Reactivation Of Herpes Simplex Virus Type Research Articles

Interleukin 1β receptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1

Abstract Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer's disease. However, the molecular mechanisms underlying this association are not completely understood. Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role. Here, we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain, highlighting the role of interleukins and, in particular, interleukin 1β as a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.

HSV-1 reactivation results in post-herpetic neuralgia by upregulating Prmt6 and inhibiting cGAS-STING.

Chronic varicella zoster virus (VZV) infection induced neuroinflammatory condition is the critical pathology of postherpetic neuralgia (PHN). The immune escape mechanism of VZV remains to be elusive. Due to mice have no VZV infection receptor, herpes simplex virus type 1 (HSV-1) infection is a well-established PHN mice model. Transcriptional expression analysis identified that the protein arginine methyltransferases 6 (Prmt6) was upregulated upon HSV-1 infection, which was further confirmed by immunofluorescence staining in spinal dorsal horn. Prmt6 deficiency decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load in vivo and in vitro. Overexpression of Prmt6 in microglia dampened antiviral innate immunity and increased HSV-1 load. Mechanistically, Prmt6 methylated and inactivated STING, resulting in reduced phosphorylation of TANK binding kinase-1 (TBK1) and interferon regulatory factor 3 (IRF3), diminished production of type I interferon (IFN-I) and antiviral innate immunity. Furthermore, intrathecal or intraperitoneal administration of the Prmt6 inhibitor EPZ020411 decreased HSV-1-induced neuroinflammation and PHN by enhancing antiviral innate immunity and decreasing HSV-1 load. Our findings revealed that HSV-1 escapes antiviral innate immunity and results in PHN by upregulating Prmt6 expression and inhibiting cGAS-STING pathway, providing novel insights and a potential therapeutic target for PHN.

Seroprevalence of VZV and HSV-2 Antibodies among Women of Childbearing Age Referring to Health Centres of Mashhad, Iran: The Need for Consideration of VZV Vaccination Program.

Infections with herpes simplex virus type 2 (HSV-2) and varicella-zoster virus (VZV) are associated with serious maternal and neonatal health consequences. The literature review reveals a research gap regarding the seroprevalence of HSV-2 and VZV among women of reproductive age in Mashhad, Northeast of Iran. The present study aims to evaluate the seroprevalence of these viruses among a group of women in Mashhad, Iran. Sera were collected by health center personnel using a cluster sampling method from healthy women with specific age characteristics residing in three distinct socioeconomic regions of the city. The participants, aged 20-35, were divided into three groups (20-25, 26-30, and 31-35 years). The levels of VZV and HSV-2 IgG antibodies were evaluated using commercial ELISA kits. Subsequently, the results were analyzed using SPSS software. A total of 93 women were included in the study. Anti-HSV-2 IgG antibody was detected in 3 out of 93 participants (7.5%), while anti-VZV IgG antibody was found positive in 80 out of 93 individuals (83.3%). The HSV-2 positive cases were concurrently positive for the VZV antibody. There was no significant difference in the positivity of anti-HSV-2 and anti-VZV antibody positivity within age groups or socioeconomic status (P > 0.05). The high seroprevalence of VZV among nonvaccinated participants indicates a widespread presence of the virus and underscores its potentially serious impact on community health. Therefore, it is recommended that a VZV vaccination program be considered by the health system. Furthermore, the reactivation of latent HSV-2, whether symptomatic or asymptomatic, during pregnancy should not be disregarded as a life-threatening threat.

Herpes simplex virus reactivation among severe COVID-19 patients: to treat or not to treat?

