RESUMO
ETHNOPHAMACOLOGICAL RELEVANCE: The Chinese herbal prescription JieZe-1 (JZ-1) is based on the modification of Yihuang Tang, which was first described in Fu Qingzhu Nvke by the famous Qing Dynasty doctor Shan Fu as a treatment for leukorrheal diseases. As an in-hospital preparation, JZ-1 has been used in Tongji Hospital for many years to treat various infectious diseases of the lower female genital tract, including cervicitis, vaginitis, genital herpes and condyloma acuminatum. Our previous studies have shown that JZ-1 has curative effects on Candida albicans, Trichomonas vaginalis and Ureaplasma urealyticum infections. AIM OF THE STUDY: Genital herpes is among the most common sexually transmitted diseases (STDs) worldwide and is mainly caused by herpes simplex virus type-2 (HSV-2). Current therapies can relieve symptoms in patients but do not cure or prevent the spread of the virus. This study was designed to investigate the effect of JZ-1 on HSV-2 infection and its mechanism, which is based on autophagy induction, to provide new ideas and a basis for the study of antiviral drugs. MATERIALS AND METHODS: Evaluation of the antiviral activity of JZ-1 was conducted by MTT assay and western blotting. Then, Western blot and immunofluorescence analyses, observations through transmission electron microscopy and experiments with the recombinant lentivirus vector mRFP-GFP-LC3B were used to monitor autophagic flux in VK2/E6E7 cells. To explore the mechanism by which JZ-1 regulates autophagy, western blotting and real-time quantitative PCR (qRT-PCR) were used to determine the expression of phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway proteins and to detect changes in critical molecules in the pathway after the application of a PI3K inhibitor. Additionally, the mRNA expression levels of inflammatory cytokines, namely, IL-6, IFN-α, IFN-ß and TNF-α, were measured with qRT-PCR. RESULTS: HSV-2 infection inhibited autophagy in the VK2/E6E7 cells. Further study revealed that the activation of the PI3K/Akt/mTOR pathway induced by HSV-2 infection may result in the blocked autophagic flux and inhibited autophagosome and autolysosome formation. JZ-1 exhibited significant antiviral activity in the VK2/E6E7 cells, which showed increased cell vitality and reduced viral protein expression, namely, earliest virus-specific infected cell polypeptides 5 (ICP5) and glycoprotein D (gD). We found that JZ-1 treatment inhibited the upregulation of the PI3K/Akt/mTOR pathway proteins and promoted autophagy to combat HSV-2 infection, while PI3K inhibitor pretreatment prevented the enhanced autophagy induced by JZ-1. Moreover, JZ-1 attenuated the increase in inflammatory cytokines that had been induced HSV-2 infection. CONCLUSION: Our results showed that JZ-1 protects against HSV-2 infection, and this beneficial effect may be mediated by inducing autophagy via inhibition of the PI3K/Akt/mTOR signaling axis.
