RESUMO
Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are two of the most prevalent human viruses worldwide. They are known to cause a variety of diseases including genital herpes, meningitis, encephalitis, cold sores and herpes stromal keratitis. The seropositive rate for HSV-1 is around 90%, whereas for HSV-2 it remains around 20-25% for the general adult population. The infections caused by these viruses remain difficult to study because a large proportion of infected individuals are asymptomatic. Furthermore, given the neurotropic characteristics of the virus, studies aimed at understanding the complex pathogenesis in humans is difficult. As a result, animal models have been developed to understand several characteristics of HSV biology, pathogenesis, disease and host responses to infection. These models are also commonly used as the first evaluation of new drugs and vaccines. There are several well-established animal models to study infection with HSV, including mice, guinea pigs and rabbits. Variables within the animal models depend on the species of animal, route of infection, viral strain, dosage, etc. This review aims at summarizing the most commonly used animal models to study HSV pathogenesis and therapies.
Assuntos
Modelos Animais de Doenças , Herpes Simples , Herpesvirus Humano 1 , Herpesvirus Humano 2 , Animais , Herpes Simples/virologia , Cobaias , Camundongos , Humanos , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 2/fisiologia , Coelhos , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 1/patogenicidadeRESUMO
Tissue-resident-memory T cells (TRM) populate the body's barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Epiteliais/imunologia , Herpes Genital/imunologia , Herpesvirus Humano 2/imunologia , Imunidade Inata , Memória Imunológica , Células T de Memória/imunologia , Pele/imunologia , Imunidade Adaptativa/genética , Adulto , Idoso , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Perfilação da Expressão Gênica , Herpes Genital/genética , Herpes Genital/metabolismo , Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata/genética , Interferon gama/genética , Interferon gama/metabolismo , Masculino , Células T de Memória/metabolismo , Células T de Memória/virologia , Pessoa de Meia-Idade , Fenótipo , Pele/metabolismo , Pele/virologia , TranscriptomaRESUMO
Herpes viruses are known for infecting epithelial cells and manifesting as vesicles. However, herpes viruses can also infect stromal cells. While established in the ocular setting, cutaneous stromal herpes (deep herpes) is previously unreported and may evade clinical and microscopic detection. We searched for skin biopsies with herpes stromal disease. Clinical information was retrieved via electronic medical records and pathology records system. Hematoxylin and eosin slides, immunohistochemical staining, and polymerase chain reaction detection of viral DNA was performed. We identified 12 specimens from 10 patients with cutaneous stromal herpes simplex virus 1/2 (n=7) or varicella-zoster virus infection (n=5). The most common site involved was the buttocks/perianal region (n=6). Ulceration was a frequent dermatologic finding (n=8). Pyoderma gangrenosum was clinically suspected in 6 specimens (50%). Eight patients (80%) were immunosuppressed. Biopsies frequently demonstrated a dense dermal mixed inflammatory infiltrate with subcutaneous extension and enlarged cells with viral cytopathic changes confirmed by herpes simplex virus 1/2 or varicella-zoster virus immunohistochemistry (n=10) or polymerase chain reaction (n=2). Most specimens (67%) lacked evidence of characteristic epidermal keratinocyte infection. This study presents the first known report of the ability of herpes virus to infect deep stromal cells of the dermis. We raise awareness of cutaneous stromal herpes in patients presenting with atypical clinical lesions, particularly while immunocompromised. Establishing the correct diagnosis is critical for initiating therapy.
