Role Of Herpes Simplex Virus Research Articles

Herpes Simplex Virus Infection and in vivo Alzheimer’s Disease Pathologies

AbstractBackgroundInterest in the role of Herpes Simplex Virus (HSV) infection in the pathogenesis of Alzheimer’s disease (AD) has increased in recent years. However, previous studies yielded inconsistent findings and no studies have yet investigated the relationship between HSV infection and in vivo AD pathologies such as beta‐amyloid (Aβ) and tau deposition in brain. We examined whether the level of serum anti‐HSV immunoglobulin G (IgG) antibodies (HSV‐IgG), an index of past infection of HSV, is associated with in vivo Aβ and tau deposition in nondemented individuals. We also investigated the modulating effect of HSV‐IgG titer on the relationship between Aβ and tau deposition.MethodA total of 426 nondemented older individuals (55‐90 years old) were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. All participants underwent comprehensive clinical assessment, [11C]‐Pittsburgh Compound B positron emission tomography (PET), and blood sampling for measurement of serum HSV antibodies. A subset of participants (N = 129) underwent [18F] AV‐1451 PET. Individuals whose HSV‐IgG titer was lower than 25 percentile of the whole group was classified as the HSVlow group, while those with HSV‐IgG titer higher than 25 percentile were classified as the HSVhigh group.ResultThere was no significant difference in age, sex, clinical diagnosis (cognitive normal vs. mild cognitive impairment), and apolipoprotein E e4 positivity (APOE4) between the HSVlow (N = 106) and HSVhigh (N = 320) groups. In terms of AD biomarkers, neither global Aβ nor tau deposition was different between the HSVhigh and HSVlow groups, even after controlling the effect of age, sex, and APOE4. However, there was a significant HSV group x Aβ deposition interaction effect on tau deposition (p = 0.037), suggesting the level of HSV‐IgG modulates the relationship between Aβ and tau deposition. Subsequent subgroup analyses showed a significant positive association between Aβ and tau deposition only in the HSVhigh group (p < 0.001), but not in the HSVlow group.ConclusionOur finding suggests that past HSV infection may aggravate the influence of Aβ on tau deposition. In regard of AD prevention, the result also supports that more attention needed to be paid to controlling HSV infection.

Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer's disease.

Alzheimer's Disease (AD) is an aging-associated neurodegenerative disorder, threatening millions of people worldwide. The onset and progression of AD can be accelerated by environmental risk factors, such as bacterial and viral infections. Human herpesviruses are ubiquitous infectious agents that underpin numerous inflammatory disorders including neurodegenerative diseases. Published studies concerning human herpesviruses in AD imply an active role HSV-1 in the pathogenesis of AD. This review will summarize the current understanding of HSV-1 infection in AD and highlight some barriers to advance this emerging field.

Detection of herpes simplex viruses in the oral lesions of patients with pemphigus vulgaris: Is it diagnostic or predictive of disease severity?

Some studies emphasise the relationship between the herpes simplex virus (HSV) and pemphigus. Although the possible role of HSV in the pathogenesis of pemphigus and the severity of the disease is obscure, we aimed to evaluate the presence of herpes simplex viruses (HSV 1/2) in the oral lesions of patients with pemphigus vulgaris and also assess its association with disease severity and types of lesions. A retrospective study was conducted on collected data in the form of collecting paraffin blocks, slides, and relevant pathology reports and referring to patients' medical records. A questionnaire containing details on the degree of skin, scalp, and mucosal involvement (Pemphigus Disease Area Index (PDAI)) was fulfiled. The immunoassay result was also collected to check the anti-desmoglein 3 and 1 antibodies (using ELISA technique). In this study, 52 patients of pemphigus vulgaris with oral lesions (case) and 52 patients with oral lesions not related to the disease (control) were evaluated. HSV1 was detected in 13.5% of oral pemphigus lesions and 1.9% of the control group (p=0.0598). There were no positive cases of HSV2 in either group. There was no significant association between the positivity of HSV1 and the site of lesions (p=1.00) or disease severity (p=0.28). However, we found a strong correlation between the PDAI disease severity score with the titre of the AntiDsg3 antibody (r=0.487, p=0.001) and AntiDsg1 antibody (r=0.309, p=0.026). This study demonstrated a significant prevalence of HSV1 in oral pemphigus lesions, and acyclovir therapy may play a significant role in managing these patients. However, HSV's role in the pathogenesis of pemphigus vulgaris cannot be clearly determined.