Assuntos
Autofagia/fisiologia , Medicamentos de Ervas Chinesas/farmacologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/fisiologia , Fosfatidilinositol 3-Quinases/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , Serina-Treonina Quinases TOR/biossíntese , Antivirais/farmacologia , Células Cultivadas , Células Epiteliais/metabolismo , Feminino , Herpes Genital/metabolismo , Herpes Genital/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
INTRODUCTION: Approximately two-thirds of HIV-infected individuals reside in sub-Saharan Africa. The region accounts for 68% of the new HIV infections occurring worldwide with almost one-half of these infections being among young adults aged 12-24 years. Cowan and colleagues conducted a community-based, multi-component HIV intervention aimed at youth in rural Zimbabwe. Despite some changes in knowledge and attitudes, the community-based intervention did not affect the prevalence of HIV or HSV-2. We selected this frequently cited study for replication since it incorporates individual-, community-, and structural- level intervention components that are often considered in global HIV/AIDS prevention programs. Additionally, the intervention could be easily scaled-up, which is especially important in the context of limited resources. Although this study indicated no intervention effects in reducing HIV, the authors acknowledged some key methodological challenges. Our replication analysis provided important insights regarding the impact of these challenges to the interpretation of the results of this study. METHODS: Our replication study focused on replicating Cowan's findings and assessing the robustness of Cowan's results to alternative analytical models based on their study design. We determined how out-migration occurring during Cowan's study may have affected the population characteristics, the intervention exposure level, and the study findings. While the original intervention targeted knowledge and attitudes as a mechanism to decrease HIV/HSV-2, the Cowan study evaluated the intervention effects on knowledge, attitudes, and prevalence of HIV or HSV-2 separately. To better identify the pathway describing the interrelationship among the intervention and knowledge, attitudes, and prevalence of HIV or HSV-2, we assessed whether increases in knowledge or attitudes were associated with decreased HIV or HSV-2 prevalence. RESULTS: We replicated the original findings with minor discrepancies during the pure replication. Our additional analyses revealed that the study population characteristics changed over time in ways that may have affected outcomes. These changes also affected the levels of intervention exposure, with 48.7% males and 75.5% females of the intervention group receiving low-level exposure. Both genders with higher level intervention exposure experienced higher increments in multiple knowledge, attitude, and sexual risk behavior outcomes. Unfortunately, these did not translate to a significant reduction in HIV or HSV-2 regardless of the level and combination of knowledge and attitude domains. However, males receiving high-level intervention exposure compared to control indicated significantly lower odds of having HIV or HSV-2 under a Bayesian modeling paradigm. CONCLUSIONS: Our findings suggest a more robust conclusion on the study intervention effects. Further study based on a design that more consistently maximizes the exposure level of the intervention is necessary and should ideally be an evaluated goal in similar studies. Evaluation of the intervention impact for key subgroups of the target population is important and would better advise the use and scale-up of the evaluated interventions in various contexts. Our observation of a consistent lack of relationship between knowledge/attitudes and HIV/HSV-2 suggests a need to explore and include relevant additional and or complementary interventions, e.g., promoting effective skills in reducing risky sexual behaviors and addressing cultural and structural bottlenecks that may reduce HIV/HSV-2 risk among youth.
Assuntos
Serviços de Saúde Comunitária/métodos , Infecções por HIV/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Promoção da Saúde , Herpes Genital/prevenção & controle , Educação de Pacientes como Assunto , Adolescente , Adulto , Teorema de Bayes , Feminino , HIV/isolamento & purificação , Infecções por HIV/transmissão , Infecções por HIV/virologia , Herpes Genital/transmissão , Herpes Genital/virologia , Herpesvirus Humano 2/isolamento & purificação , Humanos , Masculino , Comportamento de Redução do Risco , Adulto Jovem , ZimbábueRESUMO
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.
Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Aciclovir/análogos & derivados , Aciclovir/farmacologia , Antivirais/uso terapêutico , Berberina/farmacologia , Linhagem Celular , Medicamentos de Ervas Chinesas/uso terapêutico , Células Epiteliais , Feminino , Guanina , Herpes Genital/virologia , Humanos , Vagina/citologia , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacosRESUMO
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.
Assuntos
Síndrome da Imunodeficiência Adquirida/prevenção & controle , Antivirais/uso terapêutico , Carragenina/uso terapêutico , Herpes Genital/prevenção & controle , Infecções por Papillomavirus/prevenção & controle , Lectinas de Plantas/uso terapêutico , Administração Intravaginal , Animais , Antivirais/química , Carragenina/química , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Feminino , Liofilização , Herpes Genital/virologia , Herpesvirus Humano 2/patogenicidade , Humanos , Macaca mulatta , Masculino , Infecções por Papillomavirus/virologia , Lectinas de Plantas/química , Lectinas de Plantas/genética , Lectinas de Plantas/isolamento & purificação , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Profilaxia Pré-Exposição/métodos , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/patogenicidade , Nicotiana/genética , Nicotiana/metabolismo , Resultado do Tratamento , Vagina/virologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Equisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. AIM OF THE STUDY: To assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. MATERIALS AND METHODS: Equisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. RESULTS: Equisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. CONCLUSIONS: These studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Müll. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides.