Assuntos
Derme/virologia , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 3/patogenicidade , Células Estromais/virologia , Infecção pelo Vírus da Varicela-Zoster/virologia , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , DNA Viral/genética , Derme/efeitos dos fármacos , Derme/patologia , Feminino , Herpes Simples/diagnóstico , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/genética , Herpesvirus Humano 3/efeitos dos fármacos , Herpesvirus Humano 3/genética , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Resultado do Tratamento , Infecção pelo Vírus da Varicela-Zoster/diagnóstico , Infecção pelo Vírus da Varicela-Zoster/tratamento farmacológico , Adulto JovemRESUMO
OBJECTIVE: To characterise epidemiology of herpes simplex virus type 2 (HSV-2) in Latin America and the Caribbean. METHODS: HSV-2 reports were systematically reviewed and synthesised, and findings were reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses and metaregressions were conducted. FINDING: 102 relevant reports were identified including 13 overall incidence measures, 163 overall (and 402 stratified) seroprevalence measures, and 7 and 10 proportions of virus detection in genital ulcer disease and in genital herpes, respectively. Pooled mean seroprevalence was 20.6% (95% CI 18.7% to 22.5%) in general populations, 33.3% (95% CI 26.0% to 41.0%) in intermediate-risk populations, 74.8% (95% CI 70.6% to 78.8%) in female sex workers, and 54.6% (95% CI 47.4% to 61.7%) in male sex workers, men who have sex with men and transgender people. In general populations, seroprevalence increased from 9.6% (95% CI 7.1% to 12.4%) in those aged <20 years to 17.9% (95% CI 13.6% to 22.5%) in those aged 20-30, 27.6% (95% CI 21.4% to 34.2%) in those aged 30-40 and 38.4% (95% CI 32.8% to 44.2%) in those aged >40. Compared with women, men had lower seroprevalence with an adjusted risk ratio (ARR) of 0.68 (95% CI 0.60 to 0.76). Seroprevalence declined by 2% per year over the last three decades (ARR of 0.98, 95% CI 0.97 to 0.99). Pooled mean proportions of HSV-2 detection in GUD and genital herpes were 41.4% (95% CI 18.9% to 67.0%) and 91.1% (95% CI 82.7% to 97.2%), respectively. CONCLUSIONS: One in five adults is HSV-2 infected, a higher level than other world regions, but seroprevalence is declining. Despite this decline, HSV-2 persists as the aetiological cause of nearly half of GUD cases and almost all of genital herpes cases.
Assuntos
Herpes Genital/epidemiologia , Herpesvirus Humano 2/imunologia , Região do Caribe/epidemiologia , Feminino , Herpes Genital/imunologia , Herpesvirus Humano 2/patogenicidade , Homossexualidade Masculina/estatística & dados numéricos , Humanos , América Latina/epidemiologia , Masculino , Razão de Chances , Análise de Regressão , Fatores de Risco , Estudos Soroepidemiológicos , Profissionais do Sexo/estatística & dados numéricos , Comportamento SexualRESUMO
OBJECTIVES: To analyze the trends of HIV/syphilis/HSV-2 seropositive rate and explore the related factors with HSV-2 infection to provide the basis for adjusting STD intervention strategies and formulating prevention and control measures among MSM in Shenzhen. METHODS: Time-location sampling was conducted among MSM in Shenzhen in 2012, 2014, 2016, and 2018. Data on demographics, sexual behaviors and the laboratory test results of HIV, syphilis, HSV-2 were collected. The χ2 trend test was used to analyze the trends of HIV/syphilis/HSV-2 seropositive rate. The binary logistic regression model was used to explore the factors associated with HSV-2 infection. RESULTS: The seropositive rate of HIV fell significantly from 15.9% in 2012 to 8.7% in 2018 (Ptrend = 0.003), syphilis seropositive rate was significantly decreased from 20.4% in 2012 to 14.8% in 2018 (Ptrend = 0.025), HSV-2 seropositive rate had no significant change (16.7% in 2012 to 14.0% in 2018; Ptrend = 0.617). In principal component logistic regression analysis showed that FAC1_1 (X1 = Ever had sex with female, X2 = Gender of first sexual partner, X3 = Marital status, X4 = Age group), FAC2_1 (X5 = Education, X6 = Monthly income (RMB), X7 = Frequency of condom use in anal sex with men in the past 6 months), and FAC4_1 (X9 = History of STDs) were significantly associated with HSV-2 infection. CONCLUSIONS: The seropositive rates of HIV and syphilis have dropped significantly but are still high. HSV-2 seropositive rate had no significant change and maintained a high level. It is necessary to continue strengthening HIV and syphilis interventions among MSM in Shenzhen. HSV-2 detection and intervention are urgently required for MSM, which might be another effective biological strategy further to control the HIV epidemic among MSM in Shenzhen.
Assuntos
Infecções por HIV/epidemiologia , Herpes Simples/epidemiologia , Homossexualidade Masculina , Sífilis/epidemiologia , Adulto , China/epidemiologia , Coinfecção/epidemiologia , Coinfecção/microbiologia , Coinfecção/virologia , Infecções por HIV/complicações , Infecções por HIV/microbiologia , Infecções por HIV/virologia , Herpes Simples/complicações , Herpes Simples/microbiologia , Herpes Simples/virologia , Herpesvirus Humano 2/patogenicidade , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sexo Seguro , Comportamento Sexual , Sífilis/complicações , Sífilis/microbiologia , Sífilis/virologiaRESUMO
Neutrophil responses against pathogens must be balanced between protection and immunopathology. Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFNα/ß receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.