Comparison of Herpes Simplex Virus Reactivation Frequency in Acute Idiopathic Cranial Mononeuropathy and Normal Population by Serological Assay

Background: Herpes simplex virus (HSV) is a neurotropic DNA virus with a high prevalence. Following primary infection, HSV remains dormant in the neural ganglia. Secondary infection can emerge after the reactivation of latent infection, presenting as neurological manifestations. Previous studies have demonstrated the relationship between HSV reactivation and selective involvement of cranial nerves. Depending on the affected nerve, cranial mononeuropathies can present with symptoms, including diplopia, blurred vision, vertigo, unilateral facial palsy, speech impairment, swallowing difficulties, and hoarseness. Objectives: This study used a serological assay to compare HSV reactivation frequency between patients with recent idiopathic cranial mononeuropathies and normal individuals. Methods: Plasma samples from 35 idiopathic cranial mononeuropathy cases (57.2% women, mean age 58.37 years) and 35 age and sex-matched healthy controls were analyzed for anti-HSV immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies by enzyme-linked immunosorbent assay (ELISA). Results: Anti-HSV IgG antibody was positive in 91.4% of patients and 88.6% of controls. The mean serum anti-HSV IgG antibody level was significantly higher in patients (146.78 ± 60 RU/mL) than in the controls (130.61 ± 52.99 RU/mL) (P-value = 0.037). Anti-HSV IgM antibody was positive in 37.1% of patients and 14.3% of controls (P = 0.042). Conclusions: The frequency of HSV reactivation was significantly higher in patients with acute idiopathic cranial mononeuropathy than in the healthy controls, indicating the possible role of HSV as an etiology of cranial mononeuropathy.

Does herpes simplex virus have a role in the pathogenesis of systemic lupus erythematosus in Egyptians?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune mediated tissue damage affecting a wide range of organs. The pathogenesis of SLE is complex. Infectious agents, including viruses, can act as environmental triggers, inducing or promoting onset and exacerbations of autoimmune disease in genetically predisposed individuals. Viral infections may be involved in the pathogenesis of SLE. To date, there is no published data about role of herpes simplex virus (HSV) in pathogenesis of SLE in Egyptian population. This study was designed to investigate a possible role of HSV in pathogenesis of SLE and its relation to disease activity. This study included 90 SLE female patients and 83 apparently healthy age-matched female subjects. SLE disease activity was assessed using SLEDAI-2K score. Qualitative assessment of anti-HSV antibodies (HSV1/2 IgM and IgG) was performed using ELISA kits. There was no statistically significant difference in frequency of HSV1/2 IgG positive test between SLE patients (97.6%) and control subjects (94.4%). There was a statistically significant increase in frequency of HSV1/2 IgM positive test in SLE patients compared to control subjects (P < 0.001). There was no difference in the frequency of HSV1/2 IgM and HSV1/2 IgG positive test results between SLE patients with higher disease activity score (60% and 95.6%, respectively) and those with lower disease activity score (60% and 93.3%, respectively). High prevalence of HSV1/2 IgG antibodies was observed among Egyptians. The lack of significant difference in frequency of HSV1/2 IgG between SLE patients and control subjects may indicate that HSV is not involved in SLE pathogenesis. Also, HSV infection may have no role in SLE disease exacerbation due to the absence of significant difference in the frequency of HSV1/2 IgM and HSV1/2 IgG antibodies in SLE patients with higher disease activity compared to those with lower disease activity.

Importance of herpes simplex virus in development of infertility in married couples

The article considers the role of herpes simplex viruses of 1st, 2nd types in the development of reproductive disorders in married couples. The clinical example shows the difficulties of diagnosis, possible errors in treatment approaches, and the lack of results from the use of artificial insemination methods in the presence of persistent herpetic infection. Prolonged antiviral therapy led to the onset of pregnancy and the birth of a child.

