The mucosa of the oral cavity is exposed to a large number of different microorganisms such as archaea, bacteria, fungi, parasites, and viruses. Among those, viruses cause specific infections, which can easily be transmitted from one person to another. The infectious route may not only include patients and their relatives but also the dental professional team. Thus, a wide knowledge regarding specific viral infections is crucial for the daily routine. Signs and symptoms of oral viral infections can be completely absent or develop into a pronounced clinical picture, so that early detection and information determine the further course of the infection and its influence on other inflammatory diseases, such as periodontitis, as well as the safety of family members and the social environment. As the clinical manifestation of viral infections may be highly variable leading to heterogenous mucosal lesions it is, in most cases, mandatory to differentiate them by specific microbiological tests in addition to clinical examination procedures. This article will give an overview of the role of viruses infecting the oral mucosa, and in addition, describe their clinical manifestation and management.

Human herpes virus-6 (HHV-6) is a common cause of viral infection in humans, recognized for causing exanthema subitem during the first two years of life. Chronic inflammatory states in different autoimmune diseases can be associated with an immunosuppressed microenvironment. We report a case of HHV-6-associated meningitis in a patient with psoriasis. A 36-year-old man with a history of psoriasis presented with worsening bifrontal headache as well as painful oral lesions on the tongue and soft palate. Computed tomographic (CT) scan of the brain was nondiagnostic. Cerebrospinal fluid (CSF) analysis was diagnostic for HHV-6 infection and was treated with intravenous ganciclovir for two weeks. This case report highlights the emergence of HHV-6 infections in people with underlying mild immune disorders, such as psoriasis. Plaque psoriasis, such as in this patient, could be related to viral infections not typically seen among adults.

UNASSIGNED: The causal associations between infections with human herpes viruses (HHVs) and amyotrophic lateral sclerosis (ALS) has been disputed. This study investigated the causal associations between herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), HHV-6, and HHV-7 infections and ALS through a bidirectional Mendelian randomization (MR) method.
UNASSIGNED: The genome-wide association studies (GWAS) database were analyzed by inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods. MR-Egger intercept test, MR-PRESSO test, Cochran\'s Q test, funnel plots, and leaveone-out analysis were used to verify the validity and robustness of the MR results.
UNASSIGNED: In the forward MR analysis of the IVW, genetically predicted HSV infections [odds ratio (OR) = 0.9917; 95% confidence interval (CI): 0.9685-1.0154; p = 0.4886], HSV keratitis and keratoconjunctivitis (OR = 0.9897; 95% CI: 0.9739-1.0059; p = 0.2107), anogenital HSV infection (OR = 1.0062; 95% CI: 0.9826-1.0304; p = 0.6081), VZV IgG (OR = 1.0003; 95% CI: 0.9849-1.0160; p = 0.9659), EBV IgG (OR = 0.9509; 95% CI: 0.8879-1.0183; p = 0.1497), CMV (OR = 0.9481; 95% CI: 0.8680-1.0357; p = 0.2374), HHV-6 IgG (OR = 0.9884; 95% CI: 0.9486-1.0298; p = 0.5765) and HHV-7 IgG (OR = 0.9991; 95% CI: 0.9693-1.0299; p = 0.9557) were not causally associated with ALS. The reverse MR analysis of the IVW revealed comparable findings, indicating no link between HHVs infections and ALS. The reliability and validity of the findings were verified by the sensitivity analysis.
UNASSIGNED: According to the MR study, there is no evidence of causal associations between genetically predicted HHVs (HSV, VZV, EBV, CMV, HHV-6, and HHV-7) and ALS.

Herpes simplex virus 1 (HSV-1) enters sensory neurons with the potential for productive or latent infection. For either outcome, HSV-1 must curtail the intrinsic immune response, regulate viral gene expression, and remove host proteins that could restrict viral processes. Infected cell protein 0 (ICP0), a virus-encoded E3 ubiquitin ligase, supports these processes by mediating the transfer of ubiquitin to target proteins to change their location, alter their function, or induce their degradation. To identify ubiquitination targets of ICP0 during productive infection in sensory neurons, we immunoprecipitated ubiquitinated proteins from primary adult sensory neurons infected with HSV-1 KOS (wild-type), HSV-1 n212 (expressing truncated, defective ICP0), and uninfected controls using anti-ubiquitin antibody FK2 (recognizing K29, K48, K63 and monoubiquitinated proteins), followed by LC-MS/MS and comparative analyses. We identified 40 unique proteins ubiquitinated by ICP0 and 17 ubiquitinated by both ICP0 and host mechanisms, of which High Mobility Group Protein I/Y (HMG I/Y) and TAR DNA Binding Protein 43 (TDP43) were selected for further analysis. We show that ICP0 ubiquitinates HMG I/Y and TDP43, altering protein expression at specific time points during productive HSV-1 infection, demonstrating that ICP0 manipulates the sensory neuronal environment in a time-dependent manner to regulate infection outcome in neurons.

