Human Herpesvirus 6A Partially Suppresses Functional Properties of DC without Viral Replication

Gustafsson, Rasmus; Engdahl, Elin; Hammarfjord, Oscar; Adikari, S. B.; Lourda, Magda; Klingström, Jonas; Svensson, Mattias; Fogdell‐Hahn, Anna

doi:10.1371/journal.pone.0058122

Cited by 13 publications

(25 citation statements)

References 36 publications

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“…Whereas, Hirata et al ( 2001 ) suggests that DC can support HHV-6A (U1102 strain) replication by increase in protein load over time, Smith et al ( 2005 ) suggests that DC cannot support HHV-6A (GS strain) replication as no increase in intracellular viral DNA was seen over time. We did not detect any increase in either viral protein or DNA when infecting DC with HHV-6A (GS strain) (Gustafsson et al, 2013b ), thus supporting the report by Smith et al To control for degraded virus or suboptimal infections both Smith et al and we infected susceptible cells in parallel with DC using the same virus supernatants. Productive infection was seen in the susceptible cells suggesting that lack of viral replication seen in DC was not due to problems with the virus stock or infection procedure.…”

Section: Virus Replicationsupporting

confidence: 87%

“…The vast majority of studies investigating HHV-6A or 6B infection in DC have studied MDC. The literature provides contradictory reports on the replication capacity of HHV-6A (Hirata et al, 2001 ; Smith et al, 2005 ; Gustafsson et al, 2013b ) (Table 1 ). Whereas, Hirata et al ( 2001 ) suggests that DC can support HHV-6A (U1102 strain) replication by increase in protein load over time, Smith et al ( 2005 ) suggests that DC cannot support HHV-6A (GS strain) replication as no increase in intracellular viral DNA was seen over time.…”

Section: Virus Replicationmentioning

confidence: 99%

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Modulatory effects on dendritic cells by human herpesvirus 6

2015

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Human herpesvirus 6A and 6B are β-herpesviruses approaching 100% seroprevalance worldwide. These viruses are involved in several clinical syndromes and have important immunomodulatory effects. Dendritic cells (DC) are key players in innate and adaptive immunity. Accordingly, DC are implicated in the pathogenesis of many human diseases, including infections. In this review the effects of HHV-6 infection on DC will be discussed.

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Section: Virus Replicationsupporting

confidence: 87%

Section: Virus Replicationmentioning

confidence: 99%

Modulatory effects on dendritic cells by human herpesvirus 6

2015

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“…Our work emphasizes, in fact, that HHV-6 infection induces a high frequency of virus-specific Tregs compared to HCMV-specific T-cell responses. These Tregs can have a broad immunosuppressive capacity and inhibit innate and adaptive immune-cell functions, which may be crucial for HHV-6-mediated latency and survival (24,25,36). In line with this possibility, we found that the frequency of HHV-6-specific regulatory T cells was inversely correlated with the frequency of conventional effector/memory T cells.…”

Section: Discussionsupporting

confidence: 73%

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells

Fastenackels

Bayard

Larsen

et al. 2019

J Virol

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Human herpesvirus 6 (HHV-6) infects >90% of the population and establishes a latent infection with asymptomatic episodes of reactivation. However, HHV-6 reactivation is associated with morbidity and sometimes mortality in immunocompromised patients. To date, control of the virus in healthy virus carriers and the failure to control it in patients with disease remain poorly understood. In particular, knowledge of HHV-6-specific T-cell responses is limited. Here, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses from peripheral blood mononuclear cells (PBMCs) of healthy donors. We studied the phenotype of effector HHV-6-specific T cells ex vivo, as well as of induced specific suppressive regulatory CD4+ T cells in vitro poststimulation, in comparison to human cytomegalovirus (HCMV) responses. Compared to that for HCMV, we show that ex vivo T-cell reactivity in peripheral blood is detectable but at very low frequency, both for HHV-6A and -6B viruses. Interestingly, the phenotype of the specific T cells also differs between the viruses. HHV-6A- and HHV-6B-specific CD4+ T lymphocytes are less differentiated than HCMV-specific T cells. Furthermore, we show a higher frequency of HHV-6-specific suppressive regulatory T cells (eTregs) than HCMV-specific eTregs in coinfected individuals. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. IMPORTANCE T cells are central to an effective defense against persistent viral infections that can be related to human cytomegalovirus (HCMV) or human herpesvirus 6 (HHV-6). However, knowledge of HHV-6-specific T-cell responses is limited. In order to deepen our knowledge of T-cell responses to HHV-6, we characterized HHV-6A- and HHV-6B-specific CD4+ and CD8+ T-cell responses directly ex vivo from healthy coinfected blood donors. Despite the strong similarity of HHV-6 and HCMV from a virologic point of view, we observed immunological differences, particularly in relation to the frequency and phenotype of effector/memory and regulatory virus-specific T cells. This suggests that different immune factors are solicited in the control of HHV-6 infection than in that of HCMV infection. Our findings may encourage immunomonitoring of patients with viral replication episodes to follow the emergence of effector versus regulatory T cells.

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“…Like other beta-herpesviruses, HHV-6B can trigger immuneevasion mechanisms (reviewed in [49, [50]]). Among the mechanisms is the downregulation of MHC molecules, although conflicting results have been reported, depending on cell type and virus studied [51][52][53][54][55]. While a potential mechanism for downregulation of MHC-I surface expression mediated by the viral protein U21 has been reported [56], for MHC-II the effect and mechanism involved are not clear.…”

Section: Isolation Of Mhc-ii Complexesmentioning

confidence: 99%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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Human herpes virus 6B (HHV‐6B) is a widespread virus that infects most people early in infancy and establishes a chronic life‐long infection with periodic reactivation. CD4 T cells have been implicated in control of HHV‐6B, but antigenic targets and functional characteristics of the CD4 T‐cell response are poorly understood. We identified 25 naturally processed MHC‐II peptides, derived from six different HHV‐6B proteins, and showed that they were recognized by CD4 T‐cell responses in HLA‐matched donors. The peptides were identified by mass spectrometry after elution from HLA‐DR molecules isolated from HHV‐6B‐infected T cells. The peptides showed strong binding to matched HLA alleles and elicited recall T‐cell responses in vitro. T‐cell lines expanded in vitro were used for functional characterization of the response. Responding cells were mainly CD3+CD4+, produced IFN‐γ, TNF‐α, and low levels of IL‐2, alone or in combination, highlighting the presence of polyfunctional T cells in the overall response. Many of the responding cells mobilized CD107a, stored granzyme B, and mediated specific killing of peptide‐pulsed target cells. These results highlight a potential role for polyfunctional cytotoxic CD4 T cells in the long‐term control of HHV‐6B infection.

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Human Herpesvirus 6A Partially Suppresses Functional Properties of DC without Viral Replication

Cited by 13 publications

References 36 publications

Modulatory effects on dendritic cells by human herpesvirus 6

Modulatory effects on dendritic cells by human herpesvirus 6

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

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