Herpes simplex virus (HSV) is a human pathogen that causes genital herpes, an incurable disease that results in recurrent sores and inflammation. Infection with HSV induces a strong antiviral immune response, which results in large numbers of immune cells arriving at these lesions. But while some of these cells help to control viral replication, others might contribute to the inflammation that drives the disease. One of the first immune cells to respond to infection are neutrophils. Although neutrophils are generally protective, especially against bacteria and fungi, they have also been implicated in tissue damage and severe inflammation during viral infections. But what determines whether a neutrophil will help to fight off an infection or increase disease severity is still an open question. To investigate this, Lebratti, Lim et al. studied mice that had been infected with the genital herpes virus HSV-2, which is known to cause significant amounts of inflammation in mice. The experiments revealed that a signaling molecule called type I interferon, which is thought to be antiviral, causes neutrophils at the site of the infection to produce proteins, such as IL-18, which trigger an inflammatory reaction. Lebratti, Lim et al. found that type I interferon and IL-18 had shifting roles during the course of infection. In the early stages, both molecules had a protective effect, confirming results from previous studies. However, as the infection progressed, sustained levels of type I interferon signaling in neutrophils led to excess amounts of IL-18. Lebratti, Lim et al. discovered that blocking interferon signaling or decreasing the levels of IL-18 later during infection unexpectedly reduced the severity of the disease and resulted in less genital tissue damage. Further experiments also showed that mice infected with another genital herpes virus called HSV-1 did not experience sustained levels of type I interferon. This may explain why this virus causes less severe disease in mice. Understanding how the immune system reacts to viruses could reveal new targets for treatments of genital herpes. At the moment, there is little information about IL-18 production during genital herpes in humans. So, the next step is to see whether neutrophils behave in the same way and whether IL-18 can be detected during human disease. It is possible that the same immune components could promote disease in other infections too. If so, this work may help uncover new drug targets for other viral diseases.
Assuntos
Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Imunidade nas Mucosas , Interferon Tipo I/metabolismo , Interleucina-18/metabolismo , Mucosa/virologia , Ativação de Neutrófilo , Neutrófilos/virologia , Vagina/virologia , Animais , Anticorpos/farmacologia , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/imunologia , Herpes Genital/metabolismo , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/imunologia , Interações Hospedeiro-Patógeno , Imunidade nas Mucosas/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mucosa/efeitos dos fármacos , Mucosa/inervação , Mucosa/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais , Vagina/efeitos dos fármacos , Vagina/imunologia , Vagina/metabolismo , Células VeroRESUMO
BACKGROUND: OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS: In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS: Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS: Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.
Assuntos
Herpesvirus Humano 2/patogenicidade , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/patogenicidade , Adulto , Idoso , China , Terapia Combinada , Feminino , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/virologia , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Critérios de Avaliação de Resposta em Tumores Sólidos , Fatores de Tempo , Resultado do TratamentoRESUMO
The frequency of central nervous system infections due to herpesvirus have been studied in various populations; however, studies in Mexican mestizo patients are scant. This paper documents the frequency of herpesvirus encephalitis in Mexican mestizo patients from the National Institute of Neurology and Neurosurgery (NINN) of Mexico. To study the frequency of herpetic viral encephalitis at the NINN in the period from 2004 to 2009. We reviewed clinical records from patients with clinically suspected encephalitis; polymerase chain reaction assays were done for detection of herpesviruses in cerebrospinal fluid (CSF) samples. The total number of patients studied was 502; in 59 (12%), the diagnosis of herpetic encephalitis was confirmed by PCR-based testing of CSF. Of them, 21 (36%) were positive for herpes simplex virus type 1, 15 (25%) for Epstein-Barr virus, 10 (17%) for varicella zoster virus, 8 (14%) for cytomegalovirus, 3 (5%) for human herpesvirus 6, and 2 (3%) for herpes simplex virus 2. Our results show a varied frequency of viral encephalitis in mestizo patients due to herpesviruses in a tertiary neurological center and point out the importance of modern molecular technology to reach the etiological diagnosis in cases of encephalitis.