A number of studies have suggested that human herpesvirus 6A (HHV-6A) may play a role in multiple sclerosis (MS). Three possible hypotheses have been investigated: (1) U24 from HHV-6A (U24-6A) mimics myelin basic protein (MBP) through analogous phosphorylation and interaction with Fyn-SH3; (2) U24-6A affects endocytic recycling by binding human neural precursor cell (NPC) expressed developmentally down-regulated protein 4-like WW3* domain (hNedd4L-WW3*); and (3) MS patients who express Killer Cell Immunoglobulin Like Receptor 2DL2 (KIR2DL2) on natural killer (NK) cells are more susceptible to HHV-6 infection. In this contribution, we examined the validity of these propositions by investigating the interactions of U24 from HHV-6B (U24-6B), a variant less commonly linked to MS, with Fyn-SH3 and hNedd4L-WW3* using heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) titrations and isothermal titration calorimetry (ITC). In addition, the importance of phosphorylation and the specific role of U24 in NK cell activation in MS patients were examined. Overall, the findings allowed us to shed light into the models linking HHV-6 to MS and the involvement of U24.

Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging.

Human herpesvirus 6 (HHV-6) manifesting as a central nervous system (CNS) infection (especially meningoencephalitis) is reported as a primary infection in children and from reactivation in immunocompromised patients; however, it has rarely been reported in immunocompetent adults. Latent infections of the CNS can cause a myriad of clinical presentations ranging from a benign, febrile, self-resolving illness to limbic encephalitis, temporal lobe seizures, and neuropsychiatric symptoms such as behavioral disturbances and psychosis. No standard diagnostic criteria or management guidelines exist for this condition. Possible neuroimaging findings include abnormalities in the medial temporal lobe involving the hippocampus and amygdala. We hereby present a case of HHV-6 meningitis in a 48-year-old immunocompetent male presenting without encephalopathic symptoms and normal neuroimaging findings.

Epstein-Barr Virus (EBV) is an extremely successful human herpes virus, which infects essentially all human beings at some time during their life span. EBV infection and the associated immune response results in production of antibodies (seroconversion), which occurs mainly during the first years of life, but may also happen during adolescence or later in life. Infection of adolescents can result in infectious mononucleosis, an acute serious condition characterized by massive lymphocytosis. Transmission of EBV mainly occurs through saliva but can rarely be spread through semen or blood, e.g. through organ transplantations and blood transfusions. EBV transmission through oral secretions results in infection of epithelial cells of the oropharynx. From the epithelial cells EBV can infect B cells, which are the major reservoir for the virus, but other cell types may also become infected. As a result, EBV can shuttle between different cell types, mainly B cells and epithelial cells. Moreover, since the virus can switch between a latent and a lytic life cycle, EBV has the ability to cause chronic relapsing/reactivating infections. Chronic or recurrent EBV infection of epithelial cells has been linked to systemic lupus erythematosus and Sjögren\'s syndrome, whereas chronic/recurrent infection of B cells has been associated with rheumatoid arthritis, multiple sclerosis and other diseases. Accordingly, since EBV can shuttle between epithelial cells and B cells, the systemic autoimmune diseases often occur as overlapping syndromes with symptoms and characteristic autoantibodies (e.g. antinuclear antibodies and rheumatoid factors) reflecting epithelial and/or B cell infection.

Human herpes viruses (HHV) have been implicated in dementia. Class II Human Leukocyte Antigens (HLA) play a critical role in host protection from foreign antigens including herpes viruses through stimulating antibody production against them. In the present study we investigated the in silico binding affinity of 9 H HV to three Class II HLA alleles that have been found to protect against dementia: DRB1*01:01, DRB1*13:02, and DRB1*15:01.
A sliding window approach was used to partition the amino acid sequences of surface glycoproteins from HHV 1-8 into subsequences. The binding affinity of the HHV subsequences to Class II HLA surface receptor proteins was predicted using the Sturniolo method in the Immune Epitope Database and reported as a percentile rank. The binding affinity of HHV subsequences to protective alleles was compared to that of three dementia-neutral Class II HLA alleles: DRB1*03:01, DRB1*07:01, and DRB1*08:01.
Binding affinity varied widely for each HLA allele, HHV type, and HHV subsequence. The protective alleles had significantly higher binding affinity that than the neutral alleles. The largest differences in binding affinity between the protective and neutral alleles was shown for HHV-6A and HHV-6B, which had the best overall binding affinity with the protective alleles.
The dementia protection conferred by the three protective HLA alleles investigated here is related to their superior ability to bind and successfully eliminate HHV epitopes - in particular, HHV6 - that could otherwise cause dementia if they persisted.

Germinotropic lymphoproliferative disorder (GLPD) is a poorly characterized lymphoproliferative entity, recently included in the World Health Organization classification of hematolymphoid neoplasms. The histological pattern of this disease comprises monotypic plasmablasts that involve the germinal centers of the lymphoid follicles (germinotrophism), forming confluent aggregates positive for both human herpes virus type 8 (HHV8) and Epstein-Barr virus. Currently, after 17 years of its first description, only 18 cases have been reported. In this article, we describe a case of a GLPD presenting in an immunocompetent 79-year-old woman with localized axillary lymphadenopathy, showing a prominent sinusoidal growth pattern, with no evidence of germinotrophism or extrasinusoidal spread. Stinking pleomorphism in tumor cells was also noted. An extension study has not revealed involvement of other groups of lymph nodes or extralymphoid sites. The patient is alive and has shown no relapse after 8 years follow-up (the longest follow-up reported period for this entity). This previously unrecognized pure sinusoidal growth pattern along with the striking pleomorphism in neoplastic cells closely mimics the appearance of an anaplastic large cell lymphoma. GLPD is not usually considered in such a setting, but it should be included in the differential diagnosis of sinusoidal proliferations. Our findings contribute to the expansion of the morphological spectrum of HHV8-associated lymphoproliferative lesions and aids in the characterization of the very infrequent GLPD entity.