Background: Herpes simplex virus type 1 (HSV-1) reactivation in the airways is a common finding among patients admitted to the intensive care unit and has been more recently been reported in critically ill COVID-19 patients. Evidence suggests that HSV-1 reactivation in critically ill patients may be associated with higher morbidity and mortality rates. However, there is conflicting data about whether treatment with acyclovir impacts outcomes. Objectives: The primary aim of this study is to assess whether acyclovir improves survival in critically ill COVID-19 patients with concomitant HSV-1 reactivation. Additionally, we explore the effect of acyclovir on cardiorespiratory instability, biochemical markers of inflammation and renal function. Incidence, potential risk factors and outcomes of HSV-1 reactivation in COVID-19 ICU patients are studied last. Methods: A retrospective single-center cohort study set in a Belgian tertiary-care university hospital. All COVID-19 patients admitted to the ICU between March 1st, 2020, and April 15th, 2021, and were tested for HSV-1 using real-time PCR in airway samples were included for analysis. The administration of acyclovir for patients with HSV-1 reactivation was not randomized. Mortality and various markers of morbidity (cardiorespiratory instability, biochemical markers of inflammation, and renal function) were compared between patients that had received acyclovir and those that had not. Secondary outcome measures were respiratory and inflammatory markers of disease severity. Results: 34.7% (42/121) of patients had HSV-1 reactivation, of which 67% (28/42) received acyclovir. ICU mortality was 36% (n = 10) in the acyclovir group versus 0% in the untreated group. Multivariate analysis resulted in OR 3.82 (95% CI 1.37 – 10.68) for ICU mortality in the treated group. Patients treated with acyclovir had a longer length of stay (41.8 vs. 26.8 days, p = .018), longer duration of invasive mechanical ventilation (33.4 vs. 21.8 days, p = .050), and lower PaO2/FiO2 ratio (59.9 vs. 73.4 mmHg, p = .008). Conclusions: The role of acyclovir in patients with HSV-1 reactivation in the ICU remains controversial. According to this study, respiratory HSV-1 reactivation for this specific patient group might be better left untreated. Treatment selection bias, however, could not be fully excluded.

Role of Innate Interferon Responses at the Ocular Surface in Herpes Simplex Virus-1-Induced Herpetic Stromal Keratitis.

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host's life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host's innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/β) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.

COVID-19 and Alzheimer's Disease: What Is the Connection?

Wang et al. found that elderly COVID-19 patients were at risk of AD. The following facts suggest a possible explanation: reactivation of herpes simplex virus type 1 (HSV1) and other herpesviruses can occur in SARS-CoV-2 patients; in cell cultures, HSV1 infection causes occurrence of many AD-like features, as does reactivation of latent HSV1 after addition of certain infectious agents; recurrent experimental reactivation of HSV1-infected mice leads to formation of the main features of AD brains, and to cognitive decline. These suggest that COVID-19 results in repeated reactivation of HSV1 in brain, with subsequent accumulation of damage and eventual development of AD.

Latent herpes simplex virus type 1 reactivation increases the susceptibility of neurodegenerative diseases: intervention with traditional Chinese medicine

Owing to environmental and lifestyle changes in modern society, physical and mental stress is on the rise among the population in attempting to compensate for the changes. Stress, defined as a series of non-specific responses to abnormal internal and external stimuli, has long been recognized to increase susceptibility to various diseases, including neurodegenerative diseases (NDs). Herpes simplex virus type 1 (HSV-1), a neurotropic herpes virus, establishes latent infections in the trigeminal ganglia for the lifetime of the host. Upon reactivation, the latent HSV-1 enters the lytic cycle, which not only causes a substantial production of reactive oxygen species (ROS) in the neurons, but also induces glial cells to produce inflammatory mediators, eventually resulting in neuronal damage and occurrence of NDs. Remarkably, both physical and psychological stress are common stimuli leading to latent HSV-1 reactivation. Acyclovir is a classic antiviral drug for the treatment of HSV-1 infection and recurrence, but acyclovir cannot reverse neuronal damage caused by HSV-1 reactivation. Recent studies have shown that traditional Chinese medicine (TCM) has advantages in the treatment of NDs. In addition, TCM is thought to prevent latent HSV-1 reactivation and NDs, which may involve regulation of the neuro-endocrine-immune network, treatment of emotional disorders, and modulation of oxidative stress. Understanding the mechanism underlying stress-induced reactivation of latent HSV-1 and the potential consequences of NDs is needed. TCM may be a promising alternative therapy for related diseases.