Assuntos
Infecções por Citomegalovirus/diagnóstico , Encefalite por Varicela Zoster/diagnóstico , Encefalite Viral/diagnóstico , Infecções por Vírus Epstein-Barr/diagnóstico , Herpes Genital/diagnóstico , Herpes Simples/diagnóstico , Infecções por Roseolovirus/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Citomegalovirus/genética , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etnologia , Infecções por Citomegalovirus/virologia , Encefalite por Varicela Zoster/epidemiologia , Encefalite por Varicela Zoster/etnologia , Encefalite por Varicela Zoster/virologia , Encefalite Viral/epidemiologia , Encefalite Viral/etnologia , Encefalite Viral/virologia , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/etnologia , Infecções por Vírus Epstein-Barr/virologia , Etnicidade , Feminino , Herpes Genital/epidemiologia , Herpes Genital/etnologia , Herpes Genital/virologia , Herpes Simples/epidemiologia , Herpes Simples/etnologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/genética , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 3/genética , Herpesvirus Humano 3/patogenicidade , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/patogenicidade , Humanos , Incidência , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Infecções por Roseolovirus/epidemiologia , Infecções por Roseolovirus/etnologia , Infecções por Roseolovirus/virologiaRESUMO
This review presents the data on the spreading of all known human herpesviruses (ÐHVs) in female urogenital tract. According to the WHO almost 500 million people worldwide suffer from genital infection caused by ÐHVs. ÐHVs were detected in various inflammatory diseases of female upper and lower genital tract (vaginitis and cervicitis), in extrauterine pregnancy (in fallopian tubes), in infertility (cervical channel, endometrium and ovaries). Herpes simplex virus 1 (HSV1) was identified for the first time in oocytes after failed in vitro fertilization (IVF). ÐHVs produce negative effect on the entire reproductive process from conception to childbirth. It was established that HSV, cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) markedly increase the risk of spontaneous abortion, preterm birth and stillbirth. Intrauterine ÐHV infection is a major cause of congenital malformations. Data on humoral and cell immunity in genital herpesvirus infections (ÐHVI) are also reviewed. Intravaginal HSV2 infection changes cell composition of vaginal mucosa, i.e., together with cells mobilized from the blood, protective role is performed by resident memory Tcells (TRM), natural killer cells (NKcells) and regulatory Tcells (Treg) whose function consists in maintaining the balance of the activities of lymphocytes. Constant ÐHVI spreading is largely explained by transition of primary infection to potentially reactivating latent form, since latent virus is unavailable to immune recognition and medicines. The genome editing system CRISPR/Cas9 can recognize and modify not only active but also latent viruses. The promising pilot results with the use of this system offer the possibility of developing innovative technologies for ÐHV elimination and ÐHVI eradication.
Assuntos
Herpes Genital/virologia , Herpesviridae/patogenicidade , Infertilidade Feminina/virologia , Infecções do Sistema Genital/virologia , Feminino , Herpes Genital/epidemiologia , Herpesviridae/classificação , Herpesviridae/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Herpesvirus Humano 6/patogenicidade , Humanos , Infertilidade Feminina/epidemiologia , Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/virologia , Infecções do Sistema Genital/epidemiologiaRESUMO
The infections caused by Herpes simplex viruses (HSV-1 and -2) are seriously endangering the health of all human beings. Once infected with these two viruses, it will cause life-long latency in the host, and the continuous recurrence of the infection will seriously affect the quality of life. Moreover, infections with HSV-1 and HSV-2 have been reported to make the body susceptible to other diseases, such as Alzheimer's disease and HIV. Thus, more attention should be paid to the development of novel anti-HSV drugs. Polysaccharides obtained from medicinal plants and microorganism (both land and sea) are reported to be promising anti-herpes substances. However, their antiviral mechanisms are complex and diverse, which includes direct inhibition of virus life cycle (Adsorption, penetration, genetic material and protein synthesis) and indirectly through improving the body's immunity. And each step of the research processes from extraction to structural analysis contributes to the result in terms of antiviral activity. Therefore, The complex mechanisms involved in the treatment of Herpes simplex infections makes development of new antiviral compounds is difficult. In this paper, the mechanisms of polysaccharides in the treatment of Herpes simplex infections, the research processes of polysaccharides and their potential clinical applications were reviewed.
