Family <i>Herpesviridae</i> and neuroinfections: current status and research in progress

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

Authorship

Vanessa Cristine de Souza Carneiro

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz-FiocruzBrazilRio de Janeiro, RJ, BrazilFundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Virologia Molecular, Rio de Janeiro, RJ, Brasil

Jéssica Gonçalves Pereira

Vanessa Salete de Paula ⁺+ Corresponding author: vdepaula@ioc.fiocruz.br

All authors contributed to the writing and revision of this text and declare no conflicts of interest.

http://orcid.org/0000-0002-6314-754X

+ Corresponding author: vdepaula@ioc.fiocruz.br

SCIMAGO INSTITUTIONS RANKINGS

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TABLE
Family Herpesviridae and neuroinfections

TABLE Family Herpesviridae and neuroinfections

	HSV-1	HSV-2	VZV	EBV	HCMV	HHV-6A	HHV-6B	HHV-7	HHV-8
Year of discovery	1920¹1. Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22.	1920¹1. Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22.	1952¹⁷17. Weller TH, Stoddard MB. Intranuclear inclusion bodies in cultures of human tissue inoculated with varicella vesicle fluid. J Immunol. 1952; 68(3): 311-9.	1964⁷¹71. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964; 1(7335): 702-3.	1956²⁶26. Ho M. The history of cytomegalovirus and its diseases. Med Microbiol Immunol. 2008; 197(2): 65-73.	1986⁴⁰40. 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.	1988⁴¹41. 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.	1990⁶⁰60. 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.	1994⁸⁰80. 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.
Name	Herpes simplex virus 1	Herpes simplex virus 2	Varicella-zoster virus	Epstein-Barr virus	Human cytomegalovirus	Human herpesvirus-6A	Human herpesvirus-6B	Human herpesvirus-7	Human herpesvirus-8
Taxonomy ICTV (2021)	Human alphaherpesvirus 1	Human alphaherpesvirus 2	Human alphaherpesvirus 3	Human gammaherpesvirus 4	Human betaherpesvirus 5	Human betaherpesvirus 6A	Human betaherpesvirus 6B	Human betaherpesvirus 7	Human gammaherpesvirus 8
Discoverer(s)	Gruter¹1. Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22.	Gruter¹1. Pellet PE, Roizman B. Herpesviridae. In: Lippincort WW, editor. Fields virology. 2. Philadelphia: Lippincott, Williams & Wilkins; 2013. p. 1802-22.	Thomas H. Weller¹⁷17. Weller TH, Stoddard MB. Intranuclear inclusion bodies in cultures of human tissue inoculated with varicella vesicle fluid. J Immunol. 1952; 68(3): 311-9.	Michael Anthony Epstein⁷¹71. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964; 1(7335): 702-3.	Weller Smith and Rowe²⁶26. Ho M. The history of cytomegalovirus and its diseases. Med Microbiol Immunol. 2008; 197(2): 65-73.	Salahuddin⁴⁰40. 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.	Yamanishi⁴¹41. 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.	Frenkel⁶⁰60. 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.	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.
Genome	152 kb³3. 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.	155 kb⁴4. 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.	125 kb¹⁸18. 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.	170 kb⁷⁰70. 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.	236 kb²⁷27. 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.	159 kb⁴³43. 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.	162 kb⁴⁴44. Arbuckle JH, Medveczky PG. The molecular biology of human herpesvirus-6 latency and telomere integration. Microbes Infect. 2011; 13(8-9): 731-41.	144 kb⁶¹61. 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.	140 kb⁸²82. 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.
Latency	Neurons⁵5. 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.	Neurons⁵5. 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.	Neurons²⁰20. Zerboni L, Sen N, Oliver SL, Arvin AM. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol. 2014; 12(3): 197-210.	Memory B cells⁷³73. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004; 4(10): 757-68.	Renal epithelial cells and salivary glands³¹31. 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.	Monocytes, macrophage and glial cells ⁽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.^,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.	Salivary glands, monocytes, macrophages and glial cells⁴⁷47. 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.^,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.^,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.	Unclear	B lymphocytes⁸³83. 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.
Clinical manifestations	Skin lesions⁵5. 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.	Genital or anal blisters or ulcers⁶6. Grinde B. Herpesviruses: latency and reactivation - viral strategies and host response. J Oral Microbiol. 2013; 25; 5.	Varicella, herpes zoster¹⁹19. 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.^,²¹21. Mallick-Searle T, Snodgrass B, Brant JM. Postherpetic neuralgia: epidemiology, pathophysiology, and pain management pharmacology. J Multidiscip Healthc. 2016; 9: 447-54.	Infectious mononucleosis⁷²72. 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.	Congenital viral infection³⁴34. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol. 2007; 17(4): 253-76.	Asymptomatic⁴⁵45. 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.^,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.^,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.	Exanthema subitum, present in infantile roseola⁴²42. 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.^,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.^,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.^,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.	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.	Kaposi’s sarcoma, primary effusion lymphoma and multicentric Castleman disease⁸¹81. 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.
Neurological manifestations	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. 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.^-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.	Encephalitis, meningitis, and meningoencephalitis¹⁰10. 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.^-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.	Post-herpetic neuralgia, meningoencefalitis, ischemic stroke, aneurysm and cerebral venous thrombosis²¹21. 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.^-²³23. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016; 16(2): 12.	Meningitis, encephalitis, myelitis, psychoses and “Alice in Wonderland” syndrome⁷²72. 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.	Encephalitis and neurodevelopmental deficits³⁵35. Ross SA, Boppana SB. Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis. 2005; 16(1): 44-9.^,³⁶36. 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.^-³⁸38. Torrey EF. Functional psychoses and viral encephalitis. Integr Psychiatry, 1986; 4(4): 224-30.	Encephalitis and multiple sclerosis⁴⁹49. 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.^-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.^,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.^,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.	Seizures, encephalitis, mesial temporal lobe epilepsy and multiple sclerosis⁴⁹49. 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.^-⁵⁴54. Bartolini L, Theodore WH, Jacobson S, Gaillard WD. Infection with HHV-6 and its role in epilepsy. Epilepsy Res. 2019; 153: 34-9.	Seizures, encephalitis, meningoencephalitis, facial palsy, vestibular neuritis, severe headache, drowsiness, fatigue, photosensitivity, ataxia and coma⁶⁹69. 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.	Under investigation
Research in progress	Alzheimer’s disease¹⁴14. 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.	Alzheimer’s disease¹⁴14. 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.	-	Multiple sclerosis⁷⁴74. Zhang N, Zuo Y, Jiang L, Peng Y, Huang X, Zuo L. Epstein-Barr virus and neurological diseases. Front Mol Biosci. 2022; 8: 816098.^,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.^,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.	Schizophrenia³⁷37. 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.^-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.	Multiple sclerosis⁵⁶56. 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.^,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.	Epilepsy and multiple sclerosis⁴⁸48. 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.^,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.^,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.	Epilepsy⁶⁶66. 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.	_

EBV: Epstein-Barr virus; HCMV: human cytomegalovirus; HHV: human herpesvirus; HSV: herpes simplex virus; ICT: International Committee on Taxonomy of Viruses; VZV: varicella zoster virus.

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Family <i>Herpesviridae</i> and neuroinfections: current status and research in progress

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[1] + Corresponding author: vdepaula@ioc.fiocruz.br