Herpes simplex virus type 1 (HSV-1) over-infection in patients with acute respiratory distress syndrome secondary to COVID-19 pneumonia: Impact on mortality

ObjectiveHerpes simplex virus type 1 (HSV-1) reactivation have been described in patients with invasive mechanical ventilation and recently in patients with acute respiratory distress syndrome (ARDS) secondary to COVID-19 with higher rates of reactivation than were detected previously in critical care, and although the diagnosis of HSV-1 pneumonia is not easy, its presence is associate with an increase in morbidity and mortality. The objective of this study is to determinate if the identification of HSV-1 in lower airway of patients with ARDS secondary to COVID-19 have influence in clinical outcome and mortality. MethodTwo hundred twenty-four admitted patients in intensive care unit (ICU) of Complejo Hospitalario Universitario de Toledo diagnosed of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reviewed and were selected those with mechanical ventilation who had undergone (BAL). It was registered all results of HSV-1 PCR (negative and positive). ResultsDuring the study period (November 28, 2020 to April 13, 2021) was admitted 224 patients in ICU diagnosed of SARS-CoV-2 pneumonia. Eighty-three patients of them had undergone BAL, with HSV-1 PCR positive result in 47 (56%), and negative result in 36 (43.4%). We performed pathological anatomy study in BAL samples on 26 of the total BAL realized. Typical cytopathic characteristics of HSV-1 were found in 13 samples (50%) and 11 of them (84.6%) have had HSV-1 PCR positive result. Thirty days mortality was significantly higher in the group of patients with HSV-1 PCR positive result (33.5% vs. 57.4%, p = 0.015). This difference was stronger in the group of patients with HSV-1 findings in the pathological anatomy study (30.8% vs. 69.2%, p = 0.047). ConclusionOur results suggest that ARDS secondary to SARS-CoV-2 pneumonia is highly associated to HSV-1 reactivation and that the finding of HSV-1 in lower airway is associated with a worst prognostic and with significantly mortality increase. It is necessary to carry out more extensive studies to determinate if treatment with acyclovir can improve the prognosis of these patients.

Potential Involvement of Varicella Zoster Virus in Alzheimer’s Disease/Dementia via Reactivation of Herpes Simplex Virus Type 1

AbstractBackgroundInfections are associated with cognitive decline and development of AD/dementia. Epidemiological studies have revealed an increased AD/dementia risk after shingles, caused by varicella zoster virus (VZV), and/or a decreased risk after vaccination against shingles. This suggests that VZV might reside latently in brain, and on reactivation might cause direct damage in brain, as is thought to be the case with herpes simplex virus type 1 (HSV1), a virus strongly implicated in AD. Alternatively, shingles‐induced inflammation could lead to neuroinflammation and reactivation of HSV1 in brain, i.e., to an indirect consequence – a suggestion previously made to account for the risk of AD/dementia conferred by infections (Itzhaki and Dobson 2002), and for the reduction in risk after certain vaccinations ‐ by preventing occurrence of infection and consequent reactivation. Our aim was to investigate these possibilities by infecting cell cultures with VZV.MethodExperiments were carried out infecting human‐induced neural stem cells (hiNSC) cultures, and cultures quiescently infected with HSV1 with VZV. Cultures were observed for the presence of AD‐related phenotypes such as beta amyloid and P‐tau accumulation, gliosis, and neuroinflammation.ResultCells infected with VZV do not show the main AD characteristics ‐ beta amyloid and P‐tau accumulation – which HSV1 does cause ‐ but do show gliosis and increased levels of several cytokines, suggesting that VZV’s action is indirect. However, very intriguingly, we found that VZV infection of cells quiescently infected with HSV1 leads to reactivation of HSV1 and consequent AD‐like changes, including beta amyloid and P‐tau accumulation, supporting the above infection‐reactivation concept.ConclusionOur results support a role for VZV in AD/dementia via reactivation of HSV1 in brain and in combination with some current preliminary results, indicate that the risk of cognitive decline and of dementia conferred by some infectious diseases might indeed result from their causing HSV1 reactivation in brain.

Potential Involvement of Varicella Zoster Virus in Alzheimer's Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1.

Varicella zoster virus (VZV) has been implicated in Alzheimer's disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of AD/dementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain. To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected with HSV-1. We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 and/or VZV and sought the presence of AD-related phenotypes such as amyloid-β (Aβ) and P-tau accumulation, gliosis, and neuroinflammation. Cells infected with VZV did not show the main AD characteristics, Aβ and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZV's action relating to AD/dementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aβ and P-tau accumulation. Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in AD/dementia via reactivation of HSV-1 in brain.

