuals. Results of intracellular interleukin (IL)‐10 and IL‐4 further implicated the HHV‐6‐speciflc IL‐10‐producing CD4+ T cells in the suppressive activity of CD4+ T cells from HHV‐6‐infected individuals. Results of intracellular interferon (IFN)‐γ demonstrated a decreased frequency of HHV‐6‐speciflc IFN‐γ‐producing CD4+ T, but not CD8+ T cells in HHV‐6‐infected individuals, indicating that it was the CD4+ Th1 responses in HHV‐6‐infected individuals that were selectively impaired. Our findings indicated that HHV‐6‐specific IL‐10‐producing CD4+ T cells from HHV‐6‐infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL‐10 production, with a few cells expressing IFN‐γ, but none expressing IL‐4. These cells may play an important role in latent HHV‐6 infection.

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Human herpesvirus 6: molecular biology and clinical features

Cited by 98 publications

References 177 publications

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Human Herpesvirus‐6‐Specific Interleukin 10‐Producing CD4⁺ T Cells Suppress the CD4⁺ T‐Cell Response in Infected Individuals

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Human herpesvirus 6: molecular biology and clinical features

Cited by 98 publications

References 177 publications

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Viral Replication-Independent Blockade of Dendritic Cell Maturation and Interleukin-12 Production by Human Herpesvirus 6

Downregulation of the T-Cell Receptor Complex and Impairment of T-Cell Activation by Human Herpesvirus 6 U24 Protein

Human Herpesvirus‐6‐Specific Interleukin 10‐Producing CD4+ T Cells Suppress the CD4+ T‐Cell Response in Infected Individuals

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Human Herpesvirus‐6‐Specific Interleukin 10‐Producing CD4⁺ T Cells Suppress the CD4⁺ T‐Cell Response in Infected Individuals