Herpes Simplex Viral Infection Doubles the Risk of Dementia in a Contemporary Cohort of Older Adults: A Prospective Study.

Background: Evidence indicates that herpes simplex virus (HSV) participates in the pathogenesis of Alzheimer's disease (AD). Objective: We investigated AD and dementia risks according to the presence of herpesvirus antibodies in relation to anti-herpesvirus treatment and potential APOE ɛ4 carriership interaction. Methods: This study was conducted with 1002 dementia-free 70-year-olds living in Sweden in 2001-2005 who were followed for 15 years. Serum samples were analyzed to detect anti-HSV and anti-HSV-1 immunoglobulin (Ig) G, anti-cytomegalovirus (CMV) IgG, anti-HSV IgM, and anti-HSV and anti-CMV IgG levels. Diagnoses and drug prescriptions were collected from medical records. Cox proportional-hazards regression models were applied. Results: Cumulative AD and all-cause dementia incidences were 4% and 7%, respectively. Eighty-two percent of participants were anti-HSV IgG carriers, of whom 6% received anti-herpesvirus treatment. Anti-HSV IgG was associated with a more than doubled dementia risk (fully adjusted hazard ratio = 2.26, p = 0.031). No significant association was found with AD, but the hazard ratio was of the same magnitude as for dementia. Anti-HSV IgM and anti-CMV IgG prevalence, anti-herpesvirus treatment, and anti-HSV and -CMV IgG levels were not associated with AD or dementia, nor were interactions between anti-HSV IgG and APOE ɛ4 or anti-CMV IgG. Similar results were obtained for HSV-1. Conclusions: HSV (but not CMV) infection may be indicative of doubled dementia risk. The low AD incidence in this cohort may have impaired the statistical power to detect associations with AD.

Multi-phenotype analysis for enhanced classification of 11 herpes simplex virus 1 strains.

Herpes simplex virus 1 (HSV1) is best known for causing oral lesions and mild clinical symptoms, but it can produce a significant range of disease severities and rates of reactivation. To better understand this phenotypic variation, we characterized 11 HSV1 strains that were isolated from individuals with diverse infection outcomes. We provide new data on genomic and in vitro plaque phenotype analysis for these isolates and compare these data to previously reported quantitation of the disease phenotype of each strain in a murine animal model. We show that integration of these three types of data permitted clustering of these HSV1 strains into four groups that were not distinguishable by any single dataset alone, highlighting the benefits of combinatorial multi-parameter phenotyping. Two strains (group 1) produced a partially or largely syncytial plaque phenotype and attenuated disease phenotypes in mice. Three strains of intermediate plaque size, causing severe disease in mice, were genetically clustered to a second group (group 2). Six strains with the smallest average plaque sizes were separated into two subgroups (groups 3 and 4) based on their different genetic clustering and disease severity in mice. Comparative genomics and network graph analysis suggested a separation of HSV1 isolates with attenuated vs. virulent phenotypes. These observations imply that virulence phenotypes of these strains may be traceable to genetic variation within the HSV1 population.

Laboratory investigations of herpes simplex virus-1 and -2 clinical samples in Korea.

OBJECTIVE: Herpes simplex virus (HSV) infections have been reported in 60% to 95% of the adult population worldwide, making them one of the most common infectious conditions globally. HSV-1 and HSV-2 cause severe disease in immunocompromised patients. Therefore, the aim of this study was to provide information that could be used to reduce the incidence of genital herpes caused by HSV-1 and HSV-2. METHODS: From September 2018 to December 2020, 59,381 specimens were collected from outpatients across primary and secondary hospitals in Korea who requested U2Bio (Korea) to conduct molecular biological testing of their samples for sexually transmitted infections. In this study, the positivity rates of HSV-1 and HSV-2 were analyzed according to age, sex, and specimen type. RESULTS: In the age-specific analysis of HSV-1, the highest positivity rate (0.58%) was observed in patients under 19 years of age, whereas the lowest positivity rate (0.08%) was observed in patients aged over 70 years. In the age-specific analysis of HSV-2, the highest positivity rate (2.53%) was likewise observed in patients under 19 years of age. CONCLUSION: Our study identified differences in the infection rates of HSV-1 and HSV-2 depending on patients' sex and age. These differences will be useful for improving disease prevention and control measures for HSV-1 and HSV-2.

Lipopolysaccharide enhances human herpesvirus 1 replication and IL-6 release in epithelial cells.

