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Herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulcer disease and a major risk factor for acquisition and transmission of HIV. Frequent recurrent genital lesions and concerns about transmitting infection to intimate partners affect the quality of life of infected individuals. Therapeutic vaccines are urgently needed to reduce the frequency of genital lesions and transmission. S-540956 is a novel vaccine adjuvant that contains CpG oligonucleotide ODN2006 annealed to its complementary sequence and conjugated to a lipid that targets the adjuvant to lymph nodes. Our primary goal was to compare S-540956 administered with HSV-2 glycoprotein D (gD2) with no treatment in a guinea pig model of recurrent genital herpes (studies 1 and 2). Our secondary goals were to compare S-540956 with oligonucleotide ODN2006 (study1) or glucopyranosyl lipid A in a stable oil-in-water nano-emulsion (GLA-SE) (study 2). gD2/S-540956 reduced the number of days with recurrent genital lesions by 56%, vaginal shedding of HSV-2 DNA by 49%, and both combined by 54% compared to PBS, and was more efficacious than the two other adjuvants. Our results indicate that S-540956 has great potential as an adjuvant for a therapeutic vaccine for genital herpes, and merits further evaluation with the addition of potent T cell immunogens.

[EN] An epidemiological model is proposed to study the transmission dynamics of the herpes virus type 2, a sexually transmitted infectious disease. This model considers two states, susceptible and infected, divides the population into sexes, assumes only heterosexual contacts and includes different transmission rates depending on whether the transmission is woman-man or man-woman. Reported and prevalence series data are retrieved from several sources. We consider the inherent data survey errors and the sensitivity of the diagnosis tests (data uncertainty). To calibrate the model to the available data and their uncertainty, a novel technique is proposed in two steps: (1) the application of the estimation of distribution algorithm (EDA) to find sets of model parameter values close to the data uncertainty and (2) the application of a selection algorithm to get a reduced number of model parameter values whose model outputs capture accurately the data uncertainty. Then, we check its robustness, and we provide a prediction of the evolution of the infected over the next 4 years. From the technical point of view, we conclude that the proposed technique to calibrate probabilistically the model is reliable and robust. Also, it is able to provide confidence intervals for the model parameter values and the predictions. From the medical point of view, the model returns that the transmission woman-man is higher than the man-woman, according to recent literature, and there is a mild increasing trend in the number of infected people over the next years., Generalitat Valenciana, Grant/Award Number: AICO/2019/215

Background: The prevalence of Herpes simplex virus type 2 (HSV-2) in cervical lesions is under-reported, especially in Human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) and Human Papillomavirus (HPV) infected persons. Objectives: This study determined the prevalence of viral mono-infections, co-infections and squamous cell intraepithelial lesions (SIL) in HIV seropositive (HIV+) and HIV seronegative (HIV-) women. Methods: This study included HIV+ and HIV- women (105 each). Cervical smears and viral antibodies were evaluated by Papanicolaou’s technique and ELISA method, respectively. Results: The prevalence of HSV-2, HPV and EBV infections, and SIL were higher in HIV+ women (75.2, 41.9, 41 and 32.4%) than in HIV- women (45.7, 26.7, 26.7 and 13.3%) at p< 0.0001, p= 0.029, 0.041 and 0.002, respectively. Higher prevalence of viral mono-infection and tri-infection was observed in HIV+ women (43.8 and 24.8%) than in HIV- women (27.6 and 8.6%) at p= 0.021, and 0.003, respectively. The prevalence of SIL was also higher in HIV+ women with viral mo- no-infection, bi-infection and tri-infection (15.2, 42.9, and 53.8%) than in HIV- women (6.9, 12.5, and 44.4%) at p= 0.468, 0.041, and 0.711, respectively. Conclusion: This study suggests that the high prevalence of SIL in HIV+ women could be associated with viral co-infec- tions. Keywords: Epstein-Barr virus; human immunodeficiency virus; human papilloma virus; herpes simplex virus type 2; cervi- cal lesion.

Herpes simplex type 2 (HSV-2) infection causes a significant life-long disease. Long-term side effects of antiviral drugs can lead to the emergence of drug resistance. Thus, propolis, a natural product derived from beehives, has been proposed to prevent or treat HSV-2 infections. Unfortunately, therapeutic applications of propolis are still limited due its poor solubility. To overcome this, a nanoparticle-based drug delivery system was employed. An ethanolic extract of propolis (EEP) was encapsulated in nanoparticles composed of poly(lactic-co-glycolic acid) and chitosan using a modified oil-in-water single emulsion by using the solvent evaporation method. The produced nanoparticles (EEP-NPs) had a spherical shape with a size of ~450 nm and presented satisfactory physicochemical properties, including positively charged surface (38.05 ± 7.65 mV), high entrapment efficiency (79.89 ± 13.92%), and sustained release profile. Moreover, EEP-NPs were less cytotoxic on Vero cells and exhibited anti-HSV-2 activity. EEP-NPs had a direct effect on the inactivation of viral particles, and also disrupted the virion entry and release from the host cells. A significant decrease in the expression levels of the HSV-2 replication-related genes (ICP4, ICP27, and gB) was also observed. Our study suggests that EEP-NPs provide a strong anti-HSV-2 activity and serve as a promising platform for the treatment of HSV-2 infections.

The toxicity of mRNA-lipid nanoparticle (LNP) vaccines depends on the total mRNA-LNP dose. We established that the maximum tolerated dose of our trivalent mRNA-LNP genital herpes vaccine was 10 μg/immunization in mice. We then evaluated one of the mRNAs, gD2 mRNA-LNP, to determine how much of the 10 μg total dose to assign to this immunogen. We immunized mice with 0.3, 1.0, 3.0, or 10 μg of gD2 mRNA-LNP and measured serum IgG ELISA, neutralizing antibodies, and antibodies to six crucial gD2 epitopes involved in virus entry and spread. Antibodies to crucial gD2 epitopes peaked at 1 μg, while ELISA and neutralizing titers continued to increase at higher doses. The epitope results suggested no immunologic benefit above 1 μg of gD2 mRNA-LNP, while ELISA and neutralizing titers indicated higher doses may be useful. We challenged the gD2 mRNA-immunized mice intravaginally with HSV-2. The 1-μg dose provided total protection, confirming the epitope studies, and supported assigning less than one-third of the trivalent vaccine maximum dose of 10 μg to gD2 mRNA-LNP. Epitope mapping as performed in mice can also be accomplished in phase 1 human trials to help select the optimum dose of each immunogen in a multivalent vaccine.

(1) Background: Lactoferrin has been recognized as a potent inhibitor of human herpetic viruses, such as herpes simplex type 1 (HSV-1) and 2 (HSV-2). In this work, we tested if silver and gold nanoparticles modified with lactoferrin (LF-Ag/AuNPs) can become novel microbicides with additional adjuvant properties to treat genital herpes infection. (2) Methods: The antiviral and cytotoxic activities of LF-Ag/AuNPs were tested in human skin HaCaT and vaginal VK-2-E6/E7 keratinocytes. Viral titers and immune responses after treatment with LF-Ag/AuNPs were tested in murine vaginal HSV-2 infection. (3) Results: LF-Ag/AuNPs inhibited attachment and entry of HSV-2 in human keratinocytes much better than lactoferrin. Furthermore, pretreatment with LF-AgNPs led to protection from infection. Infected mice treated intravaginally with LF-Ag/AuNPs showed lower virus titers in the vaginal tissues and spinal cords in comparison to treatment with lactoferrin. Following treatment, vaginal tissues showed a significant increase in CD8+/granzyme B + T cells, NK cells and dendritic cells in comparison to NaCl-treated group. LF-Ag/AuNPs-treated animals also showed significantly better expression of IFN-γ, CXCL9, CXCL10, and IL-1β in the vaginal tissues. (4) Conclusions: Our findings show that LF-Ag/AuNPs could become effective novel antiviral microbicides with immune-stimulant properties to be applied upon the mucosal tissues.

