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Family Herpesviridae and neuroinfections: current status and research in progress

Vanessa Cristine de Souza Carneiro Jéssica Gonçalves Pereira Vanessa Salete de Paula About the authors

Abstract

This article addresses the relationship between human herpesviruses (HHVs) and neuroinfections. Alphaherpesviruses, betaherpesviruses and gammaherpesviruses are neurotropic viruses that establish latency and exhibit reactivation capacity. Encephalitis and meningitis are common in cases of HHV. The condition promoted by HHV infection is a purported trigger for certain neurodegenerative diseases. Ongoing studies have identified an association between HSV-1 and the occurrence of Alzheimer’s disease, multiple sclerosis and infections by HHV-6 and Epstein-Barr virus. In this review, we highlight the importance of research investigating the role of herpesviruses in the pathogenesis of diseases that affect the nervous system and describe other studies in progress.

Key words:
herpesvirus; neuroinfection; neurodegeneration


Neurological disorders are among the leading causes of global mortality. Although the aetiology of neuroinfections is unclear, recent studies have linked the onset of neurological disorders to herpesvirus infection, which can cause neurological symptoms or lead to immune responses that trigger pathological signs. Currently, this relationship is primarily based on epidemiological data regarding infections and the seroprevalence of patients with neurological disorders.

The Herpesviridae family comprises nine viruses that cause infections in humans and is divided into three subfamilies: Alphaherpesvirinae, Betaherpesvirinae and Gammaherpesvirinae [International Committee on Taxonomy of Viruses (ICTV 2021)]. These viruses are prevalent worldwide and cause various diseases, including cold sores, genital herpes, stromal keratitis, cancer, meningitis and encephalitis. All herpesviruses have two replication cycles: lytic and latent. Lytic replication produces particles to infect other cells and organisms, whereas latency has limited gene expression and absence of infectious particles. Herpesviruses establish latency at different sites (Table) and can cause disease during both primary infection and reactivation; however, the mechanisms leading to latency and reactivation and the viral and host factors controlling them remain unclear. Thus, we present the main clinical manifestations of each type of herpesvirus and demonstrate that, in addition to classical disorders such as encephalitis, other neurological manifestations have been associated with herpesviruses, such as multiple sclerosis (MS), epilepsy, schizophrenia and Alzheimer’s disease (AD).

TABLE
Family Herpesviridae and neuroinfections

Alphaherpesvirus Human alphaherpesvirus 1 and 2 Herpes simplex viruses (HSVs) 1 and 2

HSV, which belongs to the Alphaherpesvirinae subfamily, was first isolated in 1920 by Gruter;11. Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22. however, HSV categorisation into herpes simplex 1 (HSV-1) and herpes simplex 2 (HSV-2), based on epidemiological, clinical and immunological differences, was done only in 1968.22. Nahmias AJ, Dowdle WR. Antigenic and biologic differences in herpesvirus hominis. Prog Med Virol. 1968; 10: 110-59.) HSV has a double-stranded DNA genome, approximately 152 kb in HSV-1 and 155 kb in HSV-2.33. McGeoch DJ, Dalrymple MA, Davison AJ, Dolan A, Frame MC, McNab D, et al. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. J Gen Virol. 1988; 69 (Pt 7): 1531-74.,44. Dolan A, Jamieson FE, Cunningham C, Barnett BC, McGeoch DJ. The genome sequence of herpes simplex virus type 2. J Virol. 1998; 72(3): 2010-21.) In general, HSV-1 causes skin lesions in the orolabial region; however, it can also cause serious complications such as herpetic keratitis.55. Whitley R, Kimberlin DW, Prober CG. Pathogenesis and disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 589-601.) HSV-1 can also cause genital herpes, although this is a characteristic symptom of HSV-2 infection, with genital or anal blisters or ulcers.66. Grinde B. Herpesviruses: latency and reactivation - viral strategies and host response. J Oral Microbiol. 2013; 25; 5.

After infection and replication in epithelial cells, HSV migrates via retrograde axonal transport to the dorsal root ganglia, where it establishes latency in neurons and can cause neurological disorders.55. Whitley R, Kimberlin DW, Prober CG. Pathogenesis and disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 589-601.,77. Schelhaas M, Jansen M, Haase I, Knebel-Mörsdorf D. Herpes simplex virus type 1 exhibits a tropism for basal entry in polarized epithelial cells. J Gen Virol. 2003; 84(Pt 9): 2473-84.) After primary infection, immunological changes in the host organism can lead to HSV reactivation in which viral particles are transported to axon terminals in an anterograde fashion.88. Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci. 2019; 13: 46. Released viral particles promote the infection of new epithelial cells and can infect neurons and reach the central nervous system (CNS), triggering inflammatory responses driven by microglia. This persistent activation has harmful effects on neurons and contributes to neurological diseases.99. Waltl I, Kalinke U. Beneficial and detrimental functions of microglia during viral encephalitis. Trends Neurosci. 2022; 45(2): 158-70.

HSV is widely associated with neurological disorders, such as encephalitis, meningitis and meningoencephalitis,1010. Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, et al. Management of viral central nervous system infections: a primer for clinicians. J Cent Nerv Syst Dis. 2017; 9: 1179573517703342.) where immunosuppression by other etiological agents during the course of infection is one of the triggers for the reactivation of HSV-1 and HSV-2, worsening the prognosis.1111. Pagliano P, Ascione T, Carleo MA, Boccia G, De Caro F, Tortora F. HIV positive patient with HSV-2 encephalitis: case report. Infez Med. 2016; 24(3): 245-9.) In fact, a recent study observed the occurrence of HSV encephalitis in post-coronavirus disease (COVID) syndrome patients, possibly caused by reactivation during immune dysregulation in SARS-CoV-2 infection.1212. Gupta S, Dutta A, Chakraborty U, Kumar R, das D, Ray BK. Post-COVID-19 HSV encephalitis: a review. QJM. 2022; 115(4): 222-7.

Several studies have proposed an association between HSV-1 infection and neurodegenerative disease.88. Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci. 2019; 13: 46.,1313. Caggiu E, Paulus K, Galleri G, Arru G, Manetti R, Sechi GP, et al. Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease. J Neuroimmunol. 2017; 310: 26-31.) It is hypothesised that HSV-1 modulates neuronal apoptosis during acute and latent infection, which may be related to changes in neuronal processes, leading to neuronal damage and brain diseases.88. Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci. 2019; 13: 46.) An increasing number of studies support the involvement of HSV-1 in AD. Viral infection induces the accumulation of beta-amyloid proteins and phosphorylated tau protein, which are considered important components in AD progression.1414. Protto V, Marcocci ME, Miteva MT, Piacentini R, Li Puma DD, Grassi C, et al. Role of HSV-1 in Alzheimer's disease pathogenesis: a challenge for novel preventive/therapeutic strategies. Curr Opin Pharmacol. 2022; 63: 102200.

