Variation in human herpesvirus 6B telomeric integration, excision and transmission between tissues and individuals

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

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Human Herpesviruses 6A and 6B in Reproductive Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.648945 ◽

2021 ◽

Vol 12 ◽

Author(s):

Anthony L. Komaroff ◽

Roberta Rizzo ◽

Jeffrey L. Ecker

Keyword(s):

Viral Genome ◽

Current Practice ◽

Human Herpesvirus ◽

Unexplained Infertility ◽

Human History ◽

Hematological Diseases ◽

Human Viruses ◽

Human Herpesviruses ◽

Transplacental Infection ◽

Early Human

Human herpesviruses 6A (HHV-6A) and human herpesvirus 6B (HHV-6B)—collectively, HHV-6A/B—are recently-discovered but ancient human viruses. The vast majority of people acquire one or both viruses, typically very early in life, producing an ineradicable lifelong infection. The viruses have been linked to several neurological, pulmonary and hematological diseases. In early human history, the viruses on multiple occasions infected a germ cell, and integrated their DNA into a human chromosome. As a result, about 1% of humans are born with the full viral genome present in every cell, with uncertain consequences for health. HHV-6A may play a role in 43% of cases of primary unexplained infertility. Both the inherited and acquired viruses may occasionally trigger several of the factors that are important in the pathogenesis of preeclampsia. Transplacental infection occurs in 1-2% of pregnancies, with some evidence suggesting adverse health consequences for the child. While emerging knowledge about these viruses in reproductive diseases is not sufficient to suggest any changes in current practice, we write this review to indicate the need for further research that could prove practice-changing.

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Enzymes of Human Herpesviruses

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19921577 ◽

1992 ◽

Vol 57 (8) ◽

pp. 1577-1612 ◽

Cited By ~ 1

Author(s):

Pavel Kramata ◽

Ivan Votruba

Keyword(s):

Binding Protein ◽

Human Herpesvirus ◽

Dna Helicase ◽

Point Of View ◽

Uracil Dna Glycosylase ◽

Replication Complex ◽

Viral Genomes ◽

Origin Binding Protein ◽

Antiviral Chemotherapy ◽

Human Herpesviruses

The properties of human herpesvirus-encoded enzymes are reviewed and the importance of sequence analysis of viral genomes as well as the experiments on characteristics of enzymes isolated from infected cell cultures are emphasized. The following enzymes are described in detail: DNA replication complex consisting of DNA polymerase, DNA helicase-primase, single-stranded DNA binding protein and origin binding protein, further thymidine kinase, ribonucleotide reductase, deoxyuridine triphosphatase as well as uracil-DNA-glycosylase, deoxyribonuclease and protein kinase. The importance of these enzymes from the point of view of antiviral chemotherapy is discussed.

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Human Herpesvirus and the Immune Checkpoint PD-1/PD-L1 Pathway: Disorders and Strategies for Survival

Microorganisms ◽

10.3390/microorganisms9040778 ◽

2021 ◽

Vol 9 (4) ◽

pp. 778

Author(s):

Takayuki Murata

Keyword(s):

Cell Death ◽

Immune System ◽

Programmed Cell Death ◽

Immune Checkpoint ◽

Human Herpesvirus ◽

Barr Virus ◽

Programmed Cell Death 1 ◽

Epstein Barr ◽

Simplex Virus ◽

Human Herpesviruses

The immune system has evolved as a complex and efficient means of coping with extrinsic materials, such as pathogens and toxins, as well as intrinsic abnormalities, such as cancers. Although rapid and timely activation of the immune system is obviously important, regulated downregulation of the system is almost as significant as activation to prevent runaway immunity, such as allergies and hypercytokinemia. Therefore, the immune checkpoint programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is beneficial for the host. On the other hand, pathogens have evolved to evade host immunity by taking advantage of the PD-1/PD-L1 pathway. This review is focused on human herpesviruses, such as herpes simplex virus (HSV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV), which cause various types of disorders, and their relationships with the PD-1/PD-L1 pathway. Understanding such relationships will be useful for developing preventative and therapeutic methods for disorders caused by herpesviruses.