Herpesviruses are highly prevalent in the human population, and frequent reactivations occur throughout life. Despite antiviral drugs against herpetic infections, the increasing appearance of drug-resistant viral strains and their adverse effects prompt the research of novel antiherpetic drugs for treating lesions. Peptides obtained from natural sources have recently become of particular interest for antiviral therapy applications. In this work, we investigated the antiviral activity of the peptide A-3302-B, isolated from a marine bacterium, Micromonospora sp., strain MAG 9-7, against herpes simplex virus type 1, type 2, and human cytomegalovirus. Results showed that the peptide exerted a specific inhibitory activity against HSV-2 with an EC50 value of 14 µM. Specific antiviral assays were performed to investigate the mechanism of action of A-3302-B. We demonstrated that the peptide did not affect the expression of viral proteins, but it inhibited the late events of the HSV-2 replicative cycle. In detail, it reduced the cell-to-cell virus spread and the transmission of the extracellular free virus by preventing the egress of HSV-2 progeny from the infected cells. The dual antiviral and previously reported anti-inflammatory activities of A-3302-B, and its effect against an acyclovir-resistant HSV-2 strain are attractive features for developing a therapeutic to reduce the transmission of HSV-2 infections., International Journal of Molecular Sciences, 23 (2), ISSN:1422-0067

Herpesviruses are highly prevalent in the human population, and frequent reactivations occur throughout life. Despite antiviral drugs against herpetic infections, the increasing appearance of drug-resistant viral strains and their adverse effects prompt the research of novel antiherpetic drugs for treating lesions. Peptides obtained from natural sources have recently become of particular interest for antiviral therapy applications. In this work, we investigated the antiviral activity of the peptide A-3302-B, isolated from a marine bacterium, Micromonospora sp., strain MAG 9-7, against herpes simplex virus type 1, type 2, and human cytomegalovirus. Results showed that the peptide exerted a specific inhibitory activity against HSV-2 with an EC50 value of 14 μM. Specific antiviral assays were performed to investigate the mechanism of action of A-3302-B. We demonstrated that the peptide did not affect the expression of viral proteins, but it inhibited the late events of the HSV-2 replicative cycle. In detail, it reduced the cell-to-cell virus spread and the transmission of the extracellular free virus by preventing the egress of HSV-2 progeny from the infected cells. The dual antiviral and previously reported anti-inflammatory activities of A-3302-B, and its effect against an acyclovir-resistant HSV-2 strain are attractive features for developing a therapeutic to reduce the transmission of HSV-2 infections.

Herpes simplex virus (HSV) is an alpha herpes virus, with two subtypes: HSV-1 and HSV-2. HSV is one of the most prevalent sexually transmitted infections. It is the cause of severe neonatal infections and a leading cause of infectious blindness in the Western world. As of 2016, 13.2% of the global population ages 15–49 were existing with HSV-2 infection and 66.6% with HSV-1. This high prevalence of disease and the fact that resistance to current therapies is on the rise makes it imperative to develop and discover new methods of HSV prevention and management. Among the arsenal of therapies/treatments for this virus has been the development of a prophylactic or therapeutic vaccine to prevent the complications of HSV reactivation. Our current understanding of the immune responses involved in latency and reactivation provides a unique challenge to the development of vaccines. There are no approved vaccines currently available for either prophylaxis or therapy. However, there are various promising candidates in the pre-clinical and clinical phases of study. Vaccines are being developed with two broad focuses: preventative and therapeutic, some with a dual use as both immunotherapeutic and prophylactic. Within this article, we will review the current guidelines for the treatment of herpes simplex infections, our understanding of the immunological pathways involved, and novel vaccine candidates in development.

Deaths from herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are rare. A major exception is perinatally acquired HSV-1 or HSV-2 infection where the neonatal death rate is substantial. Fatal HSV infection also occurs occasionally in pregnant women. The goal of this review is to enumerate the reports that describe dual deaths of both a pregnant woman and her newborn from a herpesvirus infection. A total of 15 reports were found in the medical literature, of which five described pregnant women with HSV encephalitis and 10 described women with disseminated HSV infection. When the virus was typed, most cases of dual mother/newborn deaths were caused by HSV-2. Of interest, in two situations caused by HSV-1, the pregnant woman probably acquired her primary HSV-1 infection from one of her children and not by sexual transmission. Complete genomic sequencing was performed on one set of HSV-1 isolates collected from mother (blood) and newborn (blood and skin). The mother’s strain and the newborn’s skin strain were 98.9% identical. When the newborn’s two strains were compared, they were 97.4% identical. Only one mother was tested by the HerpeSelect IgG antibody kit. During the nine days of her undiagnosed disseminated infection preceding her death, her serology was negative. In summary, although dual mother/newborn deaths from HSV infection are rare, they continue to be reported as recently as 2017.

Chinese herbal prescription JieZe-1 is effective for genital herpes with no visible adverse effects clinically. It showed an excellent anti-HSV-2 effect in vitro. However, its mechanism of anti-HSV-2 effect in vivo remains unclear. This study was designed to evaluate the anti-HSV-2 effect of JieZe-1 and berberine in a genital herpes mouse model and explore the underlying mechanism. The fingerprint of JieZe-1 was determined by high-performance liquid chromatography. First, we optimized a mouse model of genital herpes. Next, the weight, symptom score, morphological changes, viral load, membrane fusion proteins, critical proteins of the Toll-like receptor signaling pathway, cytokines, and immune cells of vaginal tissue in mice at different time points were measured. Finally, we treated the genital herpes mouse model with JieZe-1 gel (2.5, 1.5, and 0.5 g/ml) and tested the above experimental indexes at 12 h and on the 9th day after modeling. JieZe-1 improved the symptoms, weight, and histopathological damage of genital herpes mice, promoted the keratin repair of tissues, and protected organelles to maintain the typical morphology of cells. It downregulated the expression of membrane fusion proteins, critical proteins of the Toll-like receptor signaling pathway, cytokines, and immune cells. The vaginal, vulvar, and spinal cord viral load and vaginal virus shedding were also significantly reduced. In summary, JieZe-1 shows significant anti-HSV-2 efficacy in vivo. The mechanism is related to the inhibition of membrane fusion, the Toll-like receptor signaling pathway, inflammatory cytokines, and cellular immunity. However, berberine, the main component of JieZe-1 monarch medicine, showed no efficacy at a concentration of 891.8 μM (0.3 mg/ml).

Recognition of unusual manifestations such as disseminated HSV or HSV‐related hemophagocytic lymphohistiocytosis among individuals with impaired cellular immunity and prompt treatment initiation are essential for a favorable outcome.

The aim of the work was to study the activity of echinochrome A, a naphthoquinoid pigment from sea urchins, and its antioxidant composition against herpes simplex virus type 2 (HSV-2) in vitro and in vivo.Materials and methods. Strain HSV-2 (G ATCC VR-734) was grown in Vero cells. The cytotoxic and anti-HSV-2 activity of the compounds was assessed in vitro by the cell viability and by cytopathic effect inhibition of virus using MTT test. The efficacy of compounds in mice model of vaginitis caused by HSV-2 was determined by the average lifetime, body weight and viral load changes.Results and discussion. The antioxidant composition (echinochrome A, ascorbic acid and α-tocopherol (5:5:1)), showed a higher antiviral efficacy than echinochrome A alone. Oral administration of the antioxidant composition protected 90% of the infected mice against death and reduced vaginal viral loads. The antiviral activity of echinochrome A and the antioxidant composition is probably due to the virus-inhibiting activity of the compounds and their antioxidant properties.Conclusion. The results obtained allow considering the tested compounds as promising agents with antiviral properties.

Background Herpes simplex virus type 2 (HSV-2) seroprevalence has been shown to be a potential sign of infection in pregnant women, and it could be applied to check HSV-2 transmission. This study evaluated the anti-HSV-2 IgG prevalence in pregnant women who were referred to health centers in Urmia, Northwest of Iran, during 2014-2015. Methods Serum samples were collected from 86 pregnant women and tested for Anti-HSV-2-specific IgG using a commercial enzyme-linked immunosorbent assays kit. Results Five (5.8%) pregnant women showed the presence of Anti-HSV-2-specific IgG antibodies. Previous abortion was reported in 16 (19.7%) and 2 subjects in the seronegative and seropositive groups, respectively. Conclusion Data from the present study indicate a lower number of HSV-2 seropositives among the pregnant women in Urmia. This reduction would be a result of low number of studied subjects used in the present study; hence, assessing a large sample is recommended.

Epithelial cells of the female reproductive tract (FRT) participate in the initial innate immunity against viral infections. Poly(dA:dT) is a synthetic analog of B form double-stranded (ds) DNA which can activate the interferon (IFN) signaling pathway-mediated antiviral immunity through DNA-dependent RNA Polymerase III. Here we investigated whether poly(dA:dT) could inhibit herpes simplex virus type 2 (HSV-2) infection of human cervical epithelial cells (End1/E6E7). We demonstrated that poly(dA:dT) treatment of End1/E6E7 cells could significantly inhibit HSV-2 infection. Mechanistically, poly(dA:dT) treatment of the cells induced the expression of the intracellular IFNs and the multiple antiviral IFN-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15), IFN-stimulated gene 56 (ISG56), 2’-5’-oligoadenylate synthetase 1 (OAS1), 2’-5’-oligoadenylate synthetase 2 (OAS2), myxovirus resistance protein A (MxA), myxovirus resistance protein B (MxB), virus inhibitory protein, endoplasmic reticulum-associated, IFN-inducible (Viperin), and guanylate binding protein 5 (GBP5). Further investigation showed that the activation of RIG-I was largely responsible for poly(dA:dT)-mediated HSV-2 inhibition and IFN/ISGs induction in the cervical epithelial cells, as RIG-I knockout abolished the poly(dA:dT) actions. These observations demonstrate the importance for design and development of AT-rich dsDNA-based intervention strategies to control HSV-2 mucosal transmission in FRT.