15. Powell-Doherty RD, Abbott ARN, Nelson LA, Bertke AS. Amyloid-ß and p-tau anti-threat response to herpes simplex virus 1 infection in primary adult murine hippocampal neurons. J Virol. 2020; 94(9): e01874-19.
-1616. Wozniak MA, Frost AL, Itzhaki RF. Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009; 16(2): 341-50.) Despite many questions that require clarification, these data indicate a strong link between HSV-1 and AD, warranting further investigation.

Human alphaherpesvirus 3 Varicella zoster virus (VZV)

VZV, isolated in 1952 by Thomas H. Weller in tissue culture, has a genome of 125 kb(17, 18) and infects epithelial cells of the upper respiratory mucosa, subsequently causing a vesicular eruption that is widely distributed throughout the body and varicella.1919. Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin. 2008; 26(3): 675-97. Similar to other alphaherpesviruses, it infects neurons during primary infection, reaching the ganglia by retrograde axonal transport where latency is established.2020. Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014; 12(3): 197-210.) Decline in immunity can reactivate VZV, causing herpes zoster and triggering complications such as neuropathic pain called post-herpetic neuralgia, resulting from neuron damage caused by the inflammatory response to the reactivation and migration of VZV.2121. Mallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology. J Multidiscip Healthc. 2016; 9: 447-54. Thus, similar to other herpesviruses, VZV also causes meningoencephalitis as a consequence of viral reactivation.2222. Khan R, Yasmeen A, Pandey AK, Al Saffar K, Narayanan SR. Cerebral venous thrombosis and acute pulmonary embolism following varicella infection. Eur J Case Rep Intern Med. 2019; 6(10): 001171. In addition, VZV penetrates the walls of cerebral arteries after reactivation in nerve ganglia and can cause vasculopathy via productive infection by the virus in the cerebral arteries, leading to ischemic stroke, aneurysm and cerebral venous thrombosis.2222. Khan R, Yasmeen A, Pandey AK, Al Saffar K, Narayanan SR. Cerebral venous thrombosis and acute pulmonary embolism following varicella infection. Eur J Case Rep Intern Med. 2019; 6(10): 001171.,2323. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016; 16(2): 12.) Studies have indicated that neuroinflammation and immunological changes triggered by some neurotropic viruses play an important role in neurodegeneration. Researchers have also aimed to identify a link between VZV infection and neurodegenerative diseases.2424. Qian L, Flood PM, Hong JS. Neuroinflammation is a key player in Parkinson's disease and a prime target for therapy. J Neural Transm (Vienna). 2010; 117(8): 971-9.,2525. Cheng CM, Bai YM, Tsai CF, Tsai SJ, Wu YH, Pan TL, et al. Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study. CNS Spectr. 2020; 25(6): 797-802.

Betaherpesviruses Human betaherpesvirus 5 Human cytomegalovirus (HCMV)

HCMV, first isolated in 1956,2626. Ho M. The history of cytomegalovirus and its diseases. Med Microbiol Immunol. 2008; 197(2): 65-73.) has the largest genome of any known human virus. Its genome is 236 kb in size and contains a double-stranded DNA molecule comprising two unique regions, each flanked by inverted repeats.2727. Dolan A, Cunningham C, Hector RD, Hassan-Walker AF, Lee L, Addison C, et al. Genetic content of wild-type human cytomegalovirus. J Gen Virol. 2004; 85(Pt 5): 1301-12. HCMV is a β-herpesvirus found at a frequency of 40-100% in the adult population worldwide.2828. Hyde TB, Schmid DS, Cannon MJ. Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol. 2010; 20(5): 311-26.) Being a herpesvirus, it establishes latency that can lead to periodic reactivation. Infections in healthy individuals are commonly asymptomatic;2929. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010; 50(11): 1439-47.) however, immunocompromised individuals can develop serious illnesses and even die because of HCMV infection.

Although the primary infection in immunocompetent adults is asymptomatic, viremia can persist for weeks or even months.3030. Zanghellini F, Boppana SB, Emery VC, Griffiths PD, Pass RF. Asymptomatic primary cytomegalovirus infection: virologic and immunologic features. J Infect Dis. 1999; 180(3): 702-7.) HCMV can infect most cells in the human body, and infection of the renal epithelial cells and salivary glands allows viral transmission through saliva and urine for months, thereby transmitting it to new hosts. When the host immune response fails, the HCMV may access the CNS through the “Trojan horse” system by infecting endothelial cells, monocytes or macrophages. Some studies have also suggested its propagation through cerebrospinal fluid (CSF).3131. Reinke P, Prösch S, Kern F, Volk HD. Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients. Transpl Infect Dis. 1999; 1(3): 157-64.

Tissue necrosis observed in the CNS is because of direct cytopathology mediated by HCMV as well as by cytotoxic cytokines, interleukins and tumour necrosis factor.3232. Maschke M, Kastrup O, Diener HC. CNS manifestations of cytomegalovirus infections: diagnosis and treatment. CNS Drugs. 2002; 16(5): 303-15.) Most pre- or immediately post-natal infections are characterised by increased viral replication, greater risk of persistence and, consequently, more severe conditions than those associated with infections acquired at an older age.3333. Prendergast AJ, Klenerman P, Goulder PJ. The impact of differential antiviral immunity in children and adults. Nat Rev Immunol. 2012; 12(9): 636-48.) HCMV is the leading cause of congenital viral infections, the most common non-genetic cause of hearing loss and a major cause of neurodevelopmental delay. It affects 0.2-2% of all newborns worldwide.3434. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007; 17(4): 253-76.) Approximately 10-15% of children with congenital HCMV are symptomatic at birth. The infection presents with various symptoms, such as intrauterine growth retardation, hepatosplenomegaly, jaundice and neurodevelopmental deficits.3535. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005; 16(1): 44-9.

In adults, HCMV encephalitis presents with several neurological symptoms, most of which occur in human immunodeficiency virus (HIV)-infected and immunosuppressed patients.3636. Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med. 1996; 125(7): 577-87. It has an observable affinity with the limbic system, an area known to be affected in schizophrenia, and is a chronic neuropsychiatric disorder characterised by abnormalities involving brain structure and function.3737. Torrey EF, Peterson MR. Schizophrenia and the limbic system. Lancet. 1974; 2(7886): 942-6.