Incidental Anaplastic Lymphoma in a Case of Herpetic Hepatitis

Abstract Introduction/Objective The role of Herpes Simplex Virus (HSV) virus in the development of lymphomas is unclear and poses a diagnostic challenge along with limited literature explaining the relationship between HSV and Anaplastic large-cell lymphoma (ALCL). Methods A 26-year-old female admitted for intractable fever (103.7 F), chills, and dysuria; her urine analysis was suggestive of a mild urinary tract infection. During the admission, she developed abdominal pain with subsequent CT- scan showing thickening of the gallbladder and possible cholecystic fluid. Her liver function tests were: albumin 2.8 g/dL, AST 394 U/L, ALT 303 U/L, ALP 156 U/L, total bilirubin 0.3 INR 1. A subsequent Magnetic Resonance Cholangiopancreatography (MRCP) showed heterogeneous enhancement pattern of the liver without any masses following which she underwent cholecystectomy, during which her liver was abnormal along with an enlarged peri- cholic lymph node. Intraoperative biopsy of the liver showed patchy hepatocyte necrosis and occasional hepatocytes with ground-glass nuclei. The morphologic features were suggestive for Herpes Simplex Virus (HSV) hepatitis, and an HSV immunohistochemical stain confirmed this diagnosis. Removal of the lymph node showed a sinusoidal infiltrate of atypical lymphohistiocytic cells with abundant pale cytoplasm and large moderately irregular nuclei and occasional prominent amphophilic nucleoli. A few “hallmark”-like cells with curved nuclei were noted with rare mitosis. A panel of adequately controlled immunohistochemical stains showed positivity for CD4, CD30 (variable), and CD45. CD2, CD3, CD5, CD7, CD8, CD10, CD15, CD20, CD68 (positive in adjacent macrophages), BCL2, ALK1 were negative. Results Flow cytometry was negative for a neoplastic leukocyte population with a polytypic B-cell population. Taken together, a diagnosis of ALK1 negative, ALCL was made. A subsequent CT scan revealed borderline enlarged para- aortic lymph nodes along with an increased number of non-enlarged lymph nodes in the bilateral axillary, mediastinal, lower neck, and subpectoral regions. A bone marrow biopsy performed was negative for lymphoma. Conclusion Off note, her hepatitis serology panel, CMV, and HIV screens were negative. Thus, with her unusual presenting symptoms and no signs of malignancy led to numerous workups, which further led to an infectious cause, however, the patient was ultimately discovered to have an occult ALCL.

The impact of the viral-bacterial consortium on occurrence and development of chronic periodontitis

Relevance. The current theory of specific bacterial biofilm fails explain why a part of patients experiences inflammatory periodontal diseases while the absence of detected specific types of “red complex” bacteria.Purpose. To clarify the microbiological and immunological mechanisms of the influence of the viral and bacterial consortium in the etiology and pathogenesis of inflammatory periodontal diseases.Materials and methods. Articles survey with elements of metanalisis. Literature review based on discussion of research results on the topic of 48 sources including 33 foreign ones.Results. The review provides evidences of the possible participation of viruses of the Herpesviridae family in the development of chronic generalized periodontitis. Evidences for the role of herpes simplex viruses of type 1.2, Epstein-Barr virus, and cytomegalovirus in the development of periodontal inflammation are analyzed. It is proven that all herpesviruses induce the release of proinflammatory cytokines that activate osteoclasts and matrix metalloproteinases, as well as violate antibacterial immune mechanisms. In turn that leads to a progressive increase of periodontal pathogenic bacteria in both the biofilm and periodontal tissues.Conclusion. It is made a conclusion that an active herpetic infection can initiate damage to periodontal tissus and participate in the development of relapses of the disease.

Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation

The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown. To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation. A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018. Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo. The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis. Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, -0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events. In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting. ClinicalTrials.gov identifier: NCT02152358.