Assuntos
Antivirais/farmacologia , Polissacarídeos Fúngicos/farmacologia , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais , Polissacarídeos Bacterianos/farmacologia , Polissacarídeos/farmacologia , Animais , Antivirais/isolamento & purificação , Polissacarídeos Fúngicos/isolamento & purificação , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/crescimento & desenvolvimento , Herpesvirus Humano 2/patogenicidade , Humanos , Extratos Vegetais/isolamento & purificação , Plantas Medicinais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos Bacterianos/isolamento & purificaçãoRESUMO
Us3 proteins of herpes simplex virus 1 (HSV-1) and HSV-2 are multifunctional serine-threonine protein kinases. Here, we identified an HSV-2 tegument protein, UL7, as a novel physiological substrate of HSV-2 Us3. Mutations in HSV-2 UL7, which precluded Us3 phosphorylation of the viral protein, significantly reduced mortality, viral replication in the vagina, and development of vaginal disease in mice following vaginal infection. These results indicated that Us3 phosphorylation of UL7 in HSV-2 was required for efficient viral replication and pathogenicity in vivo Of note, this phosphorylation was conserved in UL7 of chimpanzee herpesvirus (ChHV), which phylogenetically forms a monophyletic group with HSV-2 and the resurrected last common ancestral UL7 for HSV-2 and ChHV. In contrast, the phosphorylation was not conserved in UL7s of HSV-1, which belongs to a sister clade of the monophyletic group, the resurrected last common ancestor for HSV-1, HSV-2, and ChHV, and other members of the genus Simplexvirus that are phylogenetically close to these viruses. Thus, evolution of Us3 phosphorylation of UL7 coincided with the phylogeny of simplex viruses. Furthermore, artificially induced Us3 phosphorylation of UL7 in HSV-1, in contrast to phosphorylation in HSV-2, had no effect on viral replication and pathogenicity in mice. Our results suggest that HSV-2 and ChHV have acquired and maintained Us3 phosphoregulation of UL7 during their evolution because the phosphoregulation had an impact on viral fitness in vivo, whereas most other simplex viruses have not because the phosphorylation was not necessary for efficient fitness of the viruses in vivoIMPORTANCE It has been hypothesized that the evolution of protein phosphoregulation drives phenotypic diversity across species of organisms, which impacts fitness during their evolution. However, there is a lack of information regarding linkage between the evolution of viral phosphoregulation and the phylogeny of virus species. In this study, we clarified the novel HSV-2 Us3 phosphoregulation of UL7 in infected cells, which is important for viral replication and pathogenicity in vivo We also showed that the evolution of Us3 phosphoregulation of UL7 was linked to the phylogeny of viruses that are phylogenetically close to HSV-2 and to the phosphorylation requirements for the efficient in vivo viral fitness of HSV-2 and HSV-1, which are representative of viruses that have and have not evolved phosphoregulation, respectively. This study reports the first evidence showing that evolution of viral phosphoregulation coincides with phylogeny of virus species and supports the hypothesis regarding the evolution of viral phosphoregulation during viral evolution.
Assuntos
Regulação Viral da Expressão Gênica , Herpes Genital/virologia , Herpesvirus Humano 2/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas da Matriz Viral/genética , Proteínas Virais/genética , Proteínas Estruturais Virais/genética , Sequência de Aminoácidos , Animais , Chlorocebus aethiops , Modelos Animais de Doenças , Evolução Molecular , Feminino , Aptidão Genética , Células HEK293 , Herpes Genital/mortalidade , Herpesvirus Humano 1/classificação , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/classificação , Herpesvirus Humano 2/metabolismo , Herpesvirus Humano 2/patogenicidade , Humanos , Camundongos , Fosforilação , Filogenia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Vagina/virologia , Células Vero , Proteínas da Matriz Viral/metabolismo , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Virulência , Replicação ViralRESUMO
HSV-2 (Herpes simplex virus type 2) is a critical viral agent that mainly causes genital herpes and life-long latent infection in the dorsal root ganglia. Gene modification via CRISPR/Cas9 Clustered regularly interspaced short palindromic repeat sequences/CRISPR associated 9) was used here to construct HSV-2 mutant strains through the deletion of fragments of the RL1 (Repeat Long element 1) and/or LAT (Latency-associated Transcript) genes. The HSV-2 mutant strains LAT-HSV-2 and RL1-LAT-HSV-2 present different biological properties. The proliferation of RL1-LAT-HSV-2 in nerve cells was decreased significantly, and the plaques induced by RL1-LAT-HSV-2 in Vero cells were smaller than those induced by LAT-HSV-2 mutant and wild-type strains. The observation of mice infected with these two mutants compared to mice infected with the wild-type strain indicated that the mutant RL1-LAT-HSV-2 has an attenuated phenotype with reduced pathogenicity during both acute and latent infections and induces a stronger specific immune response than the wild-type strain, whereas the attenuation effect was not found in mice infected with the LAT-HSV-2 mutant containing the LAT gene deletion. However, the simultaneous mutation of both the RL1 and LAT genes did not completely restrict viral proliferation in nerve cells, indicating that multiple HSV genes are involved in viral replication in the neural system. This work suggests that the HSV-2 genes RL1 and/or LAT might be involved in the virulence mechanisms in mouse infections.