An immunocompetent patient who presented with auditory hallucinations, delusions, tangential thinking and flattened affect was initially diagnosed with schizophrenia until a post-mortem analysis based on neuropathological findings and CSF antibody levels indicated HCMV encephalitis.3838. Torrey EF. Functional psychoses and viral encephalitis. Integr Psychiatry, 1986; 4(4): 224-30.) An association with a sensorimotor control deficit has been identified in rodent models infected with HCMV, similar to that reported in individuals with schizophrenia.3939. Rothschild DM, O'Grady M, Wecker L. Neonatal cytomegalovirus exposure decreases prepulse inhibition in adult rats: implications for schizophrenia. J Neurosci Res. 1999; 57(4): 429-34.

Based on the literature, neuropathogenesis in individuals infected with HCMV is unclear because of the lack of an adequate experimental models and lack of dedicated research.

Human betaherpesvirus 6 Human herpesvirus 6 (HHV-6A/B)

HHV-6 was first isolated in 1986 by Salahuddin et al. (4040. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986; 234(4776): 596-601.) in patients with lymphoproliferative diseases or acquired immunodeficiency syndrome. Subsequent studies suggested the existence of two variants of HHV-6, variant A or HHV-6A, initially isolated by Salahuddin et al.,4040. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986; 234(4776): 596-601. and variant B or HHV-6B, which was isolated from peripheral blood lymphocytes of patients with sudden rash by Yamanishi et al.4141. Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988; 1(8594): 1065-7.) The IVTV has recognised HHV-6 variants as two distinct viruses: HHV-6A, having a higher level of virulence and considered the most cytolytic, and HHV-6B, the causative agent of exanthema subitum, present in infantile roseola (an acute childhood disease that characteristically presents with a high fever followed by a generalised rash).4242. Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. 2014; 159(5): 863-70. However, the term HHV-6 remains in use to collectively refer to both species. Although the genomes of the two viruses share 90% global identity, the size of the HHV-6A genome is 159 kb, whereas that of HHV-6B is 162 kb.4343. Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol. 1999; 73(10): 8040-52.,4444. Arbuckle JH, Medveczky PG. The molecular biology of human herpesvirus-6 latency and telomere integration. Microbes Infect. 2011; 13(8-9): 731-41.) HHV-6B was designated as a human B lymphotropic virus because it has tropism for B cells.4040. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986; 234(4776): 596-601. HHV-6 is pleiotropic, replicates well in CD4+ T lymphocytes and can proliferate in macrophages, fibroblasts and other cells.4545. Wells MJ, Jacobson S, Levine PH. An evaluation of HHV-6 as an etiologic agent in Hodgkin lymphoma and brain cancer using IARC criteria for oncogenicity. Infect Agent Cancer. 2019; 14(1): 31.

HHV-6B infection is very common in children between the ages of 2 and 3 years.4646. Rebello AS, Carvalho MGC, Rebello MCS, Fischer J, Carvalho PC, Carvalho JFO. Molecular detection of simultaneous reactivation of VZV and HSV in a patient with a clinical history of roseola infantum J Bras Patol Med Lab. 2003; 39(3): 207-9.) It is transmitted horizontally via saliva, as the salivary glands function as a valuable reservoir for this virus.4747. Santos MPM, Morais MPLA, Fonseca DDD, Faria ABS, Silva IHM, Carvalho AAT, et al. Human herpes virus: types, oral manifestations and treatment. Odontol Clin-Cient. 11(3): 191-6.) However, the common latency site for HHV-6A and HHV-6B is the monocyte/macrophage cell population.4848. Kondo K, Kondo T, Okuno T, Takahashi M, Yamanishi K. Latent human herpesvirus 6 infection of human monocytes/macrophages. J Gen Virol. 1991; 72(Pt 6): 1401-8.) HHV-6A and HHV-6B can also infect the CNS and cause neurological disorders.4949. Agut H, Bonnafous P, Gautheret-Dejean A. Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev. 2015; 28(2): 313-35.

Studies have reported that 95% of adults are seropositive for HHV-6. Other manifestations related to primary HHV-6 infection have already been investigated, and current research is focused on its neurotropic properties, suggesting a possible link with encephalitis, seizure disorders, AD and MS.4545. Wells MJ, Jacobson S, Levine PH. An evaluation of HHV-6 as an etiologic agent in Hodgkin lymphoma and brain cancer using IARC criteria for oncogenicity. Infect Agent Cancer. 2019; 14(1): 31.

Active or latent infection by HHV-6 in immune and glial cells can alter the sensitive balance between demyelination and remyelination, a process that defines the progression of MS. Although HHV-6 infection alone cannot trigger the onset of MS, it can worsen the inflammatory state of the CNS and exacerbate demyelination in these patients.5050. Hogestyn JM, Mock DJ, Mayer-Proschel M. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural Regen Res. 2018; 13(2): 211-21. The possible role of latent HHV-6 infection has also been considered, for no studies have reported evidence of active replication of viral particles in demyelinating MS lesions.5151. Opsahl ML, Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain. 2005; 128(Pt 3): 516-27.) Moreover, permeabilisation of the blood-brain barrier (BBB) may facilitate the entry of HHV-6 into the CNS, as it has high tropism for activated CD4+ T lymphocytes.5050. Hogestyn JM, Mock DJ, Mayer-Proschel M. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural Regen Res. 2018; 13(2): 211-21.

HHV-6 has also been associated with acute seizures and epilepsy in children.5252. Bartolini L, Piras E, Sullivan K, Gillen S, Bumbut A, Lin CM, et al. Detection of HHV-6 and EBV and cytokine levels in saliva from children with seizures: results of a multi-center cross-sectional study. Front Neurol. 2018; 9: 834.,5353. Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S. Human herpes virus 6B: a possible role in epilepsy? Epilepsia. 2008; 49(11): 1828-37.) Symptoms described in the context of primary infection and reactivation include febrile seizures, acute symptomatic seizures following encephalitis, status epilepticus and temporal lobe epilepsy.5454. Bartolini L, Theodore WH, Jacobson S, Gaillard WD. Infection with HHV-6 and its role in epilepsy. Epilepsy Res. 2019; 153: 34-9. A significant moderately positive correlation was identified between A delta and C nerve fibre damage severity and HHV-6 infection in fibromyalgia, which is a disease in which patients experience chronic pain.5555. Krumina A, Chapenko S, Kenina V, Mihailova M, Logina I, Rasa S, et al. The role of HHV-6 and HHV-7 infections in the development of fibromyalgia. J Neurovirol. 2019; 25(2): 194-207.) Owing to the high frequency of HHV-6 infection in the population, further investigations are essential.