Acyclovir for Mechanically Ventilated Patients with Herpes Simplex Virus Oropharyngeal Reactivation

Background: The role of herpes simplex virus (HSV) reactivation on morbidity/mortality in intensive care unit patients requiring mechanical ventilation remains controversial. Methods: In this multicentre study, non-immunosuppressed adults >18 years old, mechanically ventilated for at least 96 hours and expected to remain on mechanical ventilation for ≥48 hours, with HSV oropharyngeal reactivation, were double-blindly randomized to receive intravenous acyclovir (5 mg/kg tid, for 14 days) or a matching placebo (controls). Randomisation (1:1) was stratified by study site, pre-randomisation mechanical ventilation duration and number of organ failure, and performed using a secure web-based system. The primary endpoint was ventilator-free days from randomisation to day 60. Findings: The 16 participating centres randomised 238 patients: 119 to receive acyclovir and 119 the placebo. On day 60, for acyclovir recipients and controls, respectively, the median (IQR) numbers of ventilator-free days were 35 (0-53) and 36 (0-50) (p=0.17 for between-group comparison); 26 (22%) and 39 (33%) patients had died (risk difference, 0.11, 95% CI, - 0.004 to 0.22, p=0.059). The adverse-event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, p= 0.4), particularly with acute renal failure post-randomisation affecting three acyclovir recipients and two controls. Four patients in the acyclovir group (vs. none in the placebo group) stopped the study drug for treatment-related adverse event. Interpretation: In non-immunosuppressed patients mechanically ventilated for ≥96 hours with HSV reactivation in the throat, intravenous acyclovir use (5 mg/kg tid) did not increase the number of ventilator-free days on day 60, compared to a placebo. Trial Registration: The trial is registered on ClinicalTrials.gov, number NCT02152358. Funding Statement: Direction de la Recherche Clinique et du Developpement and the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2011). Declaration of Interests: No potential conflict of interest relevant to this article was reported. The following conflicts of interest are outside the area of the article. Dr Luyt reports receiving lecture fees from ThermoFischer Brahms, Biomerieux, Merck Sharp & Dohme and Aerogen, and consulting fees from Bayer Healthcare, Carmat and Faron. Dr Jaber reports receiving consulting fees from Drager, Fisher-Paykel, Xenios-Fresenius Medical and Medtronic. Dr Rimmele reports receiving consulting or lecture fees from Fresenius Medical Care, Baxter, Medtronic, Biomerieux, BBraun. Dr Lu reports receiving lectures fees from Aerogen. Dr Combes reports receiving grant support and lectures fees from Maquet and Baxter and consulting fees from Hemovent. Dr Wolff reports receiving consulting fees from Merck Sharp & Dohme, Inotrem, Correvio, Menarini and Pfizer. Dr Chastre reports receiving lecture and consulting fees from Bayer Healthcare, Pfizer, Merck Sharp & Dohme, Aridis, the Medicines Company, Astra Zenecca, Tigenix, Accelerate Diagnotics, Inotrem and Glaxo Smith Kline Ethics Approval Statement: An independent Ethics Committee (Comite de Protection des Personnes Sud Mediterranee 5) approved its protocol.

Behcet disease combined with Sjogren syndrome

Rationale:Behcet disease(BD) and Sjogren syndrome(SS) are separate conditions that rarely concomitantly affect an individual. In theory,mild symptoms of patients with BD or SS are easy to igore and,thus,remain undiagnosed. There,it is reasonable to believe there may be some clinical cases of combined diseases that go undiscovered and which needs to be taken seriously. In addition,it has been suggested that herpes simplex virus(HSV) types 1 and 2 are associated with BD,but have not been shown to be correlated to the direct pathogenesis of BD. The role of HSV in BD needs more research and attention.Patient concerns:Here,we report a young woman who had both BD and SS. The first symptom of the disease was fever. However,the HSV type 1 IgG and HSV type 2 IgM antibody results were positive in our case and,which rendered this case unique.Diagnoses:BD and SS concomitantly affect the individual,and BD was the acute type.Interventions:IV methylprednisolone was used for 9 days and then oral glucocorticoids was used to instead,and the treatment works very well.Outcomes: BD and SS can concomitantly affect an individual,and we believe that HSV-2 may be directly related to the pathogenesis of BD. The nature of BD as an auto-inflammatory disorder, autoimmune disorder, or both, is controversial. If we can find more patients who combined affected these two disease, it might helpful for us to understand the nature of BD.Lessons:For patients with clinical diagnosis of BD or SS,we need to be alert that it may combinded the other disease. Long term follow up and detailed inspection are important means to avoid undiscovered.

Role of Herpes Simplex Virus 1 γ34.5 in the Regulation of IRF3 Signaling.