OBJECTIVE: To investigate the effect of lipopolysaccharide (LPS) on human herpesvirus 1 (HHV-1) infection in epithelial cells. METHODS: Two strains of HHV-1, HHV-1 F strain (HHV-1f) and HHV-1 strain-H129 with GFP knock-in (HHV-g4), were used to infect HCE-T and VERO cells at MOIs of 0.04 and 0.02, respectively. After 1 h, 0, 10, 50, and 100 µg/ml LPS was added to serum-free medium and the cells were cultured for up to 24 h. GFP fluorescence of HHV-g4 in cells was examined under a fluorescence microscope and imaged. HHV-1f titer was determined by quantitative real-time polymerase chain reaction (qPCR) in HCE-T cells and plaque assays in VERO cells. The expression of the viral ICP4 protein of HHV-1f was detected by Western blot assay. IL-6 and IL-10 levels in culture medium were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Similar changes but at different degrees were found in HCE-T and VERO cells that were infected with HHV-1. GFP fluorescence of HHV-g4 and cell lesions increased in a dose-dependent manner. Virus titer was also enhanced by LPS stimulation in HCE-T and VERO cells. ICP4 expression was promoted at higher LPS concentrations (P = 0.04). In addition, viral infection resulted in increased expression of IL-6 in a dose-dependent manner at 12 and 24 h (P = 0.01), while IL-10 expression was unaffected by either HHV-1 infection or LPS stimulation. CONCLUSION: LPS promotes HHV-1 infection in epithelial cells, which suggests that gram-negative bacteria on ocular surfaces may aggravate HHV-1 infection.

V348I mutation in UL23 gene of human herpesvirus 1 in a case of herpetic hepatitis and haemophagocytic lymphohistiocytosis.

We herein report the case of a young immunocompetent adult patient with a rapidly fatal haemophagocytic lymphohistiocytosis syndrome related to human herpesvirus 1 (HHV-1) infection, with herpetic hepatitis and persistent high-level viraemia despite treatment with acyclovir. Haemophagocytic lymphohistiocytosis was confirmed in the patient's spleen and bone marrow. HHV-1 DNA was extracted from whole blood and liver biopsy and the UL23 gene was sequenced. A V348I natural polymorphism of the TK protein was found in blood and liver specimens. Further studies are needed to investigate the role of this polymorphism in the development of systemic immune dysregulation.

Viral genetic diversity and its potential contributions to the development and progression of neonatal herpes simplex virus (HSV) disease.

PURPOSE OF REVIEW: Neonatal infection by herpes simplex virus (HSV) 1 or 2 presents a devastating burden to new parents, due to the unpredictability of severe clinical outcomes, as well as the potential for lifelong reactivation. While just under half of neonatal HSV infections have mild clinical impacts akin to those observed in adults, the other half experience viral spread throughout the body (disseminated infection) and/or the brain (central nervous system infection). SUMMARY: Here we summarize current data on clinical diagnostic measures, antiviral therapy, and known factors of human host biology that contribute to the distinct neonatal outcomes of HSV infection. RECENT FINDINGS: We then explore recent new data on how viral genetic diversity between infections may impact clinical outcomes. Further research will be critical to build upon these early findings and to provide statistical power to our ability to discern and/or predict the potential clinical path of a given neonatal infection.

Co-infection ZIKV and HSV-1 associated with meningoencephalitis: Case report and literature review.

A man, 26years-old, presented fever, mental confusion and a progressively worsening headache 6days prior to admission. The CSF study was suggestive of meningoencephalitis, the PCR study revealed presence of HSV-1 and ZIKV, while other immunology tests were negative. ZIKV was also identified in serum. The MRI showed temporal lobe hyper-intensity in FLAIR-weight sequence with areas of contrast enhancement and the electroencephalogram showed slow wave activity in such region. Patient was treated with acyclovir and supportive measures and had good clinical outcome at evaluation after 6 months. Neurological spectrum of ZIKV manifestations is wide, but meningoencephalitis is not frequent. Co-infection HSV-1 plus ZIKV was not yet related in humans, but there is increased cellular damage caused by association of ZIKV and herpes virus family infection. ZIKV may facilitate infection or recrudescence by other viruses or cause concurrently neuronal injury by direct or indirect mechanisms. We suggest that clinicians attempt new manifestations related to ZIKV and include this agent in differential diagnosis of neurological diseases even when other agents were identified.

Long-Read Isoform Sequencing Reveals a Hidden Complexity of the Transcriptional Landscape of Herpes Simplex Virus Type 1.

In this study, we used the amplified isoform sequencing technique from Pacific Biosciences to characterize the poly(A)+ fraction of the lytic transcriptome of the herpes simplex virus type 1 (HSV-1). Our analysis detected 34 formerly unidentified protein-coding genes, 10 non-coding RNAs, as well as 17 polycistronic and complex transcripts. This work also led us to identify many transcript isoforms, including 13 splice and 68 transcript end variants, as well as several transcript overlaps. Additionally, we determined previously unascertained transcriptional start and polyadenylation sites. We analyzed the transcriptional activity from the complementary DNA strand in five convergent HSV gene pairs with quantitative RT-PCR and detected antisense RNAs in each gene. This part of the study revealed an inverse correlation between the expressions of convergent partners. Our work adds new insights for understanding the complexity of the pervasive transcriptional overlaps by suggesting that there is a crosstalk between adjacent and distal genes through interaction between their transcription apparatuses. We also identified transcripts overlapping the HSV replication origins, which may indicate an interplay between the transcription and replication machineries. The relative abundance of HSV-1 transcripts has also been established by using a novel method based on the calculation of sequencing reads for the analysis.