The high degree of homology between HHV-6A and HHV-6B hinders the investigation of these viruses separately. However, primary HHV-6B infection results in roseola, whereas information concerning the clinical manifestations of primary HHV-6A infection is limited.5656. Engdahl E, Gustafsson R, Huang J, Biström M, Lima Bomfim I, Stridh P, et al. Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. Front Immunol. 2019; 10: 2715.) Although both viruses are neurotropic and cause neurological disorders such as encephalitis, studies have reported that HHV-6A exhibits greater neurovirulence.5757. Hall CB, Caserta MT, Schnabel KC, Long C, Epstein LG, Insel RA, et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis. 1998; 26(1): 132-7.,5858. Crawford JR, Kadom N, Santi MR, Mariani B, Lavenstein BL. Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol. 2007; 22(11): 1260-8. The roles of HHV-6A and HHV-6B have been investigated in the pathogenesis of MS; however, studies have reported a higher prevalence of HHV-6A in patients with MS.5959. Leibovitch EC, Brunetto GS, Caruso B, Fenton K, Ohayon J, Reich DS, et al. Coinfection of human herpesviruses 6A (HHV-6A) and HHV-6B as demonstrated by novel digital droplet PCR assay. PLoS One. 2014; 9(3): e92328.

Human betaherpesvirus 7 Human herpesvirus 7 (HHV-7)

HHV-7, first isolated in 1990,6060. Frenkel N, Schirmer EC, Wyatt LS, Katsafanas G, Roffman E, Danovich RM, et al. Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci USA. 1990; 87(2): 748-52.) is closely related to HHV-6 and also has a double-stranded DNA genome of approximately 144 kb.6161. Megaw AG, Rapaport D, Avidor B, Frenkel N, Davison AJ. The DNA sequence of the RK strain of human herpesvirus 7. Virology. 1998; 244(1): 119-32.) On comparison, we observed that HHV-6 is the most described and investigated in the literature, which justifies the need for further investigations regarding HHV-7.

HHV-7 infects CD4+ T lymphocytes and, less frequently, CD8+ and immature T cells.6262. Berneman ZN, Ablashi DV, Li G, Eger-Fletcher M, Reitz Junior MS, Hung CL, et al. Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus. Proc Natl Acad Sci USA. 1992; 89(21): 10552-6.) Similar to other herpesviruses, it becomes established in the host after primary infection for prolonged periods, alternating between latent and lytic phases.6363. Foiadelli T, Rossi V, Paolucci S, Rovida F, Novazzi F, Orsini A, et al. Human herpes virus 7-related encephalopathy in children. Acta Biomed. 2022; 92(S4): e2021415. However, the site of latency remains unclear.6060. Frenkel N, Schirmer EC, Wyatt LS, Katsafanas G, Roffman E, Danovich RM, et al. Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci USA. 1990; 87(2): 748-52. HHV-7 is ubiquitous and primary infection occurs primarily during infancy between the ages of 1 and 3 years, slightly later than HHV-6. By the age of 5 years, approximately 90% of the population is infected with HHV-7.6464. Huang LM, Lee CY, Liu MY, Lee PI. Primary infections of human herpesvirus-7 and herpesvirus-6: a comparative, longitudinal study up to 6 years of age. Acta Paediatr. 1997; 86(6): 604-8.) HHV-7 infection has different clinical presentations in children, similar to HHV-6, such as exanthema subitum, fever without exanthema, febrile convulsions and status epilepticus6565. Torigoe S, Koide W, Yamada M, Miyashiro E, Tanaka-Taya K, Yamanishi K. Human herpesvirus 7 infection associated with central nervous system manifestations. J Pediatr. 1996; 129(2): 301-5.. Till date, available data support a possible association between HHV-7 and epilepsy.6666. Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, Benn EK, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012; 53(9): 1481-8.) Recent evidence has suggested that inflammation plays a role in epileptogenesis.6767. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011; 7(1): 31-40.

Information regarding how HHV-7 crosses the BBB and causes invasion of the CNS is scarce.6868. Chapenko S, Roga S, Skuja S, Rasa S, Cistjakovs M, Svirskis S, et al. Detection frequency of human herpesviruses-6A, -6B, and -7 genomic sequences in central nervous system DNA samples from post-mortem individuals with unspecified encephalopathy. J Neurovirol. 2016; 22(4): 488-97. Recently, a small number cases of HHV-7-related encephalitis or encephalopathy have been described in children, adults and immunocompetent or immunocompromised patients.6969. Ongrádi J, Ablashi DV, Yoshikawa T, Stercz B, Ogata M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol. 2017; 23(1): 1-19. The clinical presentation of CNS involvement may be excessively heterogeneous to distinguish it from other neurological disorders, including fever, seizures, encephalitis, meningoencephalitis, facial palsy, vestibular neuritis, severe headache, drowsiness, fatigue, nausea, vomiting, photosensitivity, ataxia and coma.6969. Ongrádi J, Ablashi DV, Yoshikawa T, Stercz B, Ogata M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol. 2017; 23(1): 1-19.

Gammaherpesviruses Human gammaherpesvirus 4 Epstein-Barr virus (EBV)

EBV is a gammaherpesvirus with a DNA genome of approximately 170 kb.7070. Kwok H, Tong AH, Lin CH, Lok S, Farrell PJ, Kwong DL, et al. Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. PLoS One. 2012; 7(5): e36939.) It was identified in 1964 by Michael Anthony Epstein in isolates from patients with Burkitt lymphoma.7171. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964; 1(7335): 702-3. EBV infection in adults leads to infectious mononucleosis; however, it can also be associated with other complications, in addition to being associated with malignancies.7272. Soldan SS, Lieberman PM. Epstein-Barr virus infection in the development of neurological disorders. Drug Discov Today Dis Models. 2020; 32(Pt A): 35-52.) EBV infects epithelial and memory B cells, where it establishes latency,7373. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004; 4(10): 757-68.) and can replicate in the CNS and disrupt the integrity of the BBB.7474. Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr virus and neurological diseases. Front Mol Biosci. 2022; 8: 816098. EBV infection is associated with neurological disorders, such as meningitis, encephalitis, myelitis, psychoses and ‘’Alice in Wonderland’’ syndrome, among others, which can affect even immunocompetent individuals both during primary infection and during reactivation.7272. Soldan SS, Lieberman PM. Epstein-Barr virus infection in the development of neurological disorders. Drug Discov Today Dis Models. 2020; 32(Pt A): 35-52.,7575. Huang L, Zhang X, Fang X. Case Report: Epstein-Barr virus encephalitis complicated with brain stem hemorrhage in an immune-competent adult. Front Immunol. 2021; 12: 618830.,7676. Häusler M, Ramaekers VT, Doenges M, Schweizer K, Ritter K, Schaade L. Neurological complications of acute and persistent Epstein-Barr virus infection in paediatric patients. J Med Virol. 2002; 68(2): 253-63.) Some studies have indicated an association between EBV infection and neurodegenerative diseases, and strong evidence suggests a role of EBV infection in the pathogenesis of MS.7474. Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr virus and neurological diseases. Front Mol Biosci. 2022; 8: 816098.) MS is an immune-mediated disease characterised by permanent inflammation of the CNS, causing loss of neural tissue. Hence, viral infection may be a crucial factor in the development and progression of MS. Several researchers have theorised that EBV may contribute to the spread of inflammation and injury in the CNS, triggering an immune response that is important in the pathogenesis of MS.7777. Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, et al. Epstein-Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol Med. 2020; 26(3): 296-310.) A longitudinal study has revealed the risk of MS after EBV infection in addition to the increased concentrations of the neurofilament light chain, a biomarker of neurodegeneration, after EBV infection.7878. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375(6578): 296-301.) These data indicate the important role of EBV infection in the pathogenesis of MS.