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Herpesvirus Infections

10.2310/neuro.1144 ◽

2018 ◽

Author(s):

Martin S. Hirsch

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Varicella Zoster Virus ◽

Ganglion Cells ◽

Human Herpesvirus ◽

Herpes Infection ◽

Varicella Zoster ◽

Clinical Syndromes ◽

Simplex Virus ◽

Human Herpesviruses

The herpes group of viruses is composed of at least eight human viruses and numerous animal viruses. The human herpesviruses include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus types 6 (HHV-6), 7 (HHV-7), and 8 (HHV-8, also known as Kaposi sarcoma–associated herpesvirus). Human herpesviruses share the properties of latency and reactivation. Members of the group can cause productive lytic infections, in which infectious virus is produced and cells are killed, or nonproductive lytic infections, in which viral DNA persists but complete replication does not occur and cells survive. After acute lytic infections, herpesviruses often persist in a latent form for years; periodic reactivations are followed by recurrent lytic infections. Sites of latency vary: HSV and VZV persist in neural ganglion cells, EBV persists in B cells, and CMV probably remains latent in many cell types. The sites of latency for HHV-6 and HHV-7 have not been identified, although both herpesviruses have been detected in salivary glands. All human herpesviruses have a worldwide distribution. Considerable efforts are being directed toward the development of vaccines and antiviral agents that will be active against herpesviruses. This chapter discusses the epidemiology, pathogenesis, diagnosis, prevention, and treatment of herpes simplex virus and varicella-zoster virus and their clinical syndromes. The descriptions of the clinical syndromes include complications and clinical features, as well as descriptions of symptoms. Tables provide information on chemotherapy for primary genital and mucocutaneous herpes infection, suppression of severe and recurring genital herpes infection, and varicella-zoster infection. Figures provide photographic illustrations of the various clinical syndromes. A sidebar about herpesvirus information on the Internet provides further detail. This review contains 123 references, 4 tables, and 6 highly rendered figures.

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Herpesvirus Infections

10.2310/im.1144 ◽

2014 ◽

Author(s):

Martin S. Hirsch

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Varicella Zoster Virus ◽

Ganglion Cells ◽

Human Herpesvirus ◽

Herpes Infection ◽

Varicella Zoster ◽

Clinical Syndromes ◽

Simplex Virus ◽

Human Herpesviruses

The herpes group of viruses is composed of at least eight human viruses and numerous animal viruses. The human herpesviruses include herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus types 6 (HHV-6), 7 (HHV-7), and 8 (HHV-8, also known as Kaposi sarcoma–associated herpesvirus). Human herpesviruses share the properties of latency and reactivation. Members of the group can cause productive lytic infections, in which infectious virus is produced and cells are killed, or nonproductive lytic infections, in which viral DNA persists but complete replication does not occur and cells survive. After acute lytic infections, herpesviruses often persist in a latent form for years; periodic reactivations are followed by recurrent lytic infections. Sites of latency vary: HSV and VZV persist in neural ganglion cells, EBV persists in B cells, and CMV probably remains latent in many cell types. The sites of latency for HHV-6 and HHV-7 have not been identified, although both herpesviruses have been detected in salivary glands. All human herpesviruses have a worldwide distribution. Considerable efforts are being directed toward the development of vaccines and antiviral agents that will be active against herpesviruses. This chapter discusses the epidemiology, pathogenesis, diagnosis, prevention, and treatment of herpes simplex virus and varicella-zoster virus and their clinical syndromes. The descriptions of the clinical syndromes include complications and clinical features, as well as descriptions of symptoms. Tables provide information on chemotherapy for primary genital and mucocutaneous herpes infection, suppression of severe and recurring genital herpes infection, and varicella-zoster infection. Figures provide photographic illustrations of the various clinical syndromes. A sidebar about herpesvirus information on the Internet provides further detail. This review contains 123 references, 4 tables, and 6 highly rendered figures.

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Detection of Human Herpesvirus 6 and Varicella-Zoster Virus in Tear Fluid of Patients with Bell's Palsy by PCR

Journal of Clinical Microbiology ◽

10.1128/jcm.38.7.2753-2755.2000 ◽

2000 ◽

Vol 38 (7) ◽

pp. 2753-2755 ◽

Cited By ~ 29

Author(s):

A. Pitkäranta ◽

H. Piiparinen ◽

L. Mannonen ◽

M. Vesaluoma ◽

A. Vaheri

Keyword(s):

Varicella Zoster Virus ◽

Human Herpesvirus ◽

Bell’S Palsy ◽

Tear Fluid ◽

Healthy Controls ◽

Human Herpesvirus 6 ◽

Bell's Palsy ◽

Varicella Zoster ◽

Herpesvirus 6 ◽

Human Herpesviruses

Human herpesvirus 6 DNA was detected by PCR in the tear fluid of 7 (35%) of 20 patients with Bell's palsy and of 1 (5%) of 20 healthy controls. Varicella-zoster virus was detected by PCR in the tear fluid of 2 of 20 Bell's palsy patients but in none of the tear fluids from 20 healthy controls. These findings suggest an association between human herpesviruses and Bell's palsy.