Assuntos
Antivirais/farmacologia , Equisetum/química , Fabaceae/química , Extratos Vegetais/farmacologia , Animais , Antivirais/isolamento & purificação , Chlorocebus aethiops , Modelos Animais de Doenças , Feminino , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células Vero , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
UNLABELLED: Subunit vaccines based on the herpes simplex virus 2 (HSV-2) glycoprotein D (gD-2) have been the major focus of HSV-2 vaccine development for the past 2 decades. Based on the promising data generated in the guinea pig model, a formulation containing truncated gD-2, aluminum salt, and MPL (gD/AS04) advanced to clinical trials. The results of these trials, however, were unexpected, as the vaccine protected against HSV-1 infection but not against HSV-2. To address this discrepancy, we developed a Depot medroxyprogesterone acetate (DMPA)-treated cotton rat Sigmodon hispidus model of HSV-2 and HSV-1 genital infection. The severity of HSV-1 genital herpes was less than that of HSV-2 genital herpes in cotton rats, and yet the model allowed for comparative evaluation of gD/AS04 immunogenicity and efficacy. Cotton rats were intramuscularly vaccinated using a prime boost strategy with gD/AS04 (Simplirix vaccine) or control vaccine formulation (hepatitis B vaccine FENDrix) and subsequently challenged intravaginally with HSV-2 or HSV-1. The gD/AS04 vaccine was immunogenic in cotton rats and induced serum IgG directed against gD-2 and serum HSV-2 neutralizing antibodies but failed to efficiently protect against HSV-2 disease or to decrease the HSV-2 viral load. However, gD/AS04 significantly reduced vaginal titers of HSV-1 and better protected animals against HSV-1 compared to HSV-2 genital disease. The latter finding is generally consistent with the clinical outcome of the Herpevac trial of Simplirix. Passive transfer of serum from gD/AS04-immunized cotton rats conferred stronger protection against HSV-1 genital disease. These findings suggest the need for alternative vaccine strategies and the identification of new correlates of protection. IMPORTANCE: In spite of the high health burden of genital herpes, there is still no effective intervention against the disease. The significant gap in knowledge on genital herpes pathogenesis has been further highlighted by the recent failure of GSK HSV-2 vaccine Simplirix (gD/AS04) to protect humans against HSV-2 and the surprising finding that the vaccine protected against HSV-1 genital herpes instead. In this study, we report that gD/AS04 has higher efficacy against HSV-1 compared to HSV-2 genital herpes in the novel DMPA-synchronized cotton rat model of HSV-1 and HSV-2 infection. The findings help explain the results of the Simplirix trial.
Assuntos
Modelos Animais de Doenças , Herpes Genital/prevenção & controle , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Sigmodontinae , Proteínas do Envelope Viral/farmacologia , Vacinas Virais/farmacologia , Hidróxido de Alumínio , Compostos de Anilina , Animais , Avaliação Pré-Clínica de Medicamentos , Ensaio de Imunoadsorção Enzimática , Feminino , Injeções Intramusculares , Lipídeo A/análogos & derivados , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/farmacologia , Proteínas do Envelope Viral/administração & dosagem , Vacinas Virais/administração & dosagemRESUMO
Sexually transmitted infections like HIV, HPV, and HSV-2, as well as unplanned pregnancy, take a huge toll on women worldwide. Woman-initiated multipurpose prevention technologies that contain antiviral/antibacterial drugs (microbicides) and a contraceptive to simultaneously target sexually transmitted infections and unplanned pregnancy are being developed to reduce these burdens. This review will consider products that are applied topically to the vagina. Rectally administered topical microbicides in development for receptive anal intercourse are outside the scope of this review. Microbicide and microbicide/contraceptive candidates must be rigorously evaluated in preclinical models of safety and efficacy to ensure that only candidates with favorable risk benefit ratios are advanced into human clinical trials. This review describes the comprehensive set of in vitro, ex vivo, and in vivo models used to evaluate the preclinical safety and antiviral efficacy of microbicide and microbicide/contraceptive candidates.