The contribution of virus components to liberation of herpes simplex virus type 2 (HSV-2) progeny virions from the surface of infected cells is poorly understood. We report that the HSV-2 mutant deficient in the expression of a mucin-like membrane-associated glycoprotein G (mgG) exhibited defect in the release of progeny virions from infected cells manifested by ~2 orders of magnitude decreased amount of infectious virus in a culture medium as compared to native HSV-2. Electron microscopy revealed that the mgG deficient virions were produced in infected cells and present at the cell surface. These virions could be forcibly liberated to a nearly native HSV-2 level by the treatment of cells with glycosaminoglycan (GAG)-mimicking oligosaccharides. Comparative assessment of the interaction of mutant and native virions with surface-immobilized chondroitin sulfate GAG chains revealed that while the mutant virions associated with GAGs ~fourfold more extensively, the lateral mobility of bound virions was much poorer than that of native virions. These data indicate that the mgG of HSV-2 balances the virus interaction with GAG chains, a feature critical to prevent trapping of the progeny virions at the surface of infected cells.

Graphical abstract, Highlights • Trivalent mRNA and protein vaccines produce robust neutralizing antibodies in dams and pups. • Trivalent mRNA and protein vaccines prevent infection of multiple organs. • Durability of vaccine protection extends into second-generation litters., Neonatal herpes is a dreaded complication of genital herpes infection in pregnancy. We recently compared two vaccine platforms for preventing genital herpes in female mice and guinea pigs and determined that HSV-2 glycoproteins C, D and E expressed using nucleoside-modified mRNA in lipid nanoparticles provided better protection than the same antigens produced as baculovirus proteins and administered with CpG and alum. Here we evaluated mRNA and protein immunization for protection against neonatal herpes. Female mice were immunized prior to mating and newborns were infected intranasally with HSV-2. IgG binding and neutralizing antibody levels in mothers and newborns were comparable using the mRNA or protein vaccines. Both vaccines protected first and second litter newborns against disseminated infection based on virus titers in multiple organs. We conclude that both vaccines are efficacious at preventing neonatal herpes, which leaves the mRNA vaccine as our preferred candidate based on better protection against genital herpes.

It is known that herpes simplex virus type 2 (HSV-2) triggers the activation of Toll-like receptor (TLR) 9 signaling pathway and the consequent production of antiviral cytokines in dendritic cells. However, the impact of HSV-2 infection on TLR9 expression and signaling in genital epithelial cells, the primary HSV-2 targets, has yet to be determined. In the current study, by using both human genital epithelial cell lines and primary genital epithelial cells as models, we found that HSV-2 infection enhances TLR9 expression at both mRNA and protein levels. Such enhancement is virus replication-dependent and CpG-independent, while the HSV-2-mediated upregulation of TLR9 does not activate TLR9 signaling pathway. Mechanistically, a SP1 binding site on TLR9 promoter appears to be essential for HSV-2-induced TLR9 transactivation. Upon HSV-2 infection, SP1 translocates from the cytoplasm to the nucleus, and consequently binds to TLR9 promoter. By using specific inhibitors, the JNK signaling pathway is shown to be involved in the HSV-2-induced TLR9 transactivation, while HSV-2 infection increases the phosphorylation but not the total level of JNK. In agreement, antagonism of JNK signaling pathway inhibits the HSV-2-induced SP1 nuclear translocation. Taken together, our study demonstrates that HSV-2 infection of human genital epithelial cells promotes TLR9 expression through SP1/JNK signaling pathway. Findings in this study provide insights into HSV-2-host interactions and potential targets for immune intervention.

Oncolytic virotherapy is a new therapeutic strategy based on the inherent cytotoxicity of viruses and their ability to replicate and spread in tumors in a selective manner. We constructed a new type of oncolytic herpes simplex virus type 2 (oHSV-2, named OH2) to treat human cancers, but a systematic evaluation of the stability and oncolytic ability of this virus is lacking. In this study, we evaluated its physical stability, gene modification stability and biological characteristics stability, including its anti-tumor activity in an animal model. The physical characteristics as well as genetic deletions and insertions in OH2 were stable, and the anti-tumor activity remained stable even after passage of the virus for more than 20 generations. In conclusion, OH2 is a virus that has stable structural and biological traits. Furthermore, OH2 is a potent oncolytic agent against tumor cells.

Aims: This study investigated the seroprevalence and sexual risk behavior factors associated with syphilis and herpes simplex virus type 2 (HSV-2) among men who have sex with men (MSM), in Manado, Indonesia. Methods: Serum samples and questionnaires regarding their socio-demographic and sexual behaviour were collected from 60 MSM in Manado . Samples were screened for anti-HSV-2 IgG for herpes, the Venereal Disease Research Laboratory (VDRL) and the Treponema Pallidum Haemagglutination (TPHA) test for syphilis. A cross sectional method was used in this study . Results: Of 60 MSM (median age was 20 years), 35% had homosexual orientation and 65% had bisexual orientation. First sexual intercourse of most participants (48.3%) within 16 to 18 years old. In the last 12 months, most participants (55%) had only one male sex partner. There were 63.3% and 16.7% participants performed oral and anal intercourse. About 23.3% participants used condom consistently, but only 35.7% used compatible lubricant. Seropositivity of VDRL and TPHA was detected in 5% participants and anti-HSV-2 IgG in 23.3% participants. The positive serology test for syphilis was associated with sexual intercourse mode (p= 0.001). Significant association was found between anti-HSV-2 IgG seropositivity and condom-use behaviour (p=0,028). Conclusions: The study demonstrated 5% and 23.3% positivity of serology test for syphilis and anti-HSV-2 IgG respectively. Seropositivity of syphilis was correlated with oral and anal intercourse while HSV-2 with no condom-use behaviour among MSM in Manado, Indonesia. Keywords : syphilis, herpes simplex virus type 2, men who have sex with men, sexual behaviou r, Manado

Objectives HIV and herpes simplex virus type 2 (HSV-2) infections are sexually transmitted and propagate in sexual networks. Using mathematical modeling, we aimed to quantify effects of key network statistics on infection transmission, and extent to which HSV-2 prevalence can be a proxy of HIV prevalence. Design/methods An individual-based simulation model was constructed to describe sex partnering and infection transmission, and was parameterized with representative natural history, transmission, and sexual behavior data. Correlations were assessed on model outcomes (HIV/HSV-2 prevalences) and multiple linear regressions were conducted to estimate adjusted associations and effect sizes. Results HIV prevalence was one-third or less of HSV-2 prevalence. HIV and HSV-2 prevalences were associated with a Spearman's rank correlation coefficient of 0.64 (95% confidence interval: 0.58-0.69). Collinearities among network statistics were detected, most notably between concurrency versus mean and variance of number of partners. Controlling for confounding, unmarried mean/variance of number of partners (or alternatively concurrency) were the strongest predictors of HIV prevalence. Meanwhile, unmarried/married mean/variance of number of partners (or alternatively concurrency), and clustering coefficient were the strongest predictors of HSV-2 prevalence. HSV-2 prevalence was a strong predictor of HIV prevalence by proxying effects of network statistics. Conclusion Network statistics produced similar and differential effects on HIV/HSV-2 transmission, and explained most of the variation in HIV and HSV-2 prevalences. HIV prevalence reflected primarily mean and variance of number of partners, but HSV-2 prevalence was affected by a range of network statistics. HSV-2 prevalence (as a proxy) can forecast a population's HIV epidemic potential, thereby informing interventions.

The herpes simplex virus type 2 (HSV-2) is a sexually transmitted infection prevalent in the world; in spite of despite diagnostic and therapeutic advances. According to estimates in 2012, it was calculated that there were 417 million people infected worldwide. The objective of this project was to detect HSV-2 in indigenous women of the Zulia state, for that 100 women of the Wayúu and Añú ethnic groups, were selected without discriminating age and/or parity. The physician proceeded to sample with an alginate swab, for the processing of the same was used the polymerase chain reaction (PCR) method to detect HSV-2 in samples of cervical-uterine origin, and cytological diagnosis was made through staining with hematoxylin-eosin. 22% of HSV-2 positive samples were obtained, the results show that a considerable percentage of patients present HSV-2 infection, which is extremely important because it can contribute to the progression of processes inflammatory agents. Resumen: El virus herpes simple tipo 2 (VHS-2), es una infección de transmisión sexual prevalente en el mundo a pesar de los avances diagnósticos y terapéuticos. Según estimaciones en el 2012, se calculaba que existían 417 millones de personas infectadas en todo el mundo. El objetivo de este proyecto fue detectar el VHS-2 en mujeres indígenas del estado Zulia, para ello se seleccionaron 100 mujeres de las etnias wayúu y añú sin discriminar edad y/o paridad. El médico procedió a realizar la toma de muestras con un hisopo de alginato, para el procesamiento de las mismas se utilizó el método de Reacción en Cadena de la Polimerasa (PCR) para detectar el VHS-2, en muestras de origen cérvico-uterino, y el diagnostico citológico se realizó a través de la coloración con hematoxilina- eosina. Se obtuvo un 22% de muestras positivas para VHS-2, los hallazgos obtenidos, demuestran que un porcentaje considerable de las pacientes presentan infección por el VHS- 2, siendo este de suma importancia debido a que el mismo puede contribuir a la progresión de procesos inflamatorios persistentes.