During viral infection, pattern recognition receptors (PRRs) and their associated adaptors recruit TANK-binding kinase 1 (TBK1) to activate interferon regulatory factor 3 (IRF3), resulting in production of type I interferons (IFNs). ICP0 and ICP34.5 are among the proteins encoded by herpes simplex virus 1 (HSV-1) that modulate type I IFN signaling. We constructed a recombinant virus (ΔXX) that lacks amino acids 87 to 106, a portion of the previously described TBK1-binding domain of the γ34.5 gene (D. Verpooten, Y. Ma, S. Hou, Z. Yan, and B. He, J Biol Chem 284:1097-1105, 2009, https://doi.org/10.1074/JBC.M805905200). These 20 residues are outside the γ34.5 beclin1-binding domain (BBD) that interacts with beclin1 and regulates autophagy. Unexpectedly, ΔXX showed no deficit in replication in vivo in a variety of tissues and showed virulence comparable to that of wild-type and marker-rescued viruses following intracerebral infection. ΔXX was fully capable of mediating the dephosphorylation of eIF2α, and the virus was capable of controlling the phosphorylation of IRF3. In contrast, a null mutant in γ34.5 failed to control IRF3 phosphorylation due to an inability of the mutant to sustain expression of ICP0. Our data show that while γ34.5 regulates IRF3 phosphorylation, the TBK1-binding domain itself has no impact on IRF3 phosphorylation or on replication and pathogenesis in mice.IMPORTANCE Interferons (IFNs) are potent activators of a variety of host responses that serve to control virus infections. The Herpesviridae have evolved countermeasures to IFN responses. Herpes simplex virus 1 (HSV-1) encodes the multifunctional neurovirulence protein ICP34.5. In this study, we investigated the biological relevance of the interaction between ICP34.5 and TANK-binding kinase 1 (TBK1), an activator of IFN responses. Here, we establish that although ICP34.5 binds TBK1 under certain conditions through a TBK1-binding domain (TBD), there was no direct impact of the TBD on viral replication or virulence in mice. Furthermore, we showed that activation of IRF3, a substrate of TBK1, was independent of the TBD. Instead, we provided evidence that the ability of ICP34.5 to control IRF3 activation is through its ability to reverse translational shutoff and sustain the expression of other IFN inhibitors encoded by the virus. This work provides new insights into the immunomodulatory functions of ICP34.5.

Positive correlation of anti-herpes simplex type I virus antibody levels with pemphigus vulgaris disease status and activity in a large patient cohort.

It is well accepted that pemphigus vulgaris (PV) is genetically linked to specific HLA class II subtypes. Environmental factors, including the role of herpes simplex virus (HSV1) in disease manifestation, have also been implicated, but in a limited number of patients and with inconsistent results. To clarify an association between HSV1 and PV in a large data set, including a stratification by dynamic and static clinical parameters, including disease activity, therapy status, HLA association, and gender. Serum HSV1 IgG levels from PV patients and healthy controls were measured by ELISA. Subjects were typed for HLA class II DRB1 and DQB1 alleles, and categorized as HLA-matched if homozygous or heterozygous for either one of the known PV-susceptibility alleles, DRB1*0402 and DQB1*0503. Our data indicate that PV patients carry significantly higher levels of anti-HSV1 antibodies than healthy controls, and that this effect was more pronounced in the active phase of disease when compared to remission. A mild positive association could also be observed for carriers of the PV-associated HLA alleles versus HLA-unmatched controls, as well as for female PV patients when compared to female control subjects. Our data suggest a role of HSV1 in the expression of PV and further show that HLA status and gender may influence HSV1 susceptibility and/or expression of anti-HSV1 antibodies. Additional research with larger datasets is required to determine whether HSV is causally linked to PV pathogenesis and conclusively link HLA status and gender to HSV1 antibody levels.