Research in “long COVID” patients has identified EBV reactivation, suggesting that its symptoms, including neurological manifestations, may be the result of EBV reactivation induced by SARS-CoV-2 infection.7979. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. 2021; 10(6): 763. Studies such as this emphasise the importance of investigating herpesvirus infections in the context of COVID-19.

Human gammaherpesvirus 8 Human herpesvirus 8 (HHV-8)

HHV-8 was identified in 1994 by Yuan Chang8080. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266(5192): 1865-9.) as the causative agent of Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Subsequent studies have strongly associated this herpesvirus with other pathologies such as primary effusion lymphoma and multicentric Castleman disease in immunodeficient individuals; however, HHV-8 can also affect immunocompetent individuals.8181. Lopes AO, Marinho PDN, Medeiros LDS, de Paula VS. Human gammaherpesvirus 8 oncogenes associated with Kaposi's sarcoma. Int J Mol Sci. 2022; 23(13): 7203.) HHV-8 contains a double-stranded DNA genome of approximately 140 kb.8282. Lopes AO, Spitz N, Reis CRS, de Paula VS. Update of the global distribution of human gammaherpesvirus 8 genotypes. Sci Rep. 2021; 11(1): 7640.) It exhibits tropism for endothelial, epithelial and lymphocyte cells and establishes latency in B lymphocytes.8383. Tso FY, Sawyer A, Kwon EH, Mudenda V, Langford D, Zhou Y, et al. Kaposi's sarcoma-associated herpesvirus infection of neurons in HIV-positive patients. J Infect Dis. 2017; 215(12): 1898-907.,8484. Dittmer DP, Damania B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016; 126(9): 3165-75.) To date, knowledge regarding the ability of HHV-8 to infect neural cells and cause neurological disorders is limited. However, research has demonstrated the ability of HHV-8 to infect neural cells and act as a reservoir for latent infection.8383. Tso FY, Sawyer A, Kwon EH, Mudenda V, Langford D, Zhou Y, et al. Kaposi's sarcoma-associated herpesvirus infection of neurons in HIV-positive patients. J Infect Dis. 2017; 215(12): 1898-907.,8585. Kong X, Li D, Mansouri A, Kang G, Sayood K, West J, et al. Bone marrow-derived SH-SY5Y neuroblastoma cells infected with Kaposi's sarcoma-associated herpesvirus display unique infection phenotypes and growth properties. J Virol. 2021; 95(13): e0000321.) Studies have investigated the association between neurological disorders and HHV-8 infection, including amyotrophic lateral sclerosis and MS.8686. Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P, et al. Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. Eur J Epidemiol. 2003; 18(2): 123-7.,8787. Merelli E, Bedin R, Sola P, Barozzi P, Mancardi GL, Ficarra G, et al. Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol. 1997; 244(7): 450-4. Although the detection of HHV-8 DNA in brain tissues of MS patients indicates neurotropism, a possible association between HHV-8 infection and MS pathogenesis needs to be further investigated.8787. Merelli E, Bedin R, Sola P, Barozzi P, Mancardi GL, Ficarra G, et al. Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol. 1997; 244(7): 450-4.) These findings provide novel insights into the association of HHV-8 with neuronal diseases and require further clarification.

Herpesvirus in the context of neuronal disorders

Herpesviruses have been strongly associated with neurological disorders, with meningitis and encephalitis being triggered by all HHVs except HHV-8.1010. Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, et al. Management of viral central nervous system infections: a primer for clinicians. J Cent Nerv Syst Dis. 2017; 9: 1179573517703342.,4949. Agut H, Bonnafous P, Gautheret-Dejean A. Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev. 2015; 28(2): 313-35.,6969. Ongrádi J, Ablashi DV, Yoshikawa T, Stercz B, Ogata M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol. 2017; 23(1): 1-19.) HCMV is associated with neurodevelopmental deficits and schizophrenia.3838. Torrey EF. Functional psychoses and viral encephalitis. Integr Psychiatry, 1986; 4(4): 224-30.,3939. Rothschild DM, O'Grady M, Wecker L. Neonatal cytomegalovirus exposure decreases prepulse inhibition in adult rats: implications for schizophrenia. J Neurosci Res. 1999; 57(4): 429-34. VZV has been implicated in cases of vasculopathy leading to ischemic stroke, aneurysm and cerebral venous thrombosis.2222. Khan R, Yasmeen A, Pandey AK, Al Saffar K, Narayanan SR. Cerebral venous thrombosis and acute pulmonary embolism following varicella infection. Eur J Case Rep Intern Med. 2019; 6(10): 001171.,2323. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016; 16(2): 12. EBV has been related to psychosis and distortion of perception, such as the Alice in Wonderland syndrome.7272. Soldan SS, Lieberman PM. Epstein-Barr virus infection in the development of neurological disorders. Drug Discov Today Dis Models. 2020; 32(Pt A): 35-52.,7575. Huang L, Zhang X, Fang X. Case Report: Epstein-Barr virus encephalitis complicated with brain stem hemorrhage in an immune-competent adult. Front Immunol. 2021; 12: 618830.,7676. Häusler M, Ramaekers VT, Doenges M, Schweizer K, Ritter K, Schaade L. Neurological complications of acute and persistent Epstein-Barr virus infection in paediatric patients. J Med Virol. 2002; 68(2): 253-63. HHV-6 and HHV-7 are considered as possible causes of epilepsy.5353. Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S. Human herpes virus 6B: a possible role in epilepsy? Epilepsia. 2008; 49(11): 1828-37.,5454. Bartolini L, Theodore WH, Jacobson S, Gaillard WD. Infection with HHV-6 and its role in epilepsy. Epilepsy Res. 2019; 153: 34-9.,6666. Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, Benn EK, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012; 53(9): 1481-8.) Although HHV-8 is not known to be associated with neurological diseases, several studies have indicated such a relationship; future research may elucidate new findings regarding this association.8585. Kong X, Li D, Mansouri A, Kang G, Sayood K, West J, et al. Bone marrow-derived SH-SY5Y neuroblastoma cells infected with Kaposi's sarcoma-associated herpesvirus display unique infection phenotypes and growth properties. J Virol. 2021; 95(13): e0000321. Ongoing studies surrounding the relationship between herpesvirus infection in neurodegenerative diseases are worth mentioning, such as the association between AD and HVS and the relationship between MS and EBV and HHV-6 infection (Table).1515. Powell-Doherty RD, Abbott ARN, Nelson LA, Bertke AS. Amyloid-ß and p-tau anti-threat response to herpes simplex virus 1 infection in primary adult murine hippocampal neurons. J Virol. 2020; 94(9): e01874-19.,5050. Hogestyn JM, Mock DJ, Mayer-Proschel M. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural Regen Res. 2018; 13(2): 211-21.,5151. Opsahl ML, Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain. 2005; 128(Pt 3): 516-27.,7878. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375(6578): 296-301. In recent years, some studies have investigated a possible association between alpha herpesvirus infections and Parkinson’s disease.1313. Caggiu E, Paulus K, Galleri G, Arru G, Manetti R, Sechi GP, et al. Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease. J Neuroimmunol. 2017; 310: 26-31.,2525. Cheng CM, Bai YM, Tsai CF, Tsai SJ, Wu YH, Pan TL, et al. Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study. CNS Spectr. 2020; 25(6): 797-802.