Reactivation of Herpes Simplex Virus Type 1 (HSV-1) Detected on Bronchoalveolar Lavage Fluid (BALF) Samples in Critically Ill COVID-19 Patients Undergoing Invasive Mechanical Ventilation: Preliminary Results from Two Italian Centers.

Reactivation of herpes simplex virus type 1 (HSV-1) has been described in critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. In the present two-center retrospective experience, we primarily aimed to assess the cumulative risk of HSV-1 reactivation detected on bronchoalveolar fluid (BALF) samples in invasively ventilated COVID-19 patients with worsening respiratory function. The secondary objectives were the identification of predictors for HSV-1 reactivation and the assessment of its possible prognostic impact. Overall, 41 patients met the study inclusion criteria, and 12/41 patients developed HSV-1 reactivation (29%). No independent predictors of HSV-1 reactivation were identified in the present study. No association was found between HSV-1 reactivation and mortality. Eleven out of 12 patients with HSV-1 reactivation received antiviral therapy with intravenous acyclovir. In conclusion, HSV-1 reactivation is frequently detected in intubated patients with COVID-19. An antiviral treatment in COVID-19 patients with HSV-1 reactivation and worsening respiratory function might be considered.

Disrupting Neurons and Glial Cells Oneness in the Brain-The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer's Disease.

Current data strongly suggest herpes simplex virus type 1 (HSV-1) infection in the brain as a contributing factor to Alzheimer’s disease (AD). The consequences of HSV-1 brain infection are multilateral, not only are neurons and glial cells damaged, but modifications also occur in their environment, preventing the transmission of signals and fulfillment of homeostatic and immune functions, which can greatly contribute to the development of disease. In this review, we discuss the pathological alterations in the central nervous system (CNS) cells that occur, following HSV-1 infection. We describe the changes in neurons, astrocytes, microglia, and oligodendrocytes related to the production of inflammatory factors, transition of glial cells into a reactive state, oxidative damage, Aβ secretion, tau hyperphosphorylation, apoptosis, and autophagy. Further, HSV-1 infection can affect processes observed during brain aging, and advanced age favors HSV-1 reactivation as well as the entry of the virus into the brain. The host activates pattern recognition receptors (PRRs) for an effective antiviral response during HSV-1 brain infection, which primarily engages type I interferons (IFNs). Future studies regarding the influence of innate immune deficits on AD development, as well as supporting the neuroprotective properties of glial cells, would reveal valuable information on how to harness cytotoxic inflammatory milieu to counter AD initiation and progression.

Overwhelming Evidence for a Major Role for Herpes Simplex Virus Type 1 (HSV1) in Alzheimer's Disease (AD); Underwhelming Evidence against.

This review describes investigations of specific topics that lie within the general subject of HSV1’s role in AD/dementia, published in the last couple of years. They include studies on the following: relationship of HSV1 to AD using neural stem cells; the apparent protective effects of treatment of HSV1 infection or of VZV infection with antivirals prior to the onset of dementia; the putative involvement of VZV in AD/dementia; the possible role of human herpes virus 6 (HHV6) in AD; the seemingly reduced risk of dementia after vaccination with diverse types of vaccine, and the association shown in some vaccine studies with reduced frequency of HSV1 reactivation; anti-HSV serum antibodies supporting the linkage of HSV1 in brain with AD in APOE-ε4 carriers, and the association between APOE and cognition, and association of APOE and infection with AD/dementia. The conclusions are that there is now overwhelming evidence for HSV1’s role—probably causal—in AD, when it is present in brain of APOE-ε4 carriers, and that further investigations should be made on possible prevention of the disease by vaccination, or by prolonged antiviral treatment of HSV1 infection in APOE-ε4 carriers, before disease onset.

Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease.

Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD). In the Bordeaux-3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSV-1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10-year risk of AD associated with anti-HSV antibodies in 1037 participants according to APOE4 status. Among APOE4 carriers, subjects for whom the frequency of HSV-1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08-12.55) and 3.28 (1.19-9.03), respectively. No significant association was found in APOE4-negative subjects. These results, in accordance with a solid pathophysiological rationale, suggest a role for HSV-1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele.

Using Primary SCG Neuron Cultures to Study Molecular Determinants of HSV-1 Latency and Reactivation.

