Absence of maternal HHV-6-specific T-cell response in the setting of human Herpesvirus-6 chromosomal integration: Potential impact on congenital infection

ABSTRACTHuman herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) are population-prevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare-cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detected a low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of open reading frame (ORF) products recognized was nine per person. Overall, the data expand the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides, and HLA restriction was defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population prevalent, including U73, U72, U95, and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens.IMPORTANCEHuman herpesvirus 6 is highly prevalent and maintains chronic infection in immunocompetent individuals, with the potential to replicate widely in settings of immunosuppression, leading to clinical disease. Antiviral compounds may be ineffective and/or pose dose-limiting toxicity, and therefore, immune-based therapies have garnered increased interest in recent years. Attempts at addressing this unmet medical need begin with understanding the cellular response to HHV-6 at the individual and population levels. The present study provides a comprehensive assessment of HHV-6-specific T-cell responses that may inform the development of cell-based therapies directed at this virus.

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Nine-year follow-up in a child with chromosomal integration of human herpesvirus 6 transmitted from an unrelated donor through the Japan Marrow Donor Program

Transplant Infectious Disease ◽

10.1111/tid.12338 ◽

2015 ◽

Vol 17 (1) ◽

pp. 160-161 ◽

Cited By ~ 3

Author(s):

H. Yagasaki ◽

H. Shichino ◽

N. Shimizu ◽

T. Ohye ◽

H. Kurahashi ◽

...

Keyword(s):

Human Herpesvirus ◽

Unrelated Donor ◽

Chromosomal Integration ◽

Human Herpesvirus 6 ◽

Herpesvirus 6

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Immunosuppressive effect of human herpesvirus 6 on T-cell functions: suppression of interleukin-2 synthesis and cell proliferation [published erratum appears in Blood 1995 Jul 1;86(1):418]

Blood ◽

10.1182/blood.v85.5.1263.bloodjournal8551263 ◽

1995 ◽

Vol 85 (5) ◽

pp. 1263-1271 ◽

Cited By ~ 106

Author(s):

L Flamand ◽

J Gosselin ◽

I Stefanescu ◽

D Ablashi ◽

J Menezes

Keyword(s):

T Cells ◽

T Cell ◽

T Lymphocyte ◽

Peripheral Blood ◽

Cellular Proliferation ◽

Interleukin 2 ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Infected Cells ◽

Herpesvirus 6

Human herpesvirus-6 (HHV-6), the etiologic agent of roseola, is ubiquitous, establishes latency in the host, and can infect a variety of immunocompetent cells, with CD4+ T lymphocytes being the targets in which it replicates most efficiently. The present study was undertaken to learn more about specific immunobiologic effects of HHV-6 infection on T-lymphocyte functions. Our data demonstrate that infection of peripheral blood mononuclear cells (PBMC) by HHV-6 results in suppression of T-lymphocyte functions, as evidenced by reduced interleukin-2 (IL-2) synthesis and cellular proliferation. In fact, HHV- 6-infected PBMC secreted 50% less IL-2 than mock-infected cells after mitogenic stimulation with OKT3 antibody or phytohemmaglutinin (PHA). The inhibition of IL-2 by HHV-6 was also observed in enriched T-cell cultures, suggesting a direct effect of this virus on this cell type. Messenger RNA (mRNA) analysis by reverse-transcriptase polymerase chain reaction (PCR) indicated that HHV-6 diminishes IL-2 mRNA levels in mitogen-stimulated peripheral blood T cells. These results were also confirmed by Northern blot using the leukemic T-cell line Jurkat. This inhibitory effect of HHV-6 did not require infectious virus, as the use of UV-irradiated HHV-6 produced similar results. Moreover, HHV-6- infected PBMC showed up to an 85% reduction in their mitogen-driven proliferative response, as compared with sham-infected cells. Proliferation of both CD4+ and CD8+ T cells was affected by HHV-6. Taken together, our data show that infection of T cells by HHV-6 results in immune suppression characterized by a downregulation of IL-2 mRNA and protein synthesis accompanied by diminished cellular proliferation.

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In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6).

Journal of Experimental Medicine ◽

10.1084/jem.167.5.1659 ◽

1988 ◽

Vol 167 (5) ◽

pp. 1659-1670 ◽

Cited By ~ 217

Author(s):

P Lusso ◽

P D Markham ◽

E Tschachler ◽

F di Marzo Veronese ◽

S Z Salahuddin ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Cell Population ◽

Mononuclear Cells ◽

Human Herpesvirus ◽

Human Herpesvirus 6 ◽

Infected Cells ◽

Cellular Tropism ◽

Herpesvirus 6

We investigated the cellular tropism of human B-lymphotropic virus (HBLV) (also designated Human Herpesvirus-6) in vitro by infecting fresh MN cells from normal human adult peripheral blood, umbilical cord blood, bone marrow, tonsil, and thymus. Cultures from all the sources examined contained infectable cells, as shown by the appearance of characteristic enlarged, round-shaped, short-lived cells expressing HBLV-specific markers. Detailed immunological analysis demonstrated that the vast majority of these cells expressed T cell-associated antigens (i.e., CD7, CD5, CD2, CD4, and to a lesser extent, CD8). The CD3 antigen and the TCR-alpha/beta heterodimer were not detectable on the surface membrane, but were identified within the cytoplasm of HBLV-infected cells, by both immunofluorescence and radioimmunoprecipitation assay. A proportion of the HBLV-infected cell population also expressed the CD15 and class II MHC DR antigens. By means of immunoselection procedures it was possible to show that a consistent proportion of HBLV-infectable cells were contained within the CD3-depleted immature T cell population, while the depletion of CD2+ cells completely abrogated the infectability of the cultures. Northern blot analysis confirmed the T cell origin of HBLV-infected cells, demonstrating the expression of full size TCR-alpha and -beta chain mRNA. In addition to fresh T cells, HBLV was able to infect normal T lymphocytes expanded in vitro with IL-2 for greater than 30 d. These results indicate that HBLV is selectively T cell tropic in the course of the in vitro infection of normal mononuclear cells and may therefore be directly involved in the pathogenesis of T cell related hematological disorders. In particular, in light of the cytopathic effect exerted in vitro on CD4+ T lymphocytes, a possible role of HBLV in immune deficiency conditions should be considered.

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