Assuntos
Antivirais/uso terapêutico , Anticoncepcionais Femininos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Modelos Biológicos , Gravidez não Planejada , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Administração Intravaginal , Animais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Femininos/farmacocinética , Avaliação Pré-Clínica de Medicamentos/normas , Feminino , Infecções por HIV/prevenção & controle , Haplorrinos , Herpes Genital/prevenção & controle , Humanos , Camundongos , Infecções por Papillomavirus/prevenção & controle , Gravidez , Vagina/fisiologia , Absorção Vaginal , Cremes, Espumas e Géis Vaginais/farmacocinética , Cremes, Espumas e Géis Vaginais/uso terapêuticoRESUMO
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Assuntos
Anti-Infecciosos Locais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Doenças Bacterianas Sexualmente Transmissíveis/prevenção & controle , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Administração Intravaginal , Administração Retal , Animais , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/classificação , Anti-Infecciosos Locais/isolamento & purificação , Anti-Infecciosos Locais/toxicidade , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Aprovação de Drogas , Inibidores Enzimáticos/farmacologia , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Herpes Genital/prevenção & controle , Herpes Genital/transmissão , Humanos , Masculino , Estudos Multicêntricos como Assunto , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/transmissão , Tensoativos/farmacologia , Tecnologia Farmacêutica/métodos , Proteínas Virais/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacosRESUMO
Herpes simplex virus-2 (HSV-2) infection increases HIV susceptibility. We previously established a rhesus macaque model of vaginal HSV-2 preexposure followed by cochallenge with HSV-2 and simian/human immunodeficiency virus-reverse transcriptase (SHIV-RT). Using this model, we showed that a gel containing the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 in carrageenan (CG) reduced SHIV-RT infection. To evaluate the efficacy of new generation microbicides against both viruses, we first established dual infection after single vaginal cochallenge with SHIV-RT and HSV-2 in HSV-2-naive macaques. All animals (6/6) became HSV-2 infected, with 4/6 coinfected with SHIV-RT. In a control group cochallenged with SHIV-RT and UV-inactivated HSV-2, 2/4 became SHIV-RT infected, and none had detectable HSV-2. Low-level HSV-2-specific antibody and T cell responses were detected in some HSV-2-infected animals. To test a CG gel containing MIV-150 and zinc acetate (MZC), which provided naive animals full protection from SHIV-RT for at least 8 h, MZC (vs. CG) was applied daily for 14 days followed by cochallenge 8 h later. MZC prevented SHIV-RT infection (0/9 infected, p=0.04 vs. 3/6 in CG controls), but only reduced HSV-2 infection by 20% (6/9 infected vs. 5/6 in CG, p=0.6). In HSV-2-infected animals, none of the gel-treated animals seroconverted, and only the CG controls had measurable HSV-2-specific T cell responses. This study shows the promise of MZC to prevent immunodeficiency virus infection (even in the presence of HSV-2) and reduce HSV-2 infection after exposure to a high-dose inoculum. Additionally, it demonstrates the potential of a macaque coinfection model to evaluate broad-spectrum microbicides.
Assuntos
Anti-Infecciosos/administração & dosagem , Quimioprevenção/métodos , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Cremes, Espumas e Géis Vaginais/administração & dosagem , Animais , Feminino , Transcriptase Reversa do HIV , Macaca mulattaRESUMO
Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause genital herpes, which can enhance the acquisition of human immunodeficiency virus. The development of anti-HSV agents with novel mechanisms of action is urgently required in the topical therapy of genital herpes. In this study, the in vitro and in vivo anti-HSV effects of Epomin SP-012(®), a highly cationic polyethylenimine, were evaluated. When the in vitro antiviral effects of SP-012 were assessed, this compound showed potent activity against HSV-1 and HSV-2. It inhibited the attachment of HSV-2 to host cells and cell-to-cell spread of infection in a concentration-dependent manner and exerted a virucidal effect. No SP-012-resistant HSV-2 was found when the virus was successively passaged in the presence of SP-012. In a mouse genital herpes model, topically administered SP-012 inhibited the progression of the disease caused by HSV infection. These data illustrate that SP-012 may be a novel class of HSV inhibitor that would be acceptable for long-term topical application.