Nonetheless, several issues need to be clarified, ranging from stresses that can induce recurrent virus reactivation to viral particles produced after reactivation that can reach the CNS, causing diffuse acute infection and/or neurological manifestations. Recently, the reactivation viral has been correlated with the production and accumulation of neuropathological biomarkers of AD.8888. Marcocci ME, Napoletani G, Protto V, Kolesova O, Piacentini R, Li Puma DD, et al. Herpes simplex virus-1 in the brain: the dark side of a sneaky infection. Trends Microbiol. 2020; 28(10): 808-20. The different cellular and molecular mechanisms underlying the acute and long-term damage caused by herpesvirus infection in the CNS should be investigated to bridge these gaps in knowledge.

It is worth noting that although herpesviruses are highly prevalent and are latently present in all infected individuals, not everyone will experience reactivation or develop neurological manifestations. The fact that certain individuals are more likely than others to develop serious diseases and neurological manifestations after herpes infection can be partially explained by the existence of genetic polymorphisms in humans and the intrinsic, innate and adaptive immune responses that are fundamental for controlling diseases and infections caused by herpesviruses.8989. Zhu S, Viejo-Borbolla A. Pathogenesis and virulence of herpes simplex virus. Virulence. 2021; 12(1): 2670-702.

Although the number of studies exploring the mechanisms of action by which viral infections can directly or indirectly contribute to the development of neurological disorders has increased over the years, these studies remain insufficient.9090. Wouk J, Rechenchoski DZ, Rodrigues BCD, Ribelato EV, Faccin-Galhardi LC. Viral infections and their relationship to neurological disorders. Arch Virol. 2021; 166(3): 733-53.

With the advancement in technologies and tools for the investigation of virological, genetic and immunological factors, several knowledge gaps can be addressed.

To summarise, understanding the pathogenesis of these diseases and exploring new theories may facilitate the development of new diagnostic and therapeutic strategies. Reviewing and updating evidence regarding the relationship between viral infection and neurological disorders are essential to confirm the hypotheses and potential of herpesviruses as triggering agents of neurological disorders.

ACKNOWLEDGEMENTS

To Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fundação Oswaldo Cruz and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