We describe a primary neuronal culture system suitable for molecular characterization of herpes simplex virus type 1 (HSV-1) infection, latency, and reactivation. While several alternative models are available, including infections of live animal or explanted ganglia, these are complicated by the presence of multiple cell types, including immune cells, and difficulties in manipulating the neuronal environment. The highly pure neuron culture system described here can be readily manipulated and is ideal for molecular studies that focus exclusively on the relationship between the virus and host neuron, the fundamental unit of latency. As such this model allows for detailed investigations of both viral and neuronal factors involved in the establishment and maintenance of HSV-1 latency and in viral reactivation induced by defined stimuli.

Traditional Chinese Medicine as a Potential Source for HSV-1 Therapy by Acting on Virus or the Susceptibility of Host.

Herpes simplex virus type 1 (HSV-1) is the most common virus, with an estimated infection rate of 60–95% among the adult population. Once infected, HSV-1 can remain latent in the host for a lifetime and be reactivated in patients with a compromised immune system. Reactivation of latent HSV-1 can also be achieved by other stimuli. Though acyclovir (ACV) is a classic drug for HSV-1 infection, ACV-resistant strains have been found in immune-compromised patients and drug toxicity has also been commonly reported. Therefore, there is an urge to search for new anti-HSV-1 agents. Natural products with potential anti-HSV-1 activity have the advantages of minimal side effects, reduced toxicity, and they exert their effect by various mechanisms. This paper will not only provide a reference for the safe dose of these agents if they are to be used in humans, referring to the interrelated data obtained from in vitro experiments, but also introduce the main pharmacodynamic mechanisms of traditional Chinese medicine (TCM) against HSV-1. Taken together, TCM functions as a potential source for HSV-1 therapy by direct (blocking viral attachment/absorption/penetration/replication) or indirect (reducing the susceptibility to HSV-1 or regulating autophagy) antiviral activities. The potential of these active components in the development of anti-HSV-1 drugs will also be described.

The HSV-1 mechanisms of cell-to-cell spread and fusion are critically dependent on host PTP1B.

All herpesviruses have mechanisms for passing through cell junctions, which exclude neutralizing antibodies and offer a clear path to neighboring, uninfected cells. In the case of herpes simplex virus type 1 (HSV-1), direct cell-to-cell transmission takes place between epithelial cells and sensory neurons, where latency is established. The spreading mechanism is poorly understood, but mutations in four different HSV-1 genes can dysregulate it, causing neighboring cells to fuse to produce syncytia. Because the host proteins involved are largely unknown (other than the virus entry receptor), we were intrigued by an earlier discovery that cells infected with wild-type HSV-1 will form syncytia when treated with salubrinal. A biotinylated derivative of this drug was used to pull down cellular complexes, which were analyzed by mass spectrometry. One candidate was a protein tyrosine phosphatase (PTP1B), and although it ultimately proved not to be the target of salubrinal, it was found to be critical for the mechanism of cell-to-cell spread. In particular, a highly specific inhibitor of PTP1B (CAS 765317-72-4) blocked salubrinal-induced fusion, and by itself resulted in a dramatic reduction in the ability of HSV-1 to spread in the presence of neutralizing antibodies. The importance of this phosphatase was confirmed in the absence of drugs by using PTP1B-/- cells. Importantly, replication assays showed that virus titers were unaffected when PTP1B was inhibited or absent. Only cell-to-cell spread was altered. We also examined the effects of salubrinal and the PTP1B inhibitor on the four Syn mutants of HSV-1, and strikingly different responses were found. That is, both drugs individually enhanced fusion for some mutants and reduced fusion for others. PTP1B is the first host factor identified to be specifically required for cell-to-cell spread, and it may be a therapeutic target for preventing HSV-1 reactivation disease.

Molecular Mechanisms for Herpes Simplex Virus Type 1 Pathogenesis in Alzheimer's Disease.

