Improved Treatment for Zoonotic BV Infections

摘要 猴B病毒是一种常见于恒河猴(恒河猴、食蟹猴)的疱疹病毒 猴子是生物医学研究的宝贵资源。当BV被传输到 人类，大约80%的患者死亡，幸存者经常经历进行性神经系统疾病 下降，使BV成为研究和兽医面临的最大人畜共患病危险 与猕猴打交道的人员。目前用于治疗BV感染的药物被开发出来 用于治疗单纯疱疹病毒(HSV)感染，对BV的效果都较差 而不是单纯疱疹病毒。即使在使用更昔洛韦(GCV)这一最有效的药物治疗时，一些BV患者 还是会死的。对小鼠的研究还表明，目前推荐的治疗方案可能是 有缺陷的，允许未被检测到的BV感染侵入中枢神经系统，导致 大大降低了患者存活的机会。由于专门针对BV的新药 由于缺乏财政激励，不太可能开发出使用现有抗病毒药物的疗法 需要优化。在拟议的研究中，药物被证明对单纯疱疹病毒和 一些实验药物将在体内测试对BV的疗效 使用鼠标模型进行管理。初步实验表明，所用药物 局部用药可以提供与全身用药一样有效的预防BV 毒品。此外，西多福韦(CDV)对BV的治疗似乎比GCV(大多数 目前推荐用于治疗BV感染的有效药物)和一种实验性药物 与GCV或CDV不同的作用模式也对BV有效，提高了 在双重用药方案中使用它以增加治疗效果的可能性。这些结果需要 后续进行更多研究，以验证使用局部给药作为一种手段 预防神经BV感染，使用CDV治疗BV感染，以及潜在的 二联用药方案的疗效分析。该项目将产生所需的验证性数据和测试 双重用药方案的疗效。研究结果将作为合理的科学依据 可能修改现有的人畜共患BV感染的治疗建议。

ABSTRACT Monkey B virus (BV) is a herpesvirus common in macaque (rhesus, cynomolgus) monkeys which are an invaluable resource for biomedical research. When BV is transmitted to humans, ~80% of patients die and survivors frequently experience progressive neurological decline, making BV the single greatest zoonotic danger facing research and veterinary personnel who work with macaques. Drugs currently used to treat BV infections were developed for treatment of herpes simplex virus (HSV) infections, and are all are less effective against BV than HSV. Even when treated with ganciclovir (GCV), the most effective drug, some BV patients still die. Studies in mice also suggest that the current recommended treatment protocol may be flawed, allowing undetected BV infections to invade the central nervous system, resulting in a drastically diminished chance of patient survival. Since new drugs specifically targeted at BV are unlikely to be developed due to a lack of financial incentive, therapy using existing antivirals needs to be optimized. In the proposed study drugs shown to be effective against HSV and some experimental drugs will be tested for in vivo efficacy against BV by systemic administration using a mouse model. Preliminary experiments indicate that drugs applied topically can provide protection against BV that is as effective as systemically administered drugs. In addition, cidofovir (CDV) appears to be more effective against BV than GCV (the most effective drug currently recommended for treatment of BV infections) and an experimental drug having a different mode of action than GCV or CDV is also effective against BV, raising the possibility of its use in a dual drug regimen for added treatment efficacy. These results need to be followed up with additional research to validate use of topical drug delivery as a means of preventing neurological BV infections, use of CDV to treat BV infections, and the potential efficacy of dual drug regimens. This project will produce the needed confirmatory data and test the efficacy of dual drug regimens. The results will serve as a rational scientific basis for possible modification of existing recommendations for treatment of zoonotic BV infections.