Assuntos
Herpesvirus Humano 2/genética , Herpesvirus Humano 2/patogenicidade , Mutação , Neurônios/virologia , Proteínas Virais/genética , Animais , Chlorocebus aethiops , Feminino , Herpes Simples/imunologia , Herpes Simples/virologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/patologia , Fenótipo , RNA Viral/genética , Células Vero , Ensaio de Placa Viral , Replicação ViralRESUMO
During primary infection, herpes simplex virus 2 (HSV-2) replicates in epithelial cells and enters neurites to infect neurons of the peripheral nervous system. Growth factors and attractive and repulsive directional cues influence neurite outgrowth and neuronal survival. We hypothesized that HSV-2 modulates the activity of such cues to increase neurite outgrowth. To test this hypothesis, we exposed sensory neurons to nerve growth factor (NGF) and mock- or HSV-2-infected HEK-293T cells, since they express repellents of neurite outgrowth. We show that HEK-293T cells secrete factors that inhibit neurite outgrowth, while infection with HSV-2 strains MS and 333 reduces this repelling phenotype, increasing neurite numbers. The HSV-2-mediated restoration of neurite outgrowth required the activity of NGF. In the absence of infection, however, NGF did not overcome the repulsion mediated by HEK-293T cells. We previously showed that recombinant, soluble glycoprotein G of HSV-2 (rSgG2) binds and enhances NGF activity, increasing neurite outgrowth. However, the effect of gG2 during infection has not been investigated. Therefore, we addressed whether gG2 contributes to overcoming neurite outgrowth repulsion. To do so, we generated viruses lacking gG2 expression and complemented them by exogenous expression of gG2. Overall, our results suggest that HSV-2 infection of nonneuronal cells reduces their repelling effect on neurite outgrowth in an NGF-dependent manner. gG2 contributed to this phenotype, but it was not the only factor. The enhanced neurite outgrowth may facilitate HSV-2 spread from epithelial cells into neurons expressing NGF receptors and increase HSV-2-mediated pathogenesis.IMPORTANCE Herpes simplex virus 2 (HSV-2) is a prevalent human pathogen that establishes lifelong latency in neurons of the peripheral nervous system. Colonization of neurons is required for HSV-2 persistence and pathogenesis. The viral and cellular factors required for efficient infection of neurons are not fully understood. We show here that nonneuronal cells repel neurite outgrowth of sensory neurons, while HSV-2 infection overcomes this inhibition and, rather, stimulates neurite outgrowth. HSV-2 glycoprotein G and nerve growth factor contribute to this phenotype, which may attract neurites to sites of infection and facilitate virus spread to neurons. Understanding the mechanisms that modulate neurite outgrowth and facilitate HSV-2 infection of neurons might foster the development of therapeutics to reduce HSV-2 colonization of the nervous system and provide insights on neurite outgrowth and regeneration.
Assuntos
Herpes Genital/metabolismo , Herpesvirus Humano 2/metabolismo , Fator de Crescimento Neural/metabolismo , Neuritos , Animais , Linhagem Celular Tumoral , Chlorocebus aethiops , Células HEK293 , Herpesvirus Humano 2/patogenicidade , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neuritos/metabolismo , Neuritos/virologia , Células VeroRESUMO
Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell-mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ-producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.
Assuntos
Herpes Simples/imunologia , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/virologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , Feminino , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Interações Hospedeiro-Patógeno , Interferon gama/biossíntese , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Norethisterone enanthate (NET-EN) and depot-medroxyprogesterone acetate (DMPA) are two forms of injectable progestin used for contraception. Whereas clinical research indicates that women using DMPA are more susceptible to HIV and other genital pathogens, causal relationships have not been determined. Providing an underlying mechanism for this connection, however, is recent work that showed DMPA weakens genital mucosal barrier function in mice and humans and respectively promotes susceptibility of wild-type and humanized mice to genital infection with HSV type 2 and HIV type 1. However, analogous effects of NET-EN treatment on antivirus immunity and host susceptibility to genital infection are much less explored. In this study, we show that compared with mice in estrus, treatment of mice with DMPA or NET-EN significantly decreased genital levels of the cell-cell adhesion molecule desmoglein-1 and increased genital mucosal permeability. These effects, however, were more pronounced in DMPA- versus NET-EN-treated mice. Likewise, we detected comparable mortality rates in DMPA- and NET-EN-treated wild-type and humanized mice after intravaginal infection with HSV type 2 or cell-associated HIV type 1, respectively, but NET-EN treatment was associated with slower onset of HSV-induced genital pathology and lower burden of systemic HIV disease. These findings reveal DMPA and NET-EN treatment of mice significantly reduces genital desmoglein-1 levels and increases genital mucosal permeability and susceptibility to genital pathogens while also implying that NET-EN generates less compromise of genital mucosal barrier function than DMPA.