This review focuses on research in the areas of epidemiology, neuropathology, molecular biology and genetics that implicates herpes simplex virus type 1 (HSV-1) as a causative agent in the pathogenesis of sporadic Alzheimer’s disease (AD). Molecular mechanisms whereby HSV-1 induces AD-related pathophysiology and pathology, including neuronal production and accumulation of amyloid beta (Aβ), hyperphosphorylation of tau proteins, dysregulation of calcium homeostasis, and impaired autophagy, are discussed. HSV-1 causes additional AD pathologies through mechanisms that promote neuroinflammation, oxidative stress, mitochondrial damage, synaptic dysfunction, and neuronal apoptosis. The AD susceptibility genes apolipoprotein E (APOE), phosphatidylinositol binding clathrin assembly protein (PICALM), complement receptor 1 (CR1) and clusterin (CLU) are involved in the HSV lifecycle. Polymorphisms in these genes may affect brain susceptibility to HSV-1 infection. APOE, for example, influences susceptibility to certain viral infections, HSV-1 viral load in the brain, and the innate immune response. The AD susceptibility gene cholesterol 25-hydroxylase (CH25H) is upregulated in the AD brain and is involved in the antiviral immune response. HSV-1 interacts with additional genes to affect cognition-related pathways and key enzymes involved in Aβ production, Aβ clearance, and hyperphosphorylation of tau proteins. Aβ itself functions as an antimicrobial peptide (AMP) against various pathogens including HSV-1. Evidence is presented supporting the hypothesis that Aβ is produced as an AMP in response to HSV-1 and other brain infections, leading to Aβ deposition and plaque formation in AD. Epidemiologic studies associating HSV-1 infection with AD and cognitive impairment are discussed. Studies are reviewed supporting subclinical chronic reactivation of latent HSV-1 in the brain as significant in the pathogenesis of AD. Finally, the rationale for and importance of clinical trials treating HSV-1-infected MCI and AD patients with antiviral medication is discussed.

Herpes simplex virus type 2 IgG antibodies in sera of umbilical cord as a proxy for placental infection in asymptomatic pregnant women.

Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent diseases worldwide and is mainly sexually transmitted. When infecting pregnant women, HSV-2 is able to infect the placenta, can reach the fetus, and may affect the fetal development. We sought to determine the prevalence of HSV-2 infection and reactivation in asymptomatic pregnant women, the correlation between IgG in the maternal circulation and cord blood, and the correlation between circulating IgG, placental, and newborn infection (blood cord). Serum samples and placental tissues from pregnant women and umbilical cord blood samples from their newborns were collected. Anti-HSV-2 antibodies were identified by ELISA, and HSV-2 DNA was detected by nested PCR. The seropositivity of IgG in pregnant women was 29.7% and IgM was detected in 1 woman (0.5%). In the umbilical cord of newborns, 33.1% were IgG-positive and IgM was detected in 2 samples (1.5%). A positive correlation between HSV-2 IgG titers in serum from pregnant women and cord blood samples was found (r=.36, P=.001). A difference between the positive and negative placental groups (maternal side) was found in titers of IgG in sera of umbilical cord, which were significantly higher in the positive placental group (P=.004). We describe for the first time that newborns from mothers with HSV-2 placental infection have higher IgG titers in sera of umbilical cord, suggesting IgGs antibodies can be indicative of placental viral infection in asymptomatic women.

Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts.

Support for the concept that herpes simplex virus type 1 (HSV1), when present in the brains of apolipoprotein E-ε4 carriers, is a major risk for Alzheimer's disease (AD) is increasing steadily, with over 120 publications providing direct or indirect evidence relevant to the hypothesis. No articles have contested the concept, apart from 3 published 13-18 yr ago. This review describes very recent studies on the role of HSV1 but refers also to older studies that provide background for some lesser-known related topics not covered in other recent reviews; these include the relevance of herpes simplex encephalitis and of epilepsy to AD, the action of IFN, and the possible relevance of the different types of DNA damage to AD-in particular, those caused by HSV1-and mechanisms of repair of damage. New epidemiologic data supporting previous studies on mild cognitive impairment and progression to AD are reviewed, as are those examining the relationship between total infectious burden (additive seropositivity to various microbes) and cognition/AD. The latter indicates the involvement of HSV1 and cytomegalovirus (and the necessity of taking into account any marked differences in sensitivity of antibody detection). Recent studies that provide further support for the occurrence of repeated reactivation of latent HSV1 in the brain in AD pathogenesis are also discussed.-Itzhaki, R. F. Herpes simplex virus type 1 and Alzheimer's disease: possible mechanisms and signposts.