REFERENCES

  • 1
    Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22.
  • 2
    Nahmias AJ, Dowdle WR. Antigenic and biologic differences in herpesvirus hominis. Prog Med Virol. 1968; 10: 110-59.
  • 3
    McGeoch DJ, Dalrymple MA, Davison AJ, Dolan A, Frame MC, McNab D, et al. The complete DNA sequence of the long unique region in the genome of herpes simplex virus type 1. J Gen Virol. 1988; 69 (Pt 7): 1531-74.
  • 4
    Dolan A, Jamieson FE, Cunningham C, Barnett BC, McGeoch DJ. The genome sequence of herpes simplex virus type 2. J Virol. 1998; 72(3): 2010-21.
  • 5
    Whitley R, Kimberlin DW, Prober CG. Pathogenesis and disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, Yamanishi K, editors. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 589-601.
  • 6
    Grinde B. Herpesviruses: latency and reactivation - viral strategies and host response. J Oral Microbiol. 2013; 25; 5.
  • 7
    Schelhaas M, Jansen M, Haase I, Knebel-Mörsdorf D. Herpes simplex virus type 1 exhibits a tropism for basal entry in polarized epithelial cells. J Gen Virol. 2003; 84(Pt 9): 2473-84.
  • 8
    Duarte LF, Farías MA, Álvarez DM, Bueno SM, Riedel CA, González PA. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci. 2019; 13: 46.
  • 9
    Waltl I, Kalinke U. Beneficial and detrimental functions of microglia during viral encephalitis. Trends Neurosci. 2022; 45(2): 158-70.
  • 10
    Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, et al. Management of viral central nervous system infections: a primer for clinicians. J Cent Nerv Syst Dis. 2017; 9: 1179573517703342.
  • 11
    Pagliano P, Ascione T, Carleo MA, Boccia G, De Caro F, Tortora F. HIV positive patient with HSV-2 encephalitis: case report. Infez Med. 2016; 24(3): 245-9.
  • 12
    Gupta S, Dutta A, Chakraborty U, Kumar R, das D, Ray BK. Post-COVID-19 HSV encephalitis: a review. QJM. 2022; 115(4): 222-7.
  • 13
    Caggiu E, Paulus K, Galleri G, Arru G, Manetti R, Sechi GP, et al. Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease. J Neuroimmunol. 2017; 310: 26-31.
  • 14
    Protto V, Marcocci ME, Miteva MT, Piacentini R, Li Puma DD, Grassi C, et al. Role of HSV-1 in Alzheimer's disease pathogenesis: a challenge for novel preventive/therapeutic strategies. Curr Opin Pharmacol. 2022; 63: 102200.
  • 15
    Powell-Doherty RD, Abbott ARN, Nelson LA, Bertke AS. Amyloid-ß and p-tau anti-threat response to herpes simplex virus 1 infection in primary adult murine hippocampal neurons. J Virol. 2020; 94(9): e01874-19.
  • 16
    Wozniak MA, Frost AL, Itzhaki RF. Alzheimer's disease-specific tau phosphorylation is induced by herpes simplex virus type 1. J Alzheimers Dis. 2009; 16(2): 341-50.
  • 17
    Weller TH, Stoddard MB. Intranuclear inclusion bodies in cultures of human tissue inoculated with varicella vesicle fluid. J Immunol. 1952; 68(3): 311-9.
  • 18
    Straus SE, Owens J, Ruyechan WT, Takiff HE, Casey TA, Vande Woude GF, et al. Molecular cloning and physical mapping of varicella-zoster virus DNA. Proc Natl Acad Sci USA. 1982; 79(4): 993-7.
  • 19
    Mueller NH, Gilden DH, Cohrs RJ, Mahalingam R, Nagel MA. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin. 2008; 26(3): 675-97.
  • 20
    Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014; 12(3): 197-210.
  • 21
    Mallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology. J Multidiscip Healthc. 2016; 9: 447-54.
  • 22
    Khan R, Yasmeen A, Pandey AK, Al Saffar K, Narayanan SR. Cerebral venous thrombosis and acute pulmonary embolism following varicella infection. Eur J Case Rep Intern Med. 2019; 6(10): 001171.
  • 23
    Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016; 16(2): 12.
  • 24
    Qian L, Flood PM, Hong JS. Neuroinflammation is a key player in Parkinson's disease and a prime target for therapy. J Neural Transm (Vienna). 2010; 117(8): 971-9.
  • 25
    Cheng CM, Bai YM, Tsai CF, Tsai SJ, Wu YH, Pan TL, et al. Risk of Parkinson's disease among patients with herpes zoster: a nationwide longitudinal study. CNS Spectr. 2020; 25(6): 797-802.
  • 26
    Ho M. The history of cytomegalovirus and its diseases. Med Microbiol Immunol. 2008; 197(2): 65-73.
  • 27
    Dolan A, Cunningham C, Hector RD, Hassan-Walker AF, Lee L, Addison C, et al. Genetic content of wild-type human cytomegalovirus. J Gen Virol. 2004; 85(Pt 5): 1301-12.
  • 28
    Hyde TB, Schmid DS, Cannon MJ. Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol. 2010; 20(5): 311-26.
  • 29
    Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. 2010; 50(11): 1439-47.
  • 30
    Zanghellini F, Boppana SB, Emery VC, Griffiths PD, Pass RF. Asymptomatic primary cytomegalovirus infection: virologic and immunologic features. J Infect Dis. 1999; 180(3): 702-7.
  • 31
    Reinke P, Prösch S, Kern F, Volk HD. Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients. Transpl Infect Dis. 1999; 1(3): 157-64.
  • 32
    Maschke M, Kastrup O, Diener HC. CNS manifestations of cytomegalovirus infections: diagnosis and treatment. CNS Drugs. 2002; 16(5): 303-15.
  • 33
    Prendergast AJ, Klenerman P, Goulder PJ. The impact of differential antiviral immunity in children and adults. Nat Rev Immunol. 2012; 12(9): 636-48.
  • 34
    Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007; 17(4): 253-76.
  • 35
    Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005; 16(1): 44-9.
  • 36
    Arribas JR, Storch GA, Clifford DB, Tselis AC. Cytomegalovirus encephalitis. Ann Intern Med. 1996; 125(7): 577-87.
  • 37
    Torrey EF, Peterson MR. Schizophrenia and the limbic system. Lancet. 1974; 2(7886): 942-6.
  • 38
    Torrey EF. Functional psychoses and viral encephalitis. Integr Psychiatry, 1986; 4(4): 224-30.
  • 39
    Rothschild DM, O'Grady M, Wecker L. Neonatal cytomegalovirus exposure decreases prepulse inhibition in adult rats: implications for schizophrenia. J Neurosci Res. 1999; 57(4): 429-34.
  • 40
    Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986; 234(4776): 596-601.
  • 41
    Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988; 1(8594): 1065-7.
  • 42
    Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol. 2014; 159(5): 863-70.
  • 43
    Dominguez G, Dambaugh TR, Stamey FR, Dewhurst S, Inoue N, Pellett PE. Human herpesvirus 6B genome sequence: coding content and comparison with human herpesvirus 6A. J Virol. 1999; 73(10): 8040-52.
  • 44
    Arbuckle JH, Medveczky PG. The molecular biology of human herpesvirus-6 latency and telomere integration. Microbes Infect. 2011; 13(8-9): 731-41.
  • 45
    Wells MJ, Jacobson S, Levine PH. An evaluation of HHV-6 as an etiologic agent in Hodgkin lymphoma and brain cancer using IARC criteria for oncogenicity. Infect Agent Cancer. 2019; 14(1): 31.
  • 46
    Rebello AS, Carvalho MGC, Rebello MCS, Fischer J, Carvalho PC, Carvalho JFO. Molecular detection of simultaneous reactivation of VZV and HSV in a patient with a clinical history of roseola infantum J Bras Patol Med Lab. 2003; 39(3): 207-9.
  • 47
    Santos MPM, Morais MPLA, Fonseca DDD, Faria ABS, Silva IHM, Carvalho AAT, et al. Human herpes virus: types, oral manifestations and treatment. Odontol Clin-Cient. 11(3): 191-6.
  • 48
    Kondo K, Kondo T, Okuno T, Takahashi M, Yamanishi K. Latent human herpesvirus 6 infection of human monocytes/macrophages. J Gen Virol. 1991; 72(Pt 6): 1401-8.
  • 49