Lei Yin,1–3 Chunhong Zhao,3 Jixia Han,4 Zengjun Li,2 Yanan Zhen,3 Ruixue Xiao,3 Zhongfa Xu,3 Yanlai Sun2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 2Department of Gastrointestinal Cancer Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, 3Department of Gastrointestinal Surgery, The Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, 4Department of General Surgery, The Sixth People’s Hospital of Jinan, Jinan, People’s Republic of China Background: The incidence of colorectal cancer (CRC) is on the rise. Furthermore, late-stage diagnoses and limited efficacious treatment options make CRC a complex clinical challenge. Therefore, a new therapeutic regimen with a completely novel therapeutic mechanism is necessary for CRC. In the present study, the therapeutic efficacy of oncolytic herpes simplex virus type 2 (oHSV2) in CRC was assessed in vitro and in vivo. oHSV2 is an oncolytic agent derived from herpes simplex virus type 2 that encodes granulocyte-macrophage colony-stimulating factor.Materials and methods: We investigated the cytopathic effects of oHSV2 in CRC cell lines using the MTT assay. Then, cell cycle progression and apoptosis of oHSV2 were examined by flow cytometry. We generated a model of CRC with mouse CRC cell CT26 in BALB/c mice. The antitumor effects and adaptive immune response of oHSV2 were assessed in tumor-bearing mice. The therapeutic efficacy of oHSV2 was compared with the traditional chemotherapeutic agent, 5-fluorouracil.Results: The in vitro data showed that oHSV2 infected the CRC cell lines successfully and that the tumor cells formed a significant number of syncytiae postinfection. The oHSV2 killed cancer cells independent of the cell cycle and mainly caused tumor cells necrosis. The in vivo results showed that oHSV2 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice without weight loss. With virus replication, oHSV2 not only resulted in a reduction of myeloid-derived suppressor cells and regulatory T cells in the spleen, but also increased the number of mature dendritic cells in tumor-draining lymph nodes and the effective CD4+T and CD8+T-cells in the tumor microenvironment.Conclusion: Our study provides the first evidence that oHSV2 induces cell death in CRC in vitro and in vivo. These findings indicate that oHSV2 is an effective therapeutic cancer candidate that causes an oncolytic effect and recruits adaptive immune responses for an enhanced therapeutic impact, thus providing a potential therapeutic tool for treatment of CRC. Keywords: colorectal cancer, oncolytic virus, herpes simplex virus type 2, granulocyte–macrophage colony-stimulating factor, immunotherapy, gene therapy

Lei Yin,1–3 Chunhong Zhao,3 Jixia Han,4 Zengjun Li,2 Yanan Zhen,3 Ruixue Xiao,3 Zhongfa Xu,3 Yanlai Sun2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, 2Department of Gastrointestinal Cancer Surgery, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, 3Department of Gastrointestinal Surgery, The Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, 4Department of General Surgery, The Sixth People’s Hospital of Jinan, Jinan, People’s Republic of China Background: The incidence of colorectal cancer (CRC) is on the rise. Furthermore, late-stage diagnoses and limited efficacious treatment options make CRC a complex clinical challenge. Therefore, a new therapeutic regimen with a completely novel therapeutic mechanism is necessary for CRC. In the present study, the therapeutic efficacy of oncolytic herpes simplex virus type 2 (oHSV2) in CRC was assessed in vitro and in vivo. oHSV2 is an oncolytic agent derived from herpes simplex virus type 2 that encodes granulocyte-macrophage colony-stimulating factor.Materials and methods: We investigated the cytopathic effects of oHSV2 in CRC cell lines using the MTT assay. Then, cell cycle progression and apoptosis of oHSV2 were examined by flow cytometry. We generated a model of CRC with mouse CRC cell CT26 in BALB/c mice. The antitumor effects and adaptive immune response of oHSV2 were assessed in tumor-bearing mice. The therapeutic efficacy of oHSV2 was compared with the traditional chemotherapeutic agent, 5-fluorouracil.Results: The in vitro data showed that oHSV2 infected the CRC cell lines successfully and that the tumor cells formed a significant number of syncytiae postinfection. The oHSV2 killed cancer cells independent of the cell cycle and mainly caused tumor cells necrosis. The in vivo results showed that oHSV2 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice without weight loss. With virus replication, oHSV2 not only resulted in a reduction of myeloid-derived suppressor cells and regulatory T cells in the spleen, but also increased the number of mature dendritic cells in tumor-draining lymph nodes and the effective CD4+T and CD8+T-cells in the tumor microenvironment.Conclusion: Our study provides the first evidence that oHSV2 induces cell death in CRC in vitro and in vivo. These findings indicate that oHSV2 is an effective therapeutic cancer candidate that causes an oncolytic effect and recruits adaptive immune responses for an enhanced therapeutic impact, thus providing a potential therapeutic tool for treatment of CRC. Keywords: colorectal cancer, oncolytic virus, herpes simplex virus type 2, granulocyte–macrophage colony-stimulating factor, immunotherapy, gene therapy

Familial benign pemphigus, or Hailey-Hailey disease (HHD), is a rare (1 in 50,000), benign, autosomal dominant cutaneous disorder that causes a painful rash and blistering commonly occurring in the intertriginous folds. Despite having a good prognosis, there is no cure for HHD and the disease can be quite debilitating to the quality of life. The complexity of HHD can be compounded by superimposed eczema herpeticum (EH) or Kaposi's varicelliform eruption, which is caused by a viral infection occurring in preexistent cutaneous conditions. We present a unique clinical presentation of HHD with superimposed EH caused by herpes simplex virus type 2 (HSV-2) infection managed in a burn unit. It is highly advised that a recalcitrant HHD with superimposed EH caused by HSV-2 infection should be managed in burn centers that offer multimodalities for prompt, rigorous management. Early diagnosis and treatment are highly suggested for EH to avoid fatal complications.

Purpose: To report the unique clinical findings of a case of Herpes Simplex Virus Type 2 herpetic retinitis manifesting as a large elevated subretinal lesion. Observations: A 26-year-old Hispanic male with no significant past medical history presented with a one-week history of right eye pain and endorsement of worsening vision. Ophthalmic examination of the right eye identified a markedly elevated white subretinal lesion with associated findings of vitritis and hypotony. Ultrasound biomicroscopy demonstrated a diffusely thickened choroid and confirmed the observed subretinal mass. Examination of the fellow left eye was largely unremarkable with the exception of lesions suggestive of inactive chorioretinal scars. Diagnostic vitrectomy and vitreous PCR (polymerase chain reaction) was positive only for HSV-2 (herpes simplex virus type 2) and verified by two independent laboratories. The observed subretinal lesion of right eye improved on intravenous acyclovir and intravitreal foscarnet treatment. Conclusions and Importance: Presented here is an unusual, novel clinical presentation of HSV-2 acute retinal necrosis manifesting as an elevated subretinal lesion along with findings of panuveitis. This case suggests that consideration should be given to the diagnosis of HSV ARN (acute retinal necrosis) when a subretinal elevation is concomitantly appreciated in the setting of vitritis and chorioretinal lesions. Keywords: Acute retinal necrosis, Herpes simplex virus type 2, Panuveitis, Polymerase chain reaction