Role of Herpes simplex virus 1 VP11/12 tyrosine-based binding motifs for Src family kinases, p85, Grb2 and Shc in activation of the phosphoinositide 3-kinase-Akt pathway

The abundant HSV-1 tegument protein VP11/12 encoded by gene UL46 is essential for induction of the PI3K/Akt-signaling pathway during infection. VP11/12 utilizes tyrosine-based motifs within its C-terminal region to bind the SH2 domains of Src family kinases, the p85 subunit of PI3 Kinase and Grb2, and the PTB domain of Shc. We previously proposed that the interaction with SFKs and p85 is used to gain control over the PI3K/Akt signaling pathway. We tested this model by evaluating the effects of mutations that eliminate each of these interactions on the ability of HSV-1 to activate Akt. Inhibiting the interaction of VP11/12 with SFKs, p85 and Grb2 reduced Akt activation, while inhibiting the interaction with Shc had little effect. Overall these data support the suggestion that VP11/12 stimulates the PI3K/Akt pathway by mimicking an activated growth factor receptor.

Transmitted HIV-1 Drug resistance and the Role of Herpes Simplex Virus -2 Coinfection among Fishermen along the Shores of Lake Victoria, Kisumu, Kenya

Introduction: Herpes simplex virus type 2 (HSV-2) infection has been associated with a 3-fold risk of HIV-1 acquisition. The prevalence of HIV-1 and HSV-2 in the fishing communities along the shores of Lake Victoria in Kisumu have been reported to be high. This may contribute to the growing HIV epidemic in Kenya including the spread of transmitted drug resistance (TDR). We report data on the association of HSV2/HIV-1 co-infection and TDR in this antiretroviral (ARV)-naïve population. Methods: Blood samples were obtained from 249 consenting fishermen from 5 beaches and a detailed sociodemographic questionnaire was administered. Blood samples were analyzed for HIV-1/HSV2 co-infection. The HSV-2 serology was performed using Kalon HSV type 2 enzyme-linked immunosorbent assay (ELISA). The HIV-1 counselling and serology were carried out according to local standards of practice in Kenya, using two parallel rapid assays (Alere Determine HIV-1/2 and Trinity Biotech Uni- Gold), with a third ELISA-Vironostika HIV Uni-Form II Ag/Ab for resolving discrepancies. All HIV positive samples were tested for TDR using an in house HIV-1 pol-RT genotyping protocol. Results: Of the 249 recruited fishermen (mean age 35.1 years), 134 (53.8%) were positive for HSV-2, 59 (23.7%) were HIV positive while 48 (19.3%) were HIV/HSV-2 coinfected. Twenty-three of 59 (38.9%) HIV positive men had TDR, with the majority (19/23, 82.6%) in HIV/HSV-2 coinfected fishermen. Among the 48 HIV/HSV-2 co-infected fishermen, 9 had nucleoside reverse-transcriptase inhibitor (NRTI) resistance mutations with NRTI- associated mutations [NAMS], M184V (77.8%) and K65R (11.1%) being the highest. Nineteen (19) fishermen had Non-NRTI (NNRTIs) mutations including; four (21.1%) each of K103N, Y181C and G190A. Three (15.7%) V179T, two V901V and single A98G and Y188L mutations. Among the 11 fishermen who had HIV-1 mono-infection, four (36.4%) had drug resistant mutations. One fisherman had NRTI resistance mutation M184V. In addition, three men (3/4) had NNRTI resistance; K103N, G190A and Y181C mutations each. In the regression model, HIV/HSV-2 co-infection was independently associated with TDR [OR 4.1 (95% CI 1.4 to 11.9)]. Conclusion: The level of TDR to NNRTIs in these ARV-naive fishermen was significantly high especially among those coinfected with HSV-2. HSV-2 infection may increase the risk of TDR in this population.

Dual Role of Herpes Simplex Virus 1 pUS9 in Virus Anterograde Axonal Transport and Final Assembly in Growth Cones in Distal Axons.