    Agut H, Bonnafous P, Gautheret-Dejean A. Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev. 2015; 28(2): 313-35.
  • 50
    Hogestyn JM, Mock DJ, Mayer-Proschel M. Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology. Neural Regen Res. 2018; 13(2): 211-21.
  • 51
    Opsahl ML, Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain. 2005; 128(Pt 3): 516-27.
  • 52
    Bartolini L, Piras E, Sullivan K, Gillen S, Bumbut A, Lin CM, et al. Detection of HHV-6 and EBV and cytokine levels in saliva from children with seizures: results of a multi-center cross-sectional study. Front Neurol. 2018; 9: 834.
  • 53
    Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S. Human herpes virus 6B: a possible role in epilepsy? Epilepsia. 2008; 49(11): 1828-37.
  • 54
    Bartolini L, Theodore WH, Jacobson S, Gaillard WD. Infection with HHV-6 and its role in epilepsy. Epilepsy Res. 2019; 153: 34-9.
  • 55
    Krumina A, Chapenko S, Kenina V, Mihailova M, Logina I, Rasa S, et al. The role of HHV-6 and HHV-7 infections in the development of fibromyalgia. J Neurovirol. 2019; 25(2): 194-207.
  • 56
    Engdahl E, Gustafsson R, Huang J, Biström M, Lima Bomfim I, Stridh P, et al. Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. Front Immunol. 2019; 10: 2715.
  • 57
    Hall CB, Caserta MT, Schnabel KC, Long C, Epstein LG, Insel RA, et al. Persistence of human herpesvirus 6 according to site and variant: possible greater neurotropism of variant A. Clin Infect Dis. 1998; 26(1): 132-7.
  • 58
    Crawford JR, Kadom N, Santi MR, Mariani B, Lavenstein BL. Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol. 2007; 22(11): 1260-8.
  • 59
    Leibovitch EC, Brunetto GS, Caruso B, Fenton K, Ohayon J, Reich DS, et al. Coinfection of human herpesviruses 6A (HHV-6A) and HHV-6B as demonstrated by novel digital droplet PCR assay. PLoS One. 2014; 9(3): e92328.
  • 60
    Frenkel N, Schirmer EC, Wyatt LS, Katsafanas G, Roffman E, Danovich RM, et al. Isolation of a new herpesvirus from human CD4+ T cells. Proc Natl Acad Sci USA. 1990; 87(2): 748-52.
  • 61
    Megaw AG, Rapaport D, Avidor B, Frenkel N, Davison AJ. The DNA sequence of the RK strain of human herpesvirus 7. Virology. 1998; 244(1): 119-32.
  • 62
    Berneman ZN, Ablashi DV, Li G, Eger-Fletcher M, Reitz Junior MS, Hung CL, et al. Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus. Proc Natl Acad Sci USA. 1992; 89(21): 10552-6.
  • 63
    Foiadelli T, Rossi V, Paolucci S, Rovida F, Novazzi F, Orsini A, et al. Human herpes virus 7-related encephalopathy in children. Acta Biomed. 2022; 92(S4): e2021415.
  • 64
    Huang LM, Lee CY, Liu MY, Lee PI. Primary infections of human herpesvirus-7 and herpesvirus-6: a comparative, longitudinal study up to 6 years of age. Acta Paediatr. 1997; 86(6): 604-8.
  • 65
    Torigoe S, Koide W, Yamada M, Miyashiro E, Tanaka-Taya K, Yamanishi K. Human herpesvirus 7 infection associated with central nervous system manifestations. J Pediatr. 1996; 129(2): 301-5.
  • 66
    Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A, Benn EK, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012; 53(9): 1481-8.
  • 67
    Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011; 7(1): 31-40.
  • 68
    Chapenko S, Roga S, Skuja S, Rasa S, Cistjakovs M, Svirskis S, et al. Detection frequency of human herpesviruses-6A, -6B, and -7 genomic sequences in central nervous system DNA samples from post-mortem individuals with unspecified encephalopathy. J Neurovirol. 2016; 22(4): 488-97.
  • 69
    Ongrádi J, Ablashi DV, Yoshikawa T, Stercz B, Ogata M. Roseolovirus-associated encephalitis in immunocompetent and immunocompromised individuals. J Neurovirol. 2017; 23(1): 1-19.
  • 70
    Kwok H, Tong AH, Lin CH, Lok S, Farrell PJ, Kwong DL, et al. Genomic sequencing and comparative analysis of Epstein-Barr virus genome isolated from primary nasopharyngeal carcinoma biopsy. PLoS One. 2012; 7(5): e36939.
  • 71
    Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964; 1(7335): 702-3.
  • 72
    Soldan SS, Lieberman PM. Epstein-Barr virus infection in the development of neurological disorders. Drug Discov Today Dis Models. 2020; 32(Pt A): 35-52.
  • 73
    Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004; 4(10): 757-68.
  • 74
    Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr virus and neurological diseases. Front Mol Biosci. 2022; 8: 816098.
  • 75
    Huang L, Zhang X, Fang X. Case Report: Epstein-Barr virus encephalitis complicated with brain stem hemorrhage in an immune-competent adult. Front Immunol. 2021; 12: 618830.
  • 76
    Häusler M, Ramaekers VT, Doenges M, Schweizer K, Ritter K, Schaade L. Neurological complications of acute and persistent Epstein-Barr virus infection in paediatric patients. J Med Virol. 2002; 68(2): 253-63.
  • 77
    Bar-Or A, Pender MP, Khanna R, Steinman L, Hartung HP, Maniar T, et al. Epstein-Barr virus in multiple sclerosis: theory and emerging immunotherapies. Trends Mol Med. 2020; 26(3): 296-310.
  • 78
    Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022; 375(6578): 296-301.
  • 79
    Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. 2021; 10(6): 763.
  • 80
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266(5192): 1865-9.
  • 81
    Lopes AO, Marinho PDN, Medeiros LDS, de Paula VS. Human gammaherpesvirus 8 oncogenes associated with Kaposi's sarcoma. Int J Mol Sci. 2022; 23(13): 7203.
  • 82
    Lopes AO, Spitz N, Reis CRS, de Paula VS. Update of the global distribution of human gammaherpesvirus 8 genotypes. Sci Rep. 2021; 11(1): 7640.
  • 83
    Tso FY, Sawyer A, Kwon EH, Mudenda V, Langford D, Zhou Y, et al. Kaposi's sarcoma-associated herpesvirus infection of neurons in HIV-positive patients. J Infect Dis. 2017; 215(12): 1898-907.
  • 84
    Dittmer DP, Damania B. Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy. J Clin Invest. 2016; 126(9): 3165-75.
  • 85
    Kong X, Li D, Mansouri A, Kang G, Sayood K, West J, et al. Bone marrow-derived SH-SY5Y neuroblastoma cells infected with Kaposi's sarcoma-associated herpesvirus display unique infection phenotypes and growth properties. J Virol. 2021; 95(13): e0000321.
  • 86
    Cermelli C, Vinceti M, Beretti F, Pietrini V, Nacci G, Pietrosemoli P, et al. Risk of sporadic amyotrophic lateral sclerosis associated with seropositivity for herpesviruses and echovirus-7. Eur J Epidemiol. 2003; 18(2): 123-7.
  • 87
    Merelli E, Bedin R, Sola P, Barozzi P, Mancardi GL, Ficarra G, et al. Human herpes virus 6 and human herpes virus 8 DNA sequences in brains of multiple sclerosis patients, normal adults and children. J Neurol. 1997; 244(7): 450-4.
  • 88
    Marcocci ME, Napoletani G, Protto V, Kolesova O, Piacentini R, Li Puma DD, et al. Herpes simplex virus-1 in the brain: the dark side of a sneaky infection. Trends Microbiol. 2020; 28(10): 808-20.
  • 89
    Zhu S, Viejo-Borbolla A. Pathogenesis and virulence of herpes simplex virus. Virulence. 2021; 12(1): 2670-702.
  • 90
    Wouk J, Rechenchoski DZ, Rodrigues BCD, Ribelato EV, Faccin-Galhardi LC. Viral infections and their relationship to neurological disorders. Arch Virol. 2021; 166(3): 733-53.

Publication Dates

  • Publication in this collection
    21 Nov 2022
  • Date of issue
    2022

History

  • Received
    26 Aug 2022
  • Accepted
    10 Oct 2022
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