Rationale: Acute respiratory disorders (ARD) have the highest proportion among infectious disease in children. Despite the fact that serological diagnostics of Mycoplasma pneumoniae, Chlamydophila pneumoniae, Pneumocystis jirovecii, herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus type 6 (HHV-6) has been available for many years, up to now some objective limitations exist that hinder reliable differentiation between the viral carriage, past or current infection. There are no widely accepted guidelines that would suggest unified strategies for diagnosis and what is of utmost importance, for therapeutic intervention on a case-to-case basis. The rationale for this study was based on underestimation of the burden of these infections in children with prolonged periods of cough and recurrent ARDs, as well as the necessity to further develop diagnostic and management strategies. Aim: To determine causative role of M. pneumoniae, P. jirovecii, C. pneumoniae, HSV-1, -2, EBV, CMV, HHV-6 in children with recurrent ARDs hospitalized to an in-patient unit. Materials and methods: We examined 50 children with recurrent ARDs aged from 1 to 7 years who were hospitalized with an acute respiratory infection. Laboratory assessments included determination of the markers of infections caused by M. pneumoniae, P. jirovecii, C. pneumoniae, HSV- 1, -2, EBV, CMV, HHV-6 by means of polymerase chain reaction, immunoenzyme analysis, and indirect immunofluorescence reaction. Results: Markers of mycoplasma, chlamydial, pneumocystic infection, as well as HSV-1, -2, EBV, CMV, HHV-6 were found in 84% (42 / 50) cases. Active infection (acute or active persistent) was found in 38% (19 / 50) patients. The most prevalent was pneumocystic infection diagnosed in 12 (24%) patients; one fifth of all patients had mycoplasma (in 10 (20%) of cases), whereas herpetic and chlamydial infections were less frequent (4 (8%) and 1 (2%) of cases, respectively). Twelve (24%) patients had a single infection, while the others had mixed infections. Conclusion: We were able to confirm the possibility of combined M. pneumonia / P. jirovecii infection (8%) in children with recurrent ARDs and history of longstanding cough; this is important for an assessment of efficacy of causative treatment. Measurement of serum titers of specific immunoglobulins M and G along with DNA/antigens of potential causative organisms can be sufficient to choose specific antibacterial treatment of obstructive bronchitis and pneumonia in children with the history of longstanding cough and recurrent bronchial obstruction.

Objective To evaluate the monogalactosyl diglyceride (MGDG) and digalactosyl diglyceride (DGDG) from Clinacanthus nutans ( C. nutans ) for their in vitro antiviral activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) by plaque reduction assay. Methods MGDG and DGDG were extracted with chloroform from C. nutans leaves. MGDG and DGDG were separated from chloroform crude extract using column chromatography, characterized by thin layer chromatography and quantified by high performance liquid chromatography. The anti HSV-1 and 2 activity against pre-treatment and post-treatment of the compounds was evaluated using plaque reduction assay. The cytotoxicity of the extract and the compounds on Vero cells were performed by MTT assay. Results MGDG and DGDG obtained by column chromatography showed identical profiles as standard MGDG and standard DGDG using thin layer chromatography and high performance liquid chromatography. MGDG and DGDG from C. nutans showed 100% inhibition of HSV-1 replication at the post step of infection at noncytotoxic concentration with IC 50 values of 36.00 and 40.00 μg/mL, and HSV-2 at 41.00 and 43.20 μg/mL, respectively. Moreover, MGDG and DGDG from C. nutans were demonstrated to have anti-herpes simplex activity at the same level as standard synthetic compounds. In contrast, pre-treatment of Vero cells with MGDG and DGDG before HSV-1 and HSV-2 infection did not show inhibitory effect against these viruses. MGDG and DGDG exhibited antiviral activity against HSV-1 with selectivity index of 26.00 and 23.00 and HSV-2 of 23.30 and 21.30. Conclusions MGDG and DGDG from C. nutans , a traditional Thai herbal medicine illustrated inhibitory activity against HSV-1 and HSV-2, probably by inhibiting the late stage of multiplication, suggesting their promising use as anti-HSV agents.

The human vaginal microbiome (VMB) is a complex bacterial community that interacts closely with vaginal epithelial cells (VECs) impacting the mucosal phenotype and its responses to pathogenic insults. The VMB and VEC relationship includes nutrient exchange and regulation of signaling molecules that controls numerous host functions and defends against invading pathogens. To better understand infection and replication of sexually transmitted viral pathogens in the human vaginal mucosa we used our ex vivo VEC multilayer culture system. We tested the hypothesis that selected VMB communities could be identified that alter the replication of sexually transmitted viruses consistent with reported clinical associations. Sterile VEC multilayer cultures or those colonized with VMB dominated by specific Lactobacillus spp., or VMB lacking lactobacilli, were infected with Zika virus, (ZIKV) a single stranded RNA virus, or Herpes Simplex Virus type 2 (HSV-2), a double stranded DNA virus. The virus was added to the apical surface of the cultured VEC multilayer to model transmission during vaginal intercourse. Viral replication was measured 48 h later by qPCR. The results indicated that VEC cultures colonized by VMB containing Staphylococcus spp., previously reported as inflammatory, significantly reduced the quantity of viral genomes produced by ZIKV. HSV-2 titers were decreased by nearly every VMB tested relative to the sterile control, although Lactobacillus spp.-dominated VMBs caused the greatest reduction in HSV-2 titer consistent with clinical observations. To explore the mechanism for reduced ZIKV titers, we investigated inflammation created by ZIKV infection, VMB colonization or pre-exposure to selected TLR agonists. Finally, expression levels of human beta defensins 1–3 were quantified in cultures infected by ZIKV and those colonized by VMBs that impacted ZIKV titers. Human beta defensins 1–3 produced by the VEC showed no association with ZIKV titers. The data presented expands the utility of this ex vivo model system providing controlled and reproducible methods to study the VMB impact on STIs and indicated an association between viral replication and specific bacterial species within the VMB.

IntroductionHerpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15–49 years old.MethodsWe developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made.ResultsWe estimated that 187 million people aged 15–49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world’s population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120–296 million). However, the estimates were sensitive to the model assumptions.ConclusionOur study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.

The human vaginal microbiome (VMB) is a complex bacterial community that interacts closely with vaginal epithelial cells (VECs) impacting the mucosal phenotype and its responses to pathogenic insults. The VMB and VEC relationship includes nutrient exchange and regulation of signaling molecules that controls numerous host functions and defends against invading pathogens. To better understand infection and replication of sexually transmitted viral pathogens in the human vaginal mucosa we used our ex vivo VEC multilayer culture system. We tested the hypothesis that selected VMB communities could be identified that alter the replication of sexually transmitted viruses consistent with reported clinical associations. Sterile VEC multilayer cultures or those colonized with VMB dominated by specific Lactobacillus spp., or VMB lacking lactobacilli, were infected with Zika virus, (ZIKV) a single stranded RNA virus, or Herpes Simplex Virus type 2 (HSV-2), a double stranded DNA virus. The virus was added to the apical surface of the cultured VEC multilayer to model transmission during vaginal intercourse. Viral replication was measured 48 h later by qPCR. The results indicated that VEC cultures colonized by VMB containing Staphylococcus spp., previously reported as inflammatory, significantly reduced the quantity of viral genomes produced by ZIKV. HSV-2 titers were decreased by nearly every VMB tested relative to the sterile control, although Lactobacillus spp.-dominated VMBs caused the greatest reduction in HSV-2 titer consistent with clinical observations. To explore the mechanism for reduced ZIKV titers, we investigated inflammation created by ZIKV infection, VMB colonization or pre-exposure to selected TLR agonists. Finally, expression levels of human beta defensins 1–3 were quantified in cultures infected by ZIKV and those colonized by VMBs that impacted ZIKV titers. Human beta defensins 1–3 produced by the VEC showed no association with ZIKV titers. The data presented expands the utility of this ex vivo model system providing controlled and reproducible methods to study the VMB impact on STIs and indicated an association between viral replication and specific bacterial species within the VMB.

Background Herpes simplex virus (HSV) has various presentations, depending on the patient’s immune status, age, and the route of transmission. In adults, HSV type 1 is found predominantly in the oral area, and HSV type 2 (HSV-2) is commonly found in the genital area. HSV-2 infection without genital lesions is uncommon. Herein we report a unique case of pharyngotonsillitis as an initial manifestation of disseminated HSV-2 infection without genital involvement. Case presentation A 46-year-old male was admitted to our hospital with a 1-week history of fever and sore throat. His past medical history included hypereosinophilic syndrome diagnosed at age 45 years. Physical examination revealed throat congestion, bilaterally enlarged tonsils with exudates, tender cervical lymphadenopathy in the left posterior triangle, and mild epigastric tenderness. The laboratory data demonstrated bicytopenia, elevated liver enzyme levels, and hyperferritinemia. A bone marrow smear showed hypocellular marrow with histiocytes and hemophagocytosis. The diagnosis of HLH was confirmed, and the patient was treated with methylprednisolone pulse therapy on days 1–3. On day 5, despite initial improvement of the fever and sore throat, multiple, new, small bullae developed on the patient’s face, trunk, and extremities. Additional testing showed that he was positive for HSV-specific immunoglobulin M and immunoglobulin G. Disseminated HSV infection was suspected, and intravenous acyclovir (10 mg/kg every 8 h) was begun. A subsequent direct antigen test of a bulla sample was positive for HSV-2. Moreover, tonsillar and esophageal biopsies revealed viral inclusion bodies. Immunohistochemical staining and a quantitative real-time polymerase chain reaction (PCR) assay confirmed the presence of HSV-2. Disseminated HSV-2 infection with multiple bullae, tonsillitis, esophagitis, and suspected hepatic involvement was diagnosed. After a 2-week course of intravenous acyclovir, his hematological status and liver function normalized, and his cutaneous skin lesions resolved. He was discharged on day 22 in good general health and continued taking oral valacyclovir for viral suppression due to his immunosuppressed status. Conclusion Disseminated HSV-2 infection should be considered as one of the differential diagnoses in patients with pharyngotonsillitis and impaired liver function of unknown etiology even if there are no genital lesions.