Assuntos
Anticoncepcionais Femininos/efeitos adversos , HIV-1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Noretindrona/análogos & derivados , Vagina/virologia , Animais , Desmogleína 1/metabolismo , Suscetibilidade a Doenças/virologia , Feminino , Infecções por HIV/virologia , HIV-1/patogenicidade , Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Acetato de Medroxiprogesterona/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Mucosa/efeitos dos fármacos , Mucosa/metabolismo , Mucosa/virologia , Noretindrona/efeitos adversos , Permeabilidade , Vagina/efeitos dos fármacos , Vagina/metabolismoRESUMO
Viral infections kill millions of people and new antivirals are needed. Nontoxic drugs that irreversibly inhibit viruses (virucidal) are postulated to be ideal. Unfortunately, all virucidal molecules described to date are cytotoxic. We recently developed nontoxic, broad-spectrum virucidal gold nanoparticles. Here, we develop further the concept and describe cyclodextrins, modified with mercaptoundecane sulfonic acids, to mimic heparan sulfates and to provide the key nontoxic virucidal action. We show that the resulting macromolecules are broad-spectrum, biocompatible, and virucidal at micromolar concentrations in vitro against many viruses [including herpes simplex virus (HSV), respiratory syncytial virus (RSV), dengue virus, and Zika virus]. They are effective ex vivo against both laboratory and clinical strains of RSV and HSV-2 in respiratory and vaginal tissue culture models, respectively. Additionally, they are effective when administrated in mice before intravaginal HSV-2 inoculation. Lastly, they pass a mutation resistance test that the currently available anti-HSV drug (acyclovir) fails.
Assuntos
Ciclodextrinas/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Viroses/tratamento farmacológico , Aciclovir/química , Aciclovir/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Ciclodextrinas/síntese química , Ciclodextrinas/química , Feminino , Ouro/química , Heparitina Sulfato/química , Heparitina Sulfato/farmacologia , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Humanos , Nanopartículas Metálicas/química , Camundongos , Simplexvirus/efeitos dos fármacos , Simplexvirus/patogenicidade , Viroses/virologia , Zika virus/efeitos dos fármacos , Zika virus/patogenicidadeRESUMO
Based on seroepidemiological studies, human herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are put in relation with a number of cancer diseases; however, they do not appear to play a direct role, being only considered cofactors. Their ability to transform the cells in vitro could be demonstrated experimentally by removing their high lytic ability by a certain dose of UV radiation or by photoinactivation in the presence of photosensitizers, such as neutral red or methylene blue, or culturing under conditions suppressing their lytic activity. However, recent studies indicate that UV irradiated or photoinactivated HSV-1 and HSV-2, able to transform non-transformed cells, behave differently in transformed cells suppressing their transformed phenotype. Furthermore, both transforming and transformed phenotype suppressing activities are pertaining only to non-syncytial virus strains. There are some proposed mechanisms explaining their transforming activity. According to the "hit and run" mechanism, viral DNA induces only initiation of transformation by interacting with cellular DNA bringing about mutations and epigenetic changes and is no longer involved in other processes of neoplastic progression. According to the "hijacking" mechanism, virus products in infected cells may activate signalling pathways and thus induce uncontrolled proliferation. Such a product is e.g. a product of HSV-2 gene designated ICP10 that encodes an oncoprotein RR1PK that activates the Ras pathway. In two cases of cancer, in the case of serous ovarian carcinoma and in some prostate tumours, virus-encoded microRNAs (miRNAs) were detected as a possible cofactor in tumorigenesis. And, recently described herpes virus-associated growth factors with transforming and transformation repressing activity might be considered important factors playing a role in tumour formation. And finally, there is a number of evidence that HSV-2 may increase the risk of cervical cancer after infection with human papillomaviruses. A similar situation is with human cytomegalovirus; however, here, a novel mechanism named oncomodulation has been proposed. Oncomodulation means that HCMV infects tumour cells and modulates their malignant properties without having a direct effect on cell transformation.