Assuntos
Anti-Infecciosos Locais/uso terapêutico , Herpes Genital/prevenção & controle , Polietilenoimina/uso terapêutico , Administração Tópica , Animais , Anti-Infecciosos Locais/farmacologia , Modelos Animais de Doenças , Feminino , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 2/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Polietilenoimina/farmacologia , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacosRESUMO
Microbicides are a new tool, still under investigation, which could help prevent infection by the human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs). Increasing evidence shows that the complexity of sexual transmission of viral pathogens requires the identification of compounds able to block the early events during the cycle of viral infection. In this manuscript we provide a comprehensive review of the different microbicide strategies that have been studied or are currently being considered for STI prevention, particularly emphasizing those having the potential to block HIV infection. The manuscript also reviews the complex process that is required to conduct future clinical studies in humans and concludes with a brief discussion of the strategies that could be part of the immediate future in microbicide research.
Assuntos
Anti-Infecciosos Locais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Doenças Bacterianas Sexualmente Transmissíveis/prevenção & controle , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Administração Intravaginal , Administração Retal , Animais , Anti-Infecciosos Locais/química , Anti-Infecciosos Locais/classificação , Anti-Infecciosos Locais/isolamento & purificação , Anti-Infecciosos Locais/toxicidade , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Aprovação de Drogas , Inibidores Enzimáticos/farmacologia , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Herpes Genital/prevenção & controle , Herpes Genital/transmissão , Humanos , Masculino , Estudos Multicêntricos como Assunto , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/transmissão , Tensoativos/farmacologia , Tecnologia Farmacêutica/métodos , Proteínas Virais/antagonistas & inibidores , Internalização do Vírus/efeitos dos fármacosRESUMO
We have evaluated the potential of four synthetic peptides (denoted HH-2, 1002, 1006, 1018) with a distant relationship to the host defense peptide bovine bactenecin dodecapeptide for their ability to prevent genital infections with herpes simplex virus type 2 (HSV-2) in mice. All four peptides showed antiviral properties in vitro and reduced HSV-2 infection of Vero cells in a dose-dependent manner. Detailed analysis showed that the peptides were able to interfere with both viral attachment and entry, but not with replication post-entry, and were effective antivirals also when HSV-2 was introduced in human semen. Two of the peptides proved especially effective in reducing HSV-2 infection also in vivo. When admixed with virus prior to inoculation, both HH-2 and 1018 reduced viral replication and disease development in a genital model of HSV-2 infection in mice, and also when using very high infectious doses of HSV-2. These data show that peptides HH-2 and 1018 have antiviral properties and can be used to prevent genital herpes infection in mice.
Assuntos
Antivirais/uso terapêutico , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Peptídeos Cíclicos/uso terapêutico , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/farmacologia , Quimioprevenção/métodos , Chlorocebus aethiops , Modelos Animais de Doenças , Herpesvirus Humano 2/fisiologia , Camundongos , Testes de Sensibilidade Microbiana , Peptídeos Cíclicos/farmacologia , Resultado do Tratamento , Células VeroAssuntos
Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Doenças Assintomáticas , Herpes Genital/tratamento farmacológico , Herpes Genital/transmissão , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez/tratamento farmacológico , Valina/análogos & derivados , Algoritmos , Antivirais/efeitos adversos , Cesárea , Procedimentos Clínicos , Feminino , Herpes Genital/diagnóstico , Herpes Genital/prevenção & controle , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Infusões Intravenosas , Funções Verossimilhança , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/prevenção & controle , Risco , Valaciclovir , Valina/uso terapêutico , Ativação Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
Arginine, among the amino acids, has demonstrated unique properties, including suppression of protein-protein interactions and virus inactivation. We investigated the effects of arginine on the infectivity of human herpesvirus 2 (HHV-2) and the potential application of arginine as a chemotherapeutic agent against genital herpes. Arginine directly inactivated HHV-2 and characterization of the inactivation demonstrated that 1 M arginine at pH 4.3 inactivated the virus more efficiently compared to 0.1 M citrate or 1 M sodium chloride, indicating that neither acidic pH nor ionic strength alone is sufficient for virus inactivation. The effect of arginine was rapid and concentration-dependent. Although virus inactivation was efficient at an acidic pH, arginine inactivated the virus even at a neutral pH, provided that a higher arginine concentration and prolonged incubation time were used. In addition, arginine suppressed the multiplication of HHV-2 under the conditions at which its effect on cell viability was insignificant. Pilot mouse model studies revealed a marked suppression of death by arginine when the mice were infected with HHV-2 through the vaginal route, followed by an intermittent application of acidic arginine by vaginal instillation.