Intracardiac Fungal Mass in a Term Neonate.

Systemic fungal infections pose insidious challenges in neonatal intensive care settings. We present the case of a 9-day-old male term neonate admitted for polymicrobial sepsis and hepatic dysfunction who later developed candidemia superinfection. Despite broad antifungal therapy, the fungemia was complicated by progressive growth of a fungus ball in the right ventricular outflow tract that threatened cardiac function. Surgical excision of the mass was undertaken by right atriotomy and histologic examination confirmed Candida albicans.

Fatal Human herpesvirus 1 (HHV-1) infection in captive marmosets (Callithrix jacchus and Callithrix penicillata) in Brazil: clinical and pathological characterization / Infecção fatal por Herpesvirus simplex Tipo 1 (HHV-1) em saguis de cativeiro (Callithrix jacchus and Callithrix penicillata) no Brasil: caracterização clínica e patológica

Fatal Human herpesvirus 1 (HHV-1) was diagnosed in 12 captive marmosets (Callithrix jacchus and Callithrix penicillata) from metropolitan region of São Paulo, São Paulo State. Clinical signs were variable among the cases, but most affected marmosets presented signs associated with viral epithelial replication: oral, lingual and facial skin ulcers and hypersalivation, and viral replication in the central nervous system: prostration, seizure and aggressive behavior. Consistent microscopic findings were diffuse mild to severe nonsuppurative necrotizing meningoencephalitis with gliosis, vasculitis and neuronal necrosis. Additionally, in the brain, oral cavity, skin, adrenal gland and myoenteric plexus intranuclear inclusion bodies were present. Immunohistochemistry confirmed the presence of the HHV-1 antigen in association with lesions in the brain, oral and lingual mucosa, facial skin, adrenal gland and myoenteric plexus. HHV-1-specific polymerase chain reaction (PCR) analysis of the brain was carried out and the virus was detected in 7/8 infected marmosets. It is concluded that HHV-1 causes widespread fatal infection in marmosets.(AU)

Infecção fatal por Herpesvirus simplex Tipo 1 (HHV-1) foi diagnosticada em 12 saguis de cativeiro (Callithrix jacchus e Callithrix penicillata) provenientes da região metropolitana de São Paulo, Estado de São Paulo. Os sinais clínicos foram variáveis entres os casos, no entanto, a maioria dos saguis afetados apresentavam sinais associados à replicação viral em epitélios: úlceras na cavidade oral, língua e pele da face e hipersalivação; e no sistema nervoso central: prostração, convulsão e comportamento agressivo. Histologicamente, o principal achado foi meningoencefalite necrosante não supurativa difusa, leve a acentuada com gliose, vasculite e necrose neuronal. Inclusões intranucleares também foram observadas em encéfalo, cavidade oral, pele, glândula adrenal e plexo mioentérico. A imuno-histoquímica anti-HHV-1 confirmou a presença do antígeno viral em associação às lesões em encéfalo, mucosa oral e lingual, pele da face, glândula adrenal e plexo mioentérico. Em 7/8 saguis infectados foi detectada a presença de HHV-1 por reação em cadeia da polimerase (PCR) a partir de amostras de encéfalo. Conclui-se que HHV-1 causa uma infecção disseminada e fatal em saguis.(AU)

Longitudinal study on oral shedding of herpes simplex virus 1 and varicella-zoster virus in individuals infected with HIV.

Primary herpes simplex virus 1 (HSV-1) and varicella-zoster virus (VZV) infection leads to a life-long latent infection of ganglia innervating the oral mucosa. HSV-1 and VZV reactivation is more common in immunocompromised individuals and may result in viral shedding in saliva. We determined the kinetics and quantity of oral HSV-1 and VZV shedding in HSV-1 and VZV seropositive individuals infected with HIV and to assess whether HSV-1 shedding involves reactivation of the same strain intra-individually. HSV-1 and VZV shedding was determined by real-time PCR of sequential daily oral swabs (n = 715) collected for a median period of 31 days from 22 individuals infected with HIV. HSV-1 was genotyped by sequencing the viral thymidine kinase gene. Herpesvirus shedding was detected in 18 of 22 participants. Shedding of HSV-1 occurred frequently, on 14.3% of days, whereas solely VZV shedding was very rare. Two participants shed VZV. The median HSV-1 load was higher compared to VZV. HSV-1 DNA positive swabs clustered into 34 shedding episodes with a median duration of 2 days. The prevalence, duration and viral load of herpesvirus shedding did not correlate with CD4 counts and HIV load. The genotypes of the HSV-1 viruses shed were identical between and within shedding episodes of the same person, but were different between individuals. One-third of the individuals shed an HSV-1 strain potentially refractory to acyclovir therapy. Compared to HSV-1, oral VZV shedding is rare in individuals infected with HIV. Recurrent oral HSV-1 shedding is likely due to reactivation of the same latent HSV-1 strain.