In this article deals with a typical clinical example of a severe form of acute neuroinfectious lesion of the spinal cord HSV2‑etiology in a patient with minor cellular immunodeficiency, who suffered from often recurrent genital herpes without adequate prophylactic antiviral treatment for the prevention of CNS damage. The patient, M., 54 years old, had acute lumbosacral myelitis, caused by herpes virus type 2, with a picture of the lower deep paraparesis, paragypesthesia, impaired pelvic organs functions. The diagnosis is confirmed on the basis of a PCR of the cerebrospinal fluid. Immunological examination revealed a selective deficiency of natural killers (CD3–CD1+CD56+ lymphocytes) — cells that are important in controlling the latent virus in the saçral sensory ganglia. A genetic survey identified a deficiency of the folate cycle that caused the minor cellular immune deficiency (MTHFR 677 С > Т homo, MTHFR 1298 А > С hetero, MTRR 66 A > G hetero). Therefore, the patient received dual treatment — acyclic analogues of guanosine to suppress viral reproduction and interferone therapy to compensate cellular immunodeficiency. This case demonstrates the feasibility of close interaction between neurologists and clinical immunologists in immunocompromised patients with neuroinfectional lesions caused by opportunistic pathogens., Приведен типичный клинический пример тяжелой формы острого нейроинфекционного поражения спинного мозга HSV2‑этиологии у пациента с минорным клеточным иммунодефицитом, который длительно страдал частыми рецидивами генитального герпеса, не получая надлежащего профилактического противовирусного лечения для предотвращения поражения ЦНС. У пациента в возрасте 54 года развился острый пояснично‑крестцовый миелит, вызванный вирусом герпеса 2 типа, с картиной нижнего глубокого парапареза, парагипестезии, нарушения функции тазовых органов. Диагноз подтвержден по результатам полимеразной цепной реакции спинномозговой жидкости. При иммунологическом обследовании выявлен выборочный дефицит естественных киллеров (CD3–CD1+CD56+‑лимфоцитов) — клеток, которые имеют важное значение для контроля над латентным вирусом в сакральных сенсорных ганглиях. При генетическом обследовании идентифицирован дефицит энзимов фолатного цикла, который был причиной минорного клеточного иммунодефицита (MTHFR 677 С > Т гомо, MTHFR 1298 А > С гетеро, MTRR 66 A > G гетеро). Поэтому пациент получал двойное лечение — ациклическими аналогами гуанозина для угнетения вирусной репродукции и интерферонотерапию для компенсации клеточного иммунодефицита. Этот случай демонстрирует необходимость тесного взаимодействия неврологов и клинических иммунологов при ведении иммуноскомпрометированных пациентов с нейроинфекционными поражениями, вызванными оппортунистическими возбудителями., Наведено типовий клінічний приклад тяжкої форми гострого нейроінфекційного ураження спинного мозку HSV2‑етіологїі у пацієнта з мінорним клітинним імунодефіцитом, який тривало страждав на часті рецидиви генітального герпесу, не отримуючи належного профілактичного противірусного лікування для запобігання ураженню ЦНС. У пацієнта віком 54 роки розвинувся гострий попереково‑крижовий мієліт, спричинений вірусом герпесу 2 типу, з картиною нижнього глибокого парапарезу, парагіпестезії, порушення функції тазових органів. Діагноз підтверджено за результатами полімеразної ланцюгової реакції спинномозкової рідини. При імунологічному обстеженні виявлено вибірковий дефіцит природних кілерів (CD3–CD16+CD56+‑лімфоцитів) — клітин, які мають важливе значення для контролю над латентним вірусом у сакральних сенсорних гангліях. При генетичному обстеженні ідентифіковано дефіцит ензимів фолатного циклу, що був причиною мінорного клітинного імунодефіциту (MTHFR 677 С > Т гомо, MTHFR 1298 А > С гетеро, MTRR 66 A > G гетеро). Тому пацієнт отримував подвійне лікування — ациклічними аналогами гуанозину для пригнічення вірусної репродукції та інтерферонотерапію для компенсації клітинного імунодефіциту. Цей випадок демонструє необхідність тісної взаємодії неврологів та клінічних імунологів при веденні імуноскомпрометованих пацієнтів з нейроінфекційними ураженнями, спричиненими опортуністичними збудниками.

International audience; Herpes simplex virus type 2 (HSV-2) is the causative pathogen of genital herpes and is closely associated with the occurrence of cervical cancer and human immunodeficiency virus (HIV) infection. The absence of an effective vaccine and the emergence of drug resistance to commonly used nucleoside analogs emphasize the urgent need for alternative antivirals against HSV-2. Recently, ABMA [1-adamantyl (5-bromo-2-methoxybenzyl) amine] has been demonstrated to be an inhibitor of several pathogens exploiting host-vesicle transport, which also participates in the HSV-2 lifecycle. Here, we showed that ABMA inhibited HSV-2-induced cytopathic effects and plaque formation with 50% effective concentrations of 1.66 and 1.08 µM, respectively. We also preliminarily demonstrated in a time of compound addition assay that ABMA exerted a dual antiviral mechanism by impairing virus entry, as well as the late stages of the HSV-2 lifecycle. Furthermore, in vivo studies showed that ABMA protected BALB/c mice from intravaginal HSV-2 challenge with an improved survival rate of 50% at 5 mg/kg (8.33% for the untreated virus infected control). Consequently, our study has identified ABMA as an effective inhibitor of HSV-2, both in vitro and in vivo, for the first time and presents an alternative to nucleoside analogs for HSV-2 infection treatment.

Liver metastasis represents the most prominent metastasis of colorectal cancer (CRC) and is the leading cause of CRC mortality, making the early prevention of this event very important. While current CRC therapies include surgery, radiotherapy and chemotherapy, no effective treatment option for CRC liver metastasis (CRLM) exists. Furthermore, the effects of currently available metastatic CRC drugs are frequently limited by their toxicity and side effects. Oncolytic herpes simplex virus type 2 (oHSV2) selectively infects tumor cells and also induces an antitumor immune response. The present study investigated the cytopathic effects of oHSV2 on CT-26 cells in vitro and tested its inhibitory effect on CRLM. In vitro experimental data demonstrated that oHSV2 effectively inhibited the growth of CT-26 cells. In vivo study data demonstrated that treatment with oHSV2 alone slowed the growth of subcutaneous xenograft tumors without inducing weight loss and also inhibited CRLM by increasing the numbers of cluster of differentiation (CD)4+ T, CD8+ T and natural killer cells. In summary, oHSV2 shows potential as a safe and effective therapeutic agent for inhibiting the metastasis of CT-26 CRC cells to the liver.

International audience; Herpes simplex virus type 2 (HSV-2) is highly prevalent in the human population producing significant morbidity, mainly because of the generation of genital ulcers and neonatal encephalitis. Additionally, HSV-2 infection significantly increases the susceptibility of the host to acquire HIV and promotes the shedding of the latter in the coinfected. Despite numerous efforts to create a vaccine against HSV-2, no licensed vaccines are currently available. A long-standing strategy, based on few viral glycoproteins combined with adjuvants, recently displayed poor results in a Phase III clinical study fueling exploration on the development of mutant HSV viruses that are attenuated in vivo and elicit protective adaptive immune components, such as antiviral antibodies and T cells. Importantly, such specialized antiviral immune components are likely induced and modulated by dendritic cells, professional antigen presenting cells that process viral antigens and present them to T cells. However, HSV interferes with several functions of DCs and ultimately induces their death. Here, we propose that for an attenuated mutant virus to confer protective immunity against HSV in vivo based on adaptive immune components, such virus should also be attenuated in dendritic cells to promote a robust and effective antiviral response. We provide a background framework for this idea, considerations, as well as the means to assess this hypothesis. Addressing this hypothesis may provide valuable insights for the development of novel, safe, and effective vaccines against herpes simplex viruses.

Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.

