EPIDEMIOLOGY & MECHANISMS OF ANTIVIRAL RESISTANCE IN HSV

流行病学

• 批准号: 2071172
• 负责人: SHARON SAFRIN
• 金额: $ 9.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2071172
• 关键词: Alphaherpesvirinae; DNA directed DNA polymerase; HIV infections; acyclovir; antiviral agents; autoradiography; drug resistance; epidemiology; foscarnet; gene mutation; human immunodeficiency virus; human subject; microorganism population study; nucleic acid hybridization; nucleic acid sequence; tissue /cell culture; virus classification

An investigation of the prevalence, diagnosis, and mechanisms of resistance to antiviral agents in herpes simplex virus (HSV) will be undertaken. Advanced stages of immunosuppression, high titers of replicating virions within chronic mucocutaneous lesions, and widespread use of acyclovir will continue to predispose to the development of acyclovir resistance in HIV-infected hosts. In addition, our preliminary data suggests that the emergence of resistance to foscarnet may become an increasingly clinically significant problem. Therefore, further information regarding the epidemiology, clinical virologic manifestations, and genotypic characterization of resistant HSV mutants will be critical in the devising of effective preventive and therapeutic maneuvers. A survey of 300 consecutive clinical isolates of HSV from HIV-infected patients at San Francisco General Hospital will be conducted to determine the prevalence of in vitro resistance to acyclovir. The presence of viral heterogeneity in recovered isolates will be assessed using plaque autoradiography, and correlative clinical information will assist in the elucidation of the interface between in vivo manifestations of antiviral resistance and in vitro testing results. Further characterization of a sample of 29 patient isolates utilized in the comparative assessment of the three primary methods of antiviral susceptibility testing currently in use will be performed in order to clarify differences in results, and a new method utilizing a non-radioisotopic DNA hybridization methodology will be critically assessed, modified and standardized for general usage. Sequencing of the DNA polymerase gene of foscarnet-resistant HSV mutants from 5 HIV-infected patients, unusual in their susceptibility to acyclovir, will be undertaken using paired prefoscarnet therapy isolates for comparison. Identification of the locus of DNA polymerase mutation will increase our understanding of the nucleotide binding site of the enzyme, and facilitate the future development of rapid diagnostic tests for antiviral resistance.

研究的患病率，诊断和机制 单纯疱疹病毒（HSV）中对抗病毒药的抗性将是 进行。免疫抑制的高级阶段，高滴度 复制慢性粘膜状病变中的病毒粒子，并普遍存在 Acyclovir的使用将继续易于发展 艾滋病毒感染宿主中的acyclovir抗性。此外，我们的初步 数据表明，对Foscarnet的抵抗力可能成为一种 临床上越来越重要的问题。因此，进一步 有关流行病学，临床病毒学表现的信息， 抗性HSV突变体的基因型表征将是关键的 在设计有效的预防和治疗性操作中。 对HIV感染的HSV连续300个临床分离株的调查 将在旧金山综合医院进行确定的患者 体外耐药性对阿昔洛韦的患病率。病毒的存在 将使用斑块评估回收分离株的异质性 放射自显影和相关临床信息将有助于 在体内体内表现抗病毒之间阐明界面 抗性和体外测试结果。进一步的表征 在比较评估中使用的29名患者分离株的样本 目前正在 将进行使用以澄清结果的差异，并且 利用非放射性异位DNA杂交方法的新方法 将对一般使用进行严格评估，修改和标准化。 抗foscarnet HSV突变体的DNA聚合酶基因的测序 来自5名HIV感染患者，对他们的敏感性不寻常 Acyclovir将使用成对的前尺寸治疗分离株进行 进行比较。 DNA聚合酶突变轨迹的鉴定 将增加我们对核苷酸结合位点的理解 酶，并促进快速诊断测试的未来开发 用于抗病毒抗性。