Assuntos
Antivirais/administração & dosagem , Arginina/administração & dosagem , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Vaginite/prevenção & controle , Administração Intravaginal , Animais , Antivirais/farmacologia , Arginina/farmacologia , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Feminino , Herpes Genital/tratamento farmacológico , Herpes Genital/virologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Vaginite/tratamento farmacológico , Vaginite/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10(6)-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.
Assuntos
Carragenina/administração & dosagem , Infecções por HIV/prevenção & controle , HIV/efeitos dos fármacos , Herpes Genital/prevenção & controle , Herpesvirus Humano 2/efeitos dos fármacos , Acetato de Zinco/administração & dosagem , Animais , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/uso terapêutico , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Carragenina/uso terapêutico , Estabilidade de Medicamentos , Feminino , Géis , HIV/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Herpes Genital/tratamento farmacológico , Herpes Genital/mortalidade , Herpes Genital/virologia , Herpesvirus Humano 2/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Mucosa/efeitos dos fármacos , Mucosa/virologia , Reto/efeitos dos fármacos , Reto/virologia , Reologia , Taxa de Sobrevida , Vagina/efeitos dos fármacos , Vagina/virologia , Acetato de Zinco/uso terapêuticoRESUMO
This study investigated the anti-HSV-2 effect of alumen through in vitro and in vivo experiments. Viable cell counting was employed to assess the toxicity of alumen on Vero cells. The inhibition rate of HSV-2 was defined as the cytopathic effect (CPE) of the cells infected with the virus. Alumen suppositories of different concentrations were vaginally applied to the guinea pigs which were then infected with HSV-2 via a vaginal route. The clinical symptoms were observed and the local virus titer calculated. The results showed that alumen had an in vitro anti-HSV-2 effect by means of antiviral duplication, direct killing of the virus, and antiviral adsorption. Alumen suppositories of different concentrations could reduce or completely inhibit HSV-2 infection in guinea pigs. It was concluded that alumen had an in vitro anti-HSV-2 effect through multiple approaches and it could suppress in vivo vaginal HSV-2 infection of guinea pig to some extent.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 2/efeitos dos fármacos , Materia Medica/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Chlorocebus aethiops , Efeito Citopatogênico Viral/efeitos dos fármacos , Feminino , Cobaias , Herpes Genital/prevenção & controle , Herpes Genital/virologia , Herpesvirus Humano 2/fisiologia , Medicina Tradicional Chinesa , Supositórios , Células VeroRESUMO
Genital herpes is a chronic infection characterized by periodic reactivation. It can produce symptomatic disease in the host although asymptomatic viral excretion can also occur. It is currently the main cause of genital ulceration and an important public health problem that has substantial clinical, psychological, and economic repercussions. This review analyzes the currently available therapeutic options and regimens, which are based mainly on systemic use of antiviral agents such as aciclovir, valacyclovir, and famciclovir. In addition, special emphasis is placed on the prevention and management of this infection in specific situations, such as pregnant, pediatric, and immunocompromised patients.