Assuntos
Transformação Celular Viral/genética , Infecções por Herpesviridae/complicações , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Neoplasias/virologia , DNA Viral/genética , Infecções por Herpesviridae/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 2/genética , HumanosRESUMO
BACKGROUND: Human encephalitis can originate from a variety of different aetiologies, of which infection is the most common one. The diagnostic work-up is specifically challenging in patients with travel history since a broader spectrum of unfamiliar additional infectious agents, e. g. tropical disease pathogens, needs to be considered. Here we present a case of encephalitis of unclear aetiology in a female traveller returning from Africa, who in addition developed an atypical herpes simplex virus (HSV) encephalitis in close temporal relation with high-dose steroid treatment. CASE PRESENTATION: A previously healthy 48-year-old female presented with confusion syndrome and impaired vigilance which had developed during a six-day trip to The Gambia. The condition rapidly worsened to a comatose state. Extensive search for infectious agents including a variety of tropical disease pathogens was unsuccessful. As encephalitic signs persisted despite of calculated antimicrobial and antiviral therapy, high-dose corticosteroids were applied intravenously based on the working diagnosis of an autoimmune encephalitis. The treatment did, however, not improve the patient's condition. Four days later, bihemispheric signal amplification in the insular and frontobasal cortex was observed on magnetic resonance imaging (MRI). The intracranial pressure rapidly increased and could not be controlled by conservative treatment. The patient died due to tonsillar herniation 21 days after onset of symptoms. Histological examination of postmortem brain tissue demonstrated a generalized lymphocytic meningoencephalitis. Immunohistochemical reactions against HSV-1/2 indicated an atypical manifestation of herpesviral encephalitis in brain tissue. Moreover, HSV-1 DNA was detected by a next-generation sequencing (NGS) metagenomics approach. Retrospective analysis of cerebrospinal fluid (CSF) and serum samples revealed HSV-1 DNA only in specimens one day ante mortem. CONCLUSIONS: This case shows that standard high-dose steroid therapy can contribute to or possibly even trigger fulminant cerebral HSV reactivation in a critically ill patient. Thus, even if extensive laboratory diagnostics including wide-ranging search for infectious pathogens has been performed before and remained without results, continuous re-evaluation of potential differential diagnoses especially regarding opportunistic infections or reactivation of latent infections is of utmost importance, particularly if new symptoms occur.
Assuntos
Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Encefalite por Herpes Simples/etiologia , Herpes Simples/diagnóstico , Herpesvirus Humano 1/isolamento & purificação , Esteroides/efeitos adversos , Autopsia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , DNA Viral/sangue , DNA Viral/líquido cefalorraquidiano , Encefalite/diagnóstico , Feminino , Gâmbia , Doença de Hashimoto/diagnóstico , Herpes Simples/diagnóstico por imagem , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 2/patogenicidade , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Estudos Retrospectivos , Esteroides/uso terapêutico , ViagemRESUMO
Herpes simplex viruses not only infect a variety of different cell types, including dendritic cells (DCs), but also modulate important cellular functions in benefit of the virus. Given the relevance of directed immune cell migration during the initiation of potent antiviral immune responses, interference with DC migration constitutes a sophisticated strategy to hamper antiviral immunity. Notably, recent reports revealed that HSV-1 significantly inhibits DC migration in vitro. Thus, we aimed to investigate whether HSV-2 also modulates distinct hallmarks of DC biology. Here, we demonstrate that HSV-2 negatively interferes with chemokine-dependent in vitro migration capacity of mature DCs (mDCs). Interestingly, rather than mediating the reduction of the cognate chemokine receptor expression early during infection, HSV-2 rapidly induces ß2 integrin (LFA-1)-mediated mDC adhesion and thereby blocks mDC migration. Mechanistically, HSV-2 triggers the proteasomal degradation of the negative regulator of ß2 integrin activity, CYTIP, which causes the constitutive activation of LFA-1 and thus mDC adhesion. In conclusion, our data extend and strengthen recent findings reporting the reduction of mDC migration in the context of a herpesviral infection. We thus hypothesize that hampering antigen delivery to secondary lymphoid organs by inhibition of mDC migration is an evolutionary conserved strategy among distinct members of Herpesviridae.
Assuntos
Movimento Celular , Células Dendríticas/patologia , Células Dendríticas/virologia , Herpesvirus Humano 2/patogenicidade , Adesão Celular , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/imunologia , Herpesvirus Humano 2/imunologia , Humanos , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Proteínas Virais/genéticaRESUMO
Good's syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good's syndrome.