The herpes simplex virus type 1 (HSV-1) envelope protein pUS9 plays an important role in virus anterograde axonal transport and spread from neuronal axons. In this study, we used both confocal microscopy and transmission electron microscopy (TEM) to examine the role of pUS9 in the anterograde transport and assembly of HSV-1 in the distal axon of human and rat dorsal root ganglion (DRG) neurons using US9 deletion (US9(-)), repair (US9R), and wild-type (strain F, 17, and KOS) viruses. Using confocal microscopy and single and trichamber culture systems, we observed a reduction but not complete block in the anterograde axonal transport of capsids to distal axons as well as a marked (∼90%) reduction in virus spread from axons to Vero cells with the US9 deletion viruses. Axonal transport of glycoproteins (gC, gD, and gE) was unaffected. Using TEM, there was a marked reduction or absence of enveloped capsids, in varicosities and growth cones, in KOS strain and US9 deletion viruses, respectively. Capsids (40 to 75%) in varicosities and growth cones infected with strain 17, F, and US9 repair viruses were fully enveloped compared to less than 5% of capsids found in distal axons infected with the KOS strain virus (which also lacks pUS9) and still lower (<2%) with the US9 deletion viruses. Hence, there was a secondary defect in virus assembly in distal axons in the absence of pUS9 despite the presence of key envelope proteins. Overall, our study supports a dual role for pUS9, first in anterograde axonal transport and second in virus assembly in growth cones in distal axons. HSV-1 has evolved mechanisms for its efficient transport along sensory axons and subsequent spread from axons to epithelial cells after reactivation. In this study, we show that deletion of the envelope protein pUS9 leads to defects in virus transport along axons (partial defect) and in virus assembly and egress from growth cones (marked defect). Virus assembly and exit in the neuronal cell body are not impaired in the absence of pUS9. Thus, our findings indicate that pUS9 contributes to the overall HSV-1 anterograde axonal transport, including a major role in virus assembly at the axon terminus, which is not essential in the neuronal cell body. Overall, our data suggest that the process of virus assembly at the growth cones differs from that in the neuronal cell body and that HSV-1 has evolved different mechanisms for virus assembly and exit from different cellular compartments.

Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study

BackgroundSeveral studies suggest a link between early-life infection and adult schizophrenia. Cross-sectional studies have reported: (1) increased prevalence of Epstein-Barr Virus (EBV), a member of the Herpesviridae family in schizophrenia; (2) a possible role of Herpes simplex virus in cognitive dysfunction in schizophrenia and healthy controls. We report a longitudinal serological study of early-life EBV infection, childhood IQ, and subsequent risk of psychotic experiences (PE) in adolescence. MethodsSerum antibodies to EBV (anti-VCA IgG) were measured in 530 participants from the ALSPAC cohort at age 4years. Assessments for IQ at age 9 and PE at age 13 were attended by 401 and 366 of these individuals, respectively. Logistic regression calculated odds ratio (OR) for PE in EBV-exposed, compared with unexposed group. Mean IQ scores were compared between these groups; effect of IQ on the EBV–PE association was examined. Potential confounders included age, gender, ethnicity, social class, household crowding, and concurrent depression and anxiety. ResultsAbout 25% of the sample was exposed to EBV at age 4. EBV exposure was associated with subsequent risk of definite PE in adolescence; OR 5.37 (95% CI 1.71–16.87), which remained significant after confounding adjustment. EBV-exposed individuals compared with unexposed performed worse on all IQ measures; mean difference in full-scale IQ 4.15 (95% CI 0.44–7.87); however, this was explained by socio-demographic differences. The EBV–PE association was not explained by IQ. ConclusionsEarly-life exposure to EBV is associated with PE in adolescence, consistent with a role of infection/immune dysfunction in the aetiology of psychosis.

Role of herpes simplex virus 1 immediate early protein ICP22 in viral nuclear egress.