Assuntos
Antivirais/uso terapêutico , Herpes Genital/tratamento farmacológico , Adolescente , Animais , Antivirais/farmacocinética , Criança , Maus-Tratos Infantis , Pré-Escolar , Avaliação Pré-Clínica de Medicamentos , Feminino , Herpes Genital/complicações , Herpes Genital/prevenção & controle , Herpes Genital/transmissão , Herpes Genital/virologia , Herpesvirus Humano 1/isolamento & purificação , Herpesvirus Humano 2/isolamento & purificação , Humanos , Hospedeiro Imunocomprometido , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Masculino , Camundongos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Recidiva , Úlcera Cutânea/etiologiaRESUMO
El herpes genital es una infección crónica que se caracteriza por una reactivación periódica, con capacidad tanto de producir una enfermedad sintomática en el huésped como de excreción viral asintomática. Hoy en día constituye la primera causa de ulceración genital y representa un importante problema de salud pública, con considerables repercusiones clínicas, psicológicas y económicas. Se revisan y actualizan las distintas opciones y pautas terapéuticas disponibles en la actualidad, basadas fundamentalmente en el empleo por vía sistémica de los fármacos antivirales aciclovir, valaciclovir y famciclovir. Por otro lado, se pone especial énfasis en la prevención y el manejo de esta infección en situaciones particulares, como en embarazadas, en niños, o en pacientes inmunodeprimidos (AU)
Genital herpes is a chronic infection characterized by periodic reactivation. It can produce symptomatic disease in the host although asymptomatic viral excretion can also occur. It is currently the main cause of genital ulceration and an important public health problem that has substantial clinical, psychological, and economic repercussions. This review analyzes the currently available therapeutic options and regimens, which are based mainly on systemic use of antiviral agents such as aciclovir, valacyclovir, and famciclovir. In addition, special emphasis is placed on the prevention and management of this infection in specific situations, such as pregnant, pediatric, and immunocompromised patients (AU)
Assuntos
Humanos , Animais , Masculino , Feminino , Gravidez , Recém-Nascido , Pré-Escolar , Criança , Adolescente , Camundongos , Antivirais/farmacocinética , Antivirais/uso terapêutico , Herpes Genital/complicações , Herpes Genital/tratamento farmacológico , Herpes Genital/prevenção & controle , Herpes Genital/transmissão , Herpes Genital/virologia , Herpesvirus Humano 2/isolamento & purificação , Maus-Tratos Infantis , Avaliação Pré-Clínica de Medicamentos , Hospedeiro Imunocomprometido , Transmissão de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Recidiva , Úlcera Cutânea/etiologiaAssuntos
Herpes Genital/prevenção & controle , Herpes Genital/transmissão , Controle de Infecções/normas , Medicina Preventiva/normas , Antivirais/uso terapêutico , Conhecimentos, Atitudes e Prática em Saúde , Herpes Genital/epidemiologia , Herpes Genital/virologia , Humanos , Controle de Infecções/métodos , Controle de Infecções/tendências , Programas Nacionais de Saúde/tendências , Medicina Preventiva/tendências , Estados Unidos/epidemiologiaRESUMO
Herpes simplex virus (HSV) Type-1 and -2 are common infections that can cause primary and recurrent herpes labialis and genitalis, as well as gingivostomatitis, keratoconjunctivitis, encephalitis, disseminated infections in immunocompromised persons and neonatal infections. Despite several decades of HSV vaccine development, no effective vaccine has been developed until recently. The following review of the genital HSV-2 glycoprotein D (gD2t, t is for truncated) subunit vaccine formulated with a new adjuvant (AS04) containing alum and 3-O deacylated monophosphoryl lipid A (MPL) provides a background in which to evaluate the vaccine as well as a brief review of other approaches to herpes vaccines. The gD2t-AS04 vaccine has been demonstrated to be safe in several large clinical trials. In two trials, the vaccine reduced genital herpes disease by 73 and 74%, but only in females with no previous HSV infection. A large ongoing trial in HSV seronegative females will provide additional data on protection from HSV disease and infection.