Topical virucides to prevent oral transmission

描述（由申请人提供）： 迫切需要找到简单和负担得起的干预战略，以减少发展中国家通过母乳喂养传播艾滋病毒。在找到有效的疫苗之前，在整个母乳喂养期间进行化学预防可能是最有效的策略。然而，如果我们的目标是维持全身抗病毒药物水平，与长期给药相关的价格和毒性风险是严重的限制。我们推测，局部（口服）给药非常低剂量的抗病毒药物替诺福韦，这是迅速采取的细胞，可能会导致粘膜细胞内的药物水平，足以赋予保护最初的靶细胞免受病毒感染。为了验证这一假设，我们建议使用猴免疫缺陷病毒（SIV）-婴儿猕猴模型的儿童艾滋病毒感染。我们最近证明，婴儿猕猴可以通过反复喂养少量SIV感染;因此，这种动物模型模拟了母乳喂养期间多次低剂量暴露于病毒。在拟议的研究中，一组1个月大的婴儿猕猴将每天口服三次低剂量的SIV。一组将接受局部替诺福韦前药溶液，而其他组将接受全身替诺福韦或将安慰剂治疗。将密切监测动物的病毒或抗病毒免疫应答检测。如果局部替诺福韦给药有效，那么这种简单的策略对发展中国家来说是非常负担得起的。

DESCRIPTION (provided by applicant): There is an urgent need to find simple and affordable intervention strategies to reduce HIV transmission through breast-feeding in developing countries. Until an effective vaccine is found, chemoprophylaxis throughout the period of breast-feeding may be the most effective strategy. However, if we aim to maintain systemic antiviral drug levels, the price associated with prolonged administration and the risk of toxicity are severe limitations. We hypothesize that topical (oral) administration of very low doses of the antiviral drug tenofovir, which is rapidly taken up by cells, may result in mucosal intracellular drug levels that are sufficient to confer protection of the initial target cells against viral infection. To test this hypothesis, we propose to use the simian immunodeficiency virus (SIV)-infant macaque model of pediatric HIV infection. We recently demonstrated that infant macaques can be infected by repeatedly feeding them small amounts of SIV; accordingly, this animal model mimics the multiple low-dose exposure to virus that occurs during breast-feeding. In the proposed study, groups of 1 -month-old infant macaques will be exposed orally three times per day to low doses of SIV. One group will receive topical tenofovir prodrug solution, while the other groups will receive systemic tenofovir or will be placebo-treated. Animals will be monitored closely for the detection of virus or antiviral immune responses. If topical tenofovir administration were effective, then this simple strategy would be highly affordable for developing countries.