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Cytomegalovirus and Epstein–Barr Virus Associations with Neurological Diseases and the Need for Vaccine Development

Vaccines ◽

10.3390/vaccines8010035 ◽

2020 ◽

Vol 8 (1) ◽

pp. 35 ◽

Cited By ~ 2

Author(s):

Peter A. C. Maple

Keyword(s):

Infectious Mononucleosis ◽

Epstein Barr Virus ◽

Vaccine Development ◽

Neurological Diseases ◽

Human Herpesvirus ◽

Middle Income ◽

Barr Virus ◽

Wide Range ◽

Epstein Barr ◽

Human Herpesviruses

Herpesviruses have been isolated from a wide range of hosts including humans—for which, nine species have been designated. The human herpesviruses are highly host adapted and possess the capacity for latency, allowing them to survive in the host for life, effectively hidden from the immune system. This ability of human herpesviruses to modulate the host immune response poses particular challenges for vaccine development but at the same time proves attractive for the application of human herpesvirus vaccines to certain spheres of medicine. In this review, congenital cytomegalovirus (CMV) infection and hearing loss will be described followed by a comment on the status of current vaccine development. Secondly, the association of Epstein–Barr virus (EBV) infection with multiple sclerosis (MS) and how EBV vaccination may be of benefit will then be discussed. Prevention of congenital CMV by vaccination is an attractive proposition and several vaccines have been evaluated for potential use. Particularly challenging for the development of CMV vaccines are the needs to prevent primary infection, reinfection, and reactivation at the same time as overcoming the capacity of the virus to generate highly sophisticated immunomodulatory mechanisms. Cost and the practicalities of administering potential vaccines are also significant issues, particularly for low- and middle-income countries, where the burden of disease is greatest. An effective EBV vaccine that could prevent the 200,000 new EBV-associated malignancies which occur globally each year is not currently available. There is increasing interest in developing EBV vaccines to prevent MS and, in view of the association of infectious mononucleosis with MS, reducing childhood infectious mononucleosis is a potential intervention. Currently, there is no licensed EBV vaccine and, in order to progress the development of EBV vaccines for preventing MS, a greater understanding of the association of EBV with MS is required.

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Long-term Outcomes of Patients With Human Herpesvirus 6 Encephalitis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz269 ◽

2019 ◽

Vol 6 (7) ◽

Cited By ~ 3

Author(s):

Madiha Fida ◽

Ahmed M Hamdi ◽

Alexandra Bryson ◽

Raymund R Razonable ◽

Omar Abu Saleh

Keyword(s):

Stem Cell ◽

Antiviral Treatment ◽

Human Herpesvirus ◽

Hematologic Malignancies ◽

Hippocampal Atrophy ◽

Human Herpesvirus 6 ◽

Long Term Outcomes ◽

Hematopoietic Stem ◽

Human Herpesviruses

Abstract Human herpesviruses 6 (HHV-6) A and B cause encephalitis in patients with hematologic malignancies, especially those undergoing allogeneic hematopoietic stem cell transplantation. In this cohort of 10 patients, persistent neurologic deficits associated with moderate to severe bilateral hippocampal atrophy were characteristic long-term findings, despite prolonged antiviral treatment.

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Inheritance of Chromosomally Integrated Human Herpesvirus 6 DNA

Blood ◽

10.1182/blood.v94.5.1545 ◽

1999 ◽

Vol 94 (5) ◽

pp. 1545-1549 ◽

Cited By ~ 129

Author(s):

Masanori Daibata ◽

Takahiro Taguchi ◽

Yuiko Nemoto ◽

Hirokuni Taguchi ◽

Isao Miyoshi

Keyword(s):

Dna Sequences ◽

Viral Genome ◽

Family Members ◽

Human Herpesvirus ◽

Single Step ◽

Human Herpesvirus 6 ◽

Viral Genomes ◽

Herpesvirus 6

Abstract Human herpesvirus 6 (HHV-6) genome has been detected in several human lymphoproliferative disorders with no signs of active viral infection, and found to be integrated into chromosomes in some cases. We previously reported a woman with HHV-6–infected Burkitt’s lymphoma. Fluorescence in situ hybridization showed that the viral genome was integrated into the long arm of chromosome 22 (22q13). The patient’s asymptomatic husband also carried HHV-6 DNA integrated at chromosome locus 1q44. To assess the possibility of chromosomal transmission of HHV-6 DNA, we looked for HHV-6 DNA in the peripheral blood of their daughter. She had HHV-6 DNA on both chromosomes 22q13 and 1q44, identical to the site of viral integration of her mother and father, respectively. The findings suggested that her viral genomes were inherited chromosomally from both parents. The 3 family members were all seropositive for HHV-6, but showed no serological signs of active infection. To confirm the presence of HHV-6 DNA sequences, we performed polymerase chain reaction (PCR) with 7 distinct primer pairs that target different regions of HHV-6. The viral sequences were consistently detected by single-step PCR in all 3 family members. We propose a novel latent form for HHV-6, in which integrated viral genome can be chromosomally transmitted. The possible role of the chromosomally integrated HHV-6 in the pathogenesis of lymphoproliferative diseases remains to be explained.

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