Inhibition of Herpes Simplex Virus Type 2 by Tenofovir

替诺福韦对 2 型单纯疱疹病毒的抑制作用

基本信息

批准号：
8223679
负责人：
Nicholas J Van Wagoner
金额：
$ 13.36万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-18 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223679
关键词：
Acquired Immunodeficiency Syndrome Acyclovir Anti-Retroviral Agents Antibodies Antiviral Agents Archives Basic Science Biological Assay Cells Chronic Cidofovir Clinical Clinical Research Clinical Services Cohort Analysis Data Diagnosis Disease Disease Progression Drug resistance Excipients Exhibits Famciclovir Foscarnet Frequencies Funding Future General Population Genome Grant HIV HIV therapy HIV-1 Human Human Herpesvirus 2 Immunocompromised Host In Vitro Incidence Infection K-Series Research Career Programs Life Light Measures Methodology Morbidity - disease rate Natural History New Agents Participant Patient Care Patients Penetration Persons Pharmaceutical Preparations Phase Population Prevention Randomized Controlled Trials Recurrence Regimen Research Research Design Role Sampling Scientist Serologic tests Seroprevalences Serum Severities Simplexvirus Techniques Tenofovir Tenofovir disoproxil fumarate Testing Therapeutic Agents Time Training Ulcer Viral Viral Drug Resistance Virus Diseases Virus Shedding antiretroviral therapy base clinically relevant clinically significant design improved in vitro activity in vivo meetings microbicide nucleoside analog prevent public health relevance skills therapy resistant transmission process vaginal microbicide valacyclovir viral detection viral resistance virology

项目摘要

DESCRIPTION (provided by applicant): Herpes Simplex Virus Type 2 (HSV-2) is a common infection that causes a spectrum of clinical disease from mild mucocutaneous, anogenital ulcers to life-threatening conditions. Prevention of HSV-2 infection is difficult and current therapy for HSV-2 is not completely effective. Immunocompromised persons such as those with HIV are particularly vulnerable to HSV-2, manifesting more severe disease and developing higher rates of resistance to therapy. For these reasons, new, more effective therapeutic agents are needed to prevent and treat HSV-2 infection and disease, respectively, especially in persons with HIV. Recent clinical and in vitro data suggest that agents, developed for the treatment of HIV, may also have activity against HSV-2. Most compelling are data suggesting that a Tenofovir Disoproxil Fumarate (TDF)-based, vaginal microbicide reduces HSV-2 acquisition. As an extension of this finding and based on our preliminary research, I hypothesize that TDF will have direct activity against HSV-2 in vitro and that orally delivered TDF, as a component of HIV therapy, will have activity against HSV-2 in vivo. To test this hypothesis, I propose the following independent but inter-related aims. Aim 1: Investigate the potential inhibitory role of TDF on HSV-2 replication in vitro. Aim 2: Determine the potential suppressive effect of systemically delivered TDF on HSV-2 infection and its suppressive effect on subclinical HSV-2 viral shedding in vivo. Using bidirectional and translational techniques as outlined in this proposal, I will establish a fundamental understanding of TDF's action on HSV-2 while providing information about clinical relevance. Of equal importance, this career development award and the research aims as outlined above are designed to provide me with additional training in virology, clinical study design, methodology, and statistical analysis to meet my specific educational needs. The opportunities created by this career development award will culminate in the creation of a translational scientist with the skills necessary to adeptly, ethically, and accurately answer important scientific questions related to HSV-2 prevention and treatment. It will also help me to successfully obtain future independent funding, and most importantly, improve patient care. Public Health Relevance: Infection with Herpes Simplex Virus Type 2 in immunocompromised populations, such as patients with HIV, is of particular concern because it can cause severe disease and harbor resistance to drug treatment in this population. There is need to identify new agents that effectively prevent and treat HSV-2, especially in HIV infected populations. In this grant, I will investigate Tenofovir's (TDF) anti-HSV-2 activity in vivo and in vitro.

描述（由申请人提供）：2 型单纯疱疹病毒 (HSV-2) 是一种常见感染，可引起一系列临床疾病，从轻度皮肤粘膜、肛门生殖器溃疡到危及生命的病症。预防HSV-2感染很困难，并且目前针对HSV-2的治疗并不完全有效。免疫功能低下的人，例如艾滋病毒感染者，特别容易感染 HSV-2，表现出更严重的疾病，并对治疗产生更高的耐药率。由于这些原因，需要新的、更有效的治疗剂来分别预防和治疗 HSV-2 感染和疾病，尤其是 HIV 感染者。最近的临床和体外数据表明，为治疗 HIV 而开发的药物也可能具有抗 HSV-2 的活性。最引人注目的是数据表明，基于富马酸替诺福韦二吡呋酯 (TDF) 的阴道杀菌剂可减少 HSV-2 的感染。作为这一发现的延伸，并基于我们的初步研究，我假设 TDF 在体外具有直接对抗 HSV-2 的活性，并且口服 TDF 作为 HIV 治疗的一个组成部分，在体内具有对抗 HSV-2 的活性。为了检验这个假设，我提出了以下独立但相互关联的目标。目标 1：研究 TDF 在体外对 HSV-2 复制的潜在抑制作用。目标 2：确定全身递送的 TDF 对 HSV-2 感染的潜在抑制作用及其对体内亚临床 HSV-2 病毒脱落的抑制作用。使用本提案中概述的双向和转化技术，我将建立对 TDF 对 HSV-2 作用的基本了解，同时提供有关临床相关性的信息。同样重要的是，该职业发展奖和上述研究目标旨在为我提供病毒学、临床研究设计、方法论和统计分析方面的额外培训，以满足我的特定教育需求。该职业发展奖所创造的机会将最终培养出一位转化科学家，他们拥有熟练、合乎道德且准确地回答与 HSV-2 预防和治疗相关的重要科学问题所需的技能。它还将帮助我成功获得未来的独立资金，最重要的是，改善患者护理。公共卫生相关性：免疫功能低下人群（例如 HIV 感染者）感染 2 型单纯疱疹病毒尤其值得关注，因为它可能导致严重疾病，并对这一人群的药物治疗产生耐药性。需要找到有效预防和治疗 HSV-2 的新药物，特别是在 HIV 感染人群中。在这笔资助中，我将研究替诺福韦 (TDF) 的体内和体外抗 HSV-2 活性。