Non-traumatic myelopathies can result from a wide spectrum of conditions including inflammatory, ischemic, and metabolic disorders. Here, we describe the case of a 60-year old immunocompetent woman who developed acute back pain followed by rapidly ascending flaccid tetraparesis, a C6 sensory level, and sphincter dysfunction within 8 h. Acyclovir and steroids were started on day 2 and herpes simplex virus type 2 (HSV-2) was confirmed by polymerase chain reaction in cerebrospinal fluid. Magnetic resonance imaging revealed a bilateral anterior horn tractopathy expanding from C2 to T2 and cervicothoracic cord swelling. Screening for paraneoplastic antibodies and cancer was negative. Neurophysiology aided in the work-up by corroborating root involvement. Recovery was poor despite early initiation of antiviral treatment, adjuvant anti-inflammatory therapy, and neurorehabilitation efforts. The clinical course, bilateral affection of the anterior horns, and early focal atrophy on follow-up magnetic resonance imaging take a necrotizing myelitis potentially caused by intraneuronal spread of the virus into consideration. Further, we summarize the literature on classical and rare presentations of HSV-2 myeloradiculitis in non-immunocompromised patients and raise awareness for the limited treatment options for a condition with frequent devastating outcome.

Background Herpes Simplex Virus Type 2 (HSV-2) is one of the most common sexually transmitted diseases. Although there is still no licensed vaccine for HSV-2, a theoretical investigation of the potential effects of a vaccine is considered important and has recently been conducted by several researchers. Although compartmental mathematical models were considered for each special case in the previous studies, as yet there are few global stability results. Results In this paper, we formulate a multi-group SVIRI epidemic model for HSV-2, which enables us to consider the effects of vaccination, of waning vaccine immunity, and of infection relapse. Since the number of groups is arbitrary, our model can be applied to various structures such as risk, sex, and age group structures. For our model, we define the basic reproduction number ℜ0 and prove that if ℜ0≤1, then the disease-free equilibrium is globally asymptotically stable, whereas if ℜ0>1, then the endemic equilibrium is so. Based on this global stability result, we estimate ℜ0 for HSV-2 by applying our model to the risk group structure and using US data from 2001 to 2014. Through sensitivity analysis, we find that ℜ0 is approximately in the range of 2-3. Moreover, using the estimated parameters, we discuss the optimal vaccination strategy for the eradication of HSV-2. Conclusions Through discussion of the optimal vaccination strategy, we come to the following conclusions. (1) Improving vaccine efficacy is more effective than increasing the number of vaccines. (2) Although the transmission risk in female individuals is higher than that in male individuals, distributing the available vaccines almost equally between female and male individuals is more effective than concentrating them within the female population.

Ethnopharmacological relevance The Chinese Herbal Prescription JieZe-1(JZ-1), added and subtracted from Yihuang Decoction, a famous formula in the 12th year of Kangxi in Qing Dynasty, has a clear effect on Genital Herpes (GH) and no obvious adverse reactions occur clinically. JZ-1 also has preventive and therapeutic effects on Trichomonas vaginitis, Candida albicans vaginitis and GH in vitro and in vivo experiments. Aim of study The effect and mechanism of JZ-1 on anti-herpes simplex virus type 2(HSV-2) in vitro focusing on adhesion and penetration stages were investigated. Materials and methods A model of HSV-2 infection of VK2/E6E7 was developed. In order to explore JZ-1's anti-HSV-2 effect in vitro, cell morphology, ultrastructural pathology, cell viability and expression of viral glycoprotein D (gD) were assessed at 6 h, 12 h, 18 h, and 24 h of JZ-1 treatment. Then we measured the exact time required for adhesion and penetration of HSV-2 into VK2/E6E7 among a series of times at room temperature and under temperature control techniques. We treated VK2/E6E7 with JZ-1, penciclovir, or berberine and explored the mechanism of JZ-1 in blocking HSV-2 adhesion and penetration of host cells by assessing the cell ultrastructural pathology, viability, viral proteins gB, gD, VP16, ICP5, and ICP4 and host cell proteins HVEM, Nectin-1, and Nectin-2. Results HSV-2 can fully adhere and penetrate into VK/E6E7 within 5 mins at room temperature while it takes 60mins under temperature control techniques. JZ-1 and penciclovir showed significant anti-HSV-2 effects, with improved host cell morphologies and increased host cell viabilities observed after treatment for 24 h. The anti-HSV-2 effect of JZ-1 can be detected after treatment for 6 h while that of penciclovir was not obvious until treatment for 12 h. JZ-1 showed distinct effect on HSV-2 adhesion and penetration stages by significantly reducing the expression of viral proteins gB, gD, VP16, ICP5, and ICP4, improving cell morphology and increasing cell viability. However, these effects were not exerted via downregulated expression of membrane fusion-related proteins such as HVEM, Nectin-1, or Nectin-2. The specific anti-HSV-2 mechanism of JZ-1 need to be further explored. Conclusion The anti-HSV-2 effect of JZ-1 was superior to that of penciclovir and berberine in vitro, and was mainly mediated by enhancing host cell defense and blocking adhesion and penetration of HSV-2., Graphical abstract Image 1

Summary Objectives This study sought to assess if there is a meaningful way in which variations in sexually transmitted infection (STI) prevalence can be classified at the level of world regions. Methods Linear regression was performed to assess if the incidence and prevalence of six STIs (HIV, herpes simplex virus type 2, chlamydia, gonorrhea, syphilis, and trichomoniasis) by world region was positively correlated. Partitioning around medoids (PAM) was then used to assess if the regions of the world can be classified according to the incidence and prevalence of these STIs. Results We found evidence that STI incidence/prevalence varies considerably in different regions around the world. Linear regression revealed that the incidence and prevalence of certain STIs by world region was positively correlated (Pearson's correlation coefficient varied from 0.664 to 0.985). PAM provided support for dividing the world regions into two, three, or four STI incidence/prevalence categories, but it provided most support for the two-category system. In each of these systems the East Asia/Pacific and North Africa/Middle East regions were in the lowest STI category and Sub-Saharan Africa was the only region in the high STI category. Conclusions The incidence and prevalence of certain STIs by world region are positively correlated. The world regions can be meaningfully classified according to STI incidence/prevalence.

This study evaluated the performance of the Kalon Biological HSV2 IgG enzyme-linked immunosorbent assay (Kalon Biological Ltd, Surrey, United Kingdom) on dried blood spots (DBS) of various dilutions compared with plasma from young women aged 18–24 years in Uganda. We estimated the sensitivity and specificity of three DBS dilutions using plasma as the reference. All three evaluated DBS dilutions yielded low sensitivities and specificities, with DBS 1:2 yielding the highest concurrence. Other herpes simplex virus type 2 assays should be examined with regard to their utility for testing DBS.

Numerous studies suggest that herpes simplex virus type 2 (HSV-2) increases the risk of HIV-1 infection but recent clinical trials of HSV-2 suppressive therapy failed to show an effect. We assessed the putative association between HSV-2 and HIV-1 in a population of HIV-concordant-negative, HIV-1-discordant and HIV-1-concordant-positive married couples from Dakar, Senegal. In agreement with previous studies, we observed a strong overall association between HSV-2 and HIV-1 (odds ratio 4.61; P < 0.001). However, this association was mainly determined by a low HSV-2 prevalence in HIV-concordant-negative couples compared with HIV-1-discordant and HIV-1-concordant-positive couples (23% versus 59% and 66%, respectively; P < 0.001). We observed no further differences in HSV-2 prevalence between HIV-1-discordant and HIV-1-concordant-positive couples (59% and 66%, respectively; P = 0.483). Neither the index (59% versus 62%, P = 1.000) nor recipient partners (41% versus 63%, P = 0.131) in HIV-1-discordant and HIV-1-concordant-positive couples showed significant differences in HSV-2 prevalence. HSV-2 does not constitute a clear risk factor for HIV-1 infection in this population.

A surprising result of the groundbreaking CAPRISA-004 trial, which demonstrated the efficacy of vaginal tenofovir 1% gel in reducing the risk of human immunodeficiency virus (HIV)-1 infection by 39% in heterosexual women, was the added benefit of this microbicide in reducing acquisition of herpes simplex virus type 2 (HSV-2) by 51%. HSV-2 is the most common cause of genital ulcer disease worldwide, and is responsible for considerable morbidity among women and neonates. The virus is further implicated in increasing the risk of both HIV acquisition and transmission, and may have additional adverse consequences in HIV-coinfected persons, making HSV-2 prevention an important clinical and public health objective. While tenofovir had not previously been widely considered to be an anti-herpes drug, in vitro activity against HSV is well documented, raising interest in potential future applications of tenofovir and its prodrugs in HSV-2 control. This article reviews the currently available data for tenofovir as an anti-herpes agent, as well as unanswered questions about delivery systems, drug formulation, rectal administration, drug resistance, and clinical applications.