In order to investigate the novel function(s) of the herpes simplex virus 1 (HSV-1) immediate early protein ICP22, we screened for ICP22-binding proteins in HSV-1-infected cells. Our results were as follows. (i) Tandem affinity purification of ICP22 from infected cells, coupled with mass spectrometry-based proteomics and subsequent analyses, demonstrates that ICP22 forms a complex(es) with the HSV-1 proteins UL31, UL34, UL47 (or VP13/14), and/or Us3. All these proteins were previously reported to be important for viral egress through the nuclear membrane. (ii) ICP22 colocalizes with UL31 and UL34 at the nuclear membrane in wild-type HSV-1-infected cells. (iii) The UL31-null mutation prevents the targeting of ICP22 to the nuclear membrane. (iv) The ICP22-null mutation resulted in UL31 and UL34 being mislocalized in the endoplasmic reticulum (in addition to the nuclear membrane) and significantly reduced numbers of primary enveloped virions in the perinuclear space, although capsids accumulated in the nuclei. Collectively, these results suggest that (i) ICP22 interacts with HSV-1 regulators of nuclear egress, including UL31, UL34, UL47, and Us3 in HSV-1-infected cells; (ii) UL31 mediates the recruitment and anchorage of ICP22 at the nuclear membrane; and (iii) ICP22 plays a regulatory role in HSV-1 primary envelopment, probably by interacting with and regulating UL31 and UL34. Here we report a previously unknown function for ICP22 in the regulation of HSV-1 nuclear egress. The herpes simplex virus 1 (HSV-1) immediate early protein ICP22 is recognized primarily as a regulator of viral gene expression. In this study, we show that ICP22 interacts with the HSV-1 proteins UL31 and UL34, which play crucial roles at the nuclear membrane in HSV-1 primary envelopment during viral nuclear egress. We also demonstrate that UL31 is required for the targeting of ICP22 to the nuclear membrane and that ICP22 is required for the correct localization of UL31 and/or UL34. Furthermore, we confirm that ICP22 is required for efficient HSV-1 primary envelopment during viral nuclear egress. Thus, we report, for the first time, that ICP22 plays a regulatory role in HSV-1 nuclear egress.

The frequency of herpes simplex virus changes in anal Pap smear and its association with squamous intraepithelial lesions in high‐risk male patients

While there are studies postulating a model of synergism between human papillomavirus (HPV) and herpes simplex virus (HSV) in cervical carcinogenesis, the frequency of anal herpes as well as its association with anal squamous intraepithelial lesions (ASILs) has been understudied in men. This study evaluates the frequency of HSV changes in anal Pap smears and its association with ASILs in a high-risk population. A computerized search for specimens associated with anal cytology that had positive findings of HSV was performed. The electronic medical records were examined for past diagnosis of herpes, HSV serology prior to or after cytology, and if the patient received treatment after cytologic diagnosis of HSV. Of the 470 anal Pap smears (Thin-prep) examined, seven had cellular changes consistent with HSV infection. All patients were asymptomatic human immunodeficiency virus (HIV) positive males with no prior HSV serology tests. Two patients had prior diagnoses of HSV infection. Cytologic abnormalities were identified in 86% ranging from atypical squamous cells of undetermined significance to high grade squamous intraepithelial lesion. Three patients were treated after the HSV cytologic diagnosis. The frequency of HSV changes in anal Pap smear is low (1.48%), but the presence of concomitant cytologic abnormalities is high (86%). While our findings suggest the possible role of HSV as a HPV co-factor in ASILs, larger studies are needed to support this. Identification of HSV infection on anal Pap smear is important for institution of patient treatment and subsequent reduction of transmission.

Herpes Simplex &amp; Cytomegalo Viruses inflicted semen substantiates infertility among men.

Infertility is a growing challenge worldwide that cause many affiliated socio-psychological problems in many cultures that carry a negative impact on many families. As a last resort, many physicians engage certain drugs to over stimulate the gonadotropins to hope for the production of healthy Sperms and Ovum to materialize the fertility. Also, Fertilization in Vitro is a growing solution for the rich but many patients are not able to afford. Over stimulation of the sperms or ovum does not constitute the chromosomal DNA/RNA to amicably contribute to the successful fertility, Normal fetal development, uneventful pregnancy and/ or normal delivery. Many countries have established the prominent link to the Cytomegaloviral and Herpes Simplex Virus to the infertility. We studied the prevalence and the role of herpes simplex virus (HSV), cytomegalovirus (CMV) in the semen of infertile men. Data was collected from sixty nine infertile men. Serum AntiHSV IgG & IgM, CMV IgG & IgM from the blood and the Real Time Polymerase chain reaction RT/ PCR test were performed on the semen to detect the presence of the HSV & CMV RNA’s in these infertile subjects. AntiCMV IgG was found in 44 (62.9%), CMV IgM in 4 (5.9%), HSV IgG in 22 (31.4%), HSV IgM in (0%) and PCR of CMV in 26 (37.1%), HSV PCR in 13 (18.8%). Overall, results revealed that the RT/ PCR of CMV were relatively more prevalent in the semen of infertile men as compared to the HSV IgG & IgM, CMV IgG & CMV IgM in the blood of infertile men.