We evaluated a new multiplex polymerase chain reaction (mPCR), "STDFinder assay", a novel multiplex ligation-dependent probe amplification (MLPA) assay for the simultaneous detection of 7 clinically relevant pathogens of STDs, i.e., Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, Mycoplasma genitalium, Treponema pallidum, and herpes simplex virus type 1 and 2 (HSV-1 and HSV-2). An internal amplification control was included in the mPCR reaction. The limits of detection for the STDFinder assay varied among the 7 target organisms from 1 to 20 copies per MLPA assay. There were no cross-reactions among any of the probes. Two hundred and forty-two vaginal swabs and an additional 80 specimens with known results for N. gonorrhoeae and C. trachomatis, obtained from infertile women seen at an infertility research clinic at the Kigali Teaching Hospital in Rwanda, were tested by STDFinder assay and the results were confirmed by single real-time PCR using different species-specific targets. Compared to the reference standard, the STDFinder assay showed specificities and sensitivities of 100% and 100%, respectively, for N. gonorrhoeae, C. trachomatis, and M. genitalium; 90.2% and 100%, respectively, for Trichomonas vaginalis; and 96.1% and 100%, respectively, for HSV-2. No specimen was found to be positive for HSV-1 by either the STDFinder assay or the comparator method. Similarly, the sensitivity for Treponema pallidum could not be calculated due to the absence of any Treponema pallidum-positive samples. In conclusion, the STDFinder assays have comparable clinical sensitivity to the conventional mono and duplex real-time PCR assay and are suitable for the routine detection of a broad spectrum of these STDs at relatively low cost due to multiplexing.

Introduction: Genital infection with herpes simplex virus type 2 (HSV-2) facilitates the acquisition of HIV, both mutually reinforcing infection. Lifelong latent HSV-2 infection raises concerns among women of reproductive age, considering the risk of neonatal transmission. In Nigeria, screening for HSV-2 and co-infection with HIV in antenatal clinics is not routine. This study was undertaken to determine the seroprevalence and co-infection of HSV-2 and HIV among pregnant women. Methods: This was a cross-sectional study conducted at the antenatal clinic of the University College Hospital, Ibadan, between March and August 2013. A total of 270 consenting pregnant women were enrolled. The study involved collecting socio-demographic data and laboratory determination of HSV-2 immunoglobulin G (IgG) and HIV seroprevalence using type-specific third-generation enzyme-linked immunosorbent assay (DIAPRO Diagnostic Bioprobes, Milan, Italy) and Uni-Gold Recombigen/ALERE determine, respectively. Data analyses were done using SPSS version 20 (SPSS Inc., IL, USA). Results: The seroprevalence for HSV-2 type-specific IgG was 33.3% (90/270), and HIV antibodies were identified in 19.63% (53/270) of the women. The HIV co-infection was 38.8% (35/90) among HSV-2-positive women and 10% (18/180) among HSV-2-negative women. Majority of the HSV-2 positive women (62.2%, 56/90) presented in their 2nd trimester while 18.9% (17/90) in their 3rd trimester. Conclusion: The seroprevalence of HSV-2 in this pregnant population is lower than what is observed in some other Sub-Saharan African countries; however, HSV-2/HIV co-infection is high. The HSV-2-seronegative women are still susceptible to primary HSV-2 infection in pregnancy with increased risk for HIV co-infection and neonatal transmission.

We found the prevalence of recurrent lymphocytic meningitis associated with herpes simplex virus type 2 (HSV-2) was 2.2/100,000 population in Finland during 1996–2006, higher than previous estimates. PCR was most sensitive in detecting HSV-2 DNA from cerebrospinal fluid if the sample was taken 2–5 days after symptom onset.

Purpose: To determine the seroprevalence of herpes simplex virus type 2 (HSV-2) in two urban communities in Delhi and to correlate the presence of HSV-2 seroprevalence with sociodemographic profile, risk factors and presence of other reproductive tract infections (RTIs). Methods: Men and women aged between 15-49 years from an urban slum and an urban middle class colony were invited to participate in the study. They provided interview information; blood for HSV-2, HIV and syphilis serology; first void urine specimens for diagnosis of Neisseria gonorrhoeae and Chlamydia trachomatis infection; and genital specimens for diagnosis of bacterial vaginosis, vaginal candidiasis and trichomoniasis. Results: The prevalence of HSV-2 seropositivity was found to be 7 and 8.6% in men and women, respectively. HSV-2 seropositivity was found to be significantly associated with urban middle class community and older age. No statistically significant correlation was found between HSV-2 seropositivity and other laboratory-confirmed RTIs. Conclusions: The findings of our study indicate a relatively low prevalence of HSV-2 seropositivity and other sexually transmitted infections in the two communities that were studied.

Los virus causan enfermedades humanas y animales de gran importancia epidemiológica y económica, para la mayoría de las cuales no existen tratamientos satisfactorios, o con las terapias se generan cepas resistentes. Extractos de plantas pertenecientes a la familia Euphorbiaceae han mostrado actividad contra virus de la familia Herpesviridae. Utilizando la técnica de tinción en placa con cristal violeta, se evaluó la citotoxicidad y la actividad antiviral de los extractos en hexano, en acetato de etilo, en metanol y en agua de las especies Caryodendron orinocense y Phyllanthus niruri contra los virus del Herpes Simplex tipo 2 (HSV-2) y del Herpes Bovino tipo 1 (HVB-1). Además, se realizó un estudio fitoquímico preliminar de las dos especies. En general, los extractos de las especies estudiadas muestran citotoxicidad a concentraciones mayores de 250 μg/mL. El extracto en acetato de etilo de la especie Caryodendron orinocense fue el que registró el mayor factor de reducción viral para HSV-2 y HVB-1, el cual fue de 10² a una concentración de 125 μg/ml y de 10(4) a 62.5 μg/ml respectivamente. Las especies estudiadas muestran una composición química determinada principalmente por aminoácidos, compuestos fenólicos, taninos y triterpenoides, metabolitos que podrían estar involucrados en su actividad antiviral.Viruses cause human and animal diseases of both epidemiological and economic importance and for many of them there are no satisfactory treatments or resistant strains are generated during drug therapy. Extracts from the Euphorbiaceae family plants have shown activity against viruses belonging to the Herpesviridae family. Both the toxicity and the antiviral activity of hexanic, ethyl acetate, methanolic and aqueous extracts from the Euphorbiaceae species Caryodendron orinocense and Phyllanthus niruri against Herpes Simplex Virus type 2 and Herpes Bovine Virus type 1, were evaluated using the crystal violet plaque staining technique. Furthermore, a preliminary phytochemical study of both species is presented. In general, extracts from the studied species showed toxic concentrations higher than 250 μg/ml. The ethyl acetate extract from Caryodendron orinocense showed the greatest viral reduction factor for both HSV-2 and HVB-1, namely, 10² at a concentration of 125 μg/ml and 10(4) a 62.5 μg/ml, respectively. The studied species showed a chemical composition determined primarily by aminoacids, phenolic compounds, tanins and triterpenes, metabolites that could be involved in their antiviral activity.

Objective: To understand the changing impact of herpes simplex 2 (HSV-2) and other sexually transmitted infections (STIs) on HIV incidence over time in four sub-Saharan African cities, using simulation models. Methods: An individual-based stochastic model was fitted to demographic, behavioural and epidemiological data from cross-sectional population-based surveys in four African cities (Kisumu, Kenya; Ndola, Zambia; Yaounde, Cameroon; and Cotonou, Benin) in 1997. To estimate the proportion of new HIV infections attributable to HSV-2 and other STIs over time, HIV incidence in the fitted model was compared with that in model scenarios in which the cofactor effect of the STIs on HIV susceptibility and infectivity were removed 5, 10, 15, 20 and 25 years into the simulated HIV epidemics. Results: The proportion of incident HIV attributable to HSV-2 infection (the model estimated population attributable fraction (PAF M )) increased with maturity of the HIV epidemic. In the different cities, the PAF M was 8–31% 5 years into the epidemic, but rose to 35–48% 15 years after the introduction of HIV. In contrast, the proportion of incident HIV attributable to chancroid decreased over time with strongest effects five years after HIV introduction, falling to no effect 15 years after. Sensitivity analyses showed that, in the model, recurrent HSV-2 ulcers had more of an impact on HIV incidence than did primary HSV-2 ulcers, and that the effect of HSV-2 on HIV infectivity may be more important for HIV spread than the effect on HIV susceptibility, assuming that HSV-2 has similar cofactor effects on HIV susceptibility and infectivity. The overall impact of other curable STIs on HIV spread (syphilis, gonorrhoea and chlamydia) remained relatively constant over time. Conclusions: Although HSV-2 appears to have a limited impact on HIV incidence in the early stages of sub-Saharan African HIV epidemics when the epidemic is concentrated in core groups, it has an increasingly large impact as the epidemic progresses. In generalised HIV epidemics where control programmes for curable STIs are already in place, interventions against HSV-2 may have a key role in HIV prevention.