Virocide as an Anti-HIV Microbicide Candidate

描述（由申请方提供）：局部杀微生物剂定义为阴道应用的产品，可预防男性对女性或女性对男性的HIV传播。HIV逆转录酶（RT）的高错误率推动了HIV耐药性和基因组多样性的发展。目前泛耐药性的所有类别的HIV抑制剂，如那些发现在O组病毒的非核苷RT和蛋白酶（PR）抑制剂，提出了一个重要的问题，关于发展的杀微生物剂靶向RT或PR。这些问题可能会扩展到抑制剂的HIV进入由于快速出现的突变的包膜（Env）糖蛋白在选择压力下。因此，迫切需要鉴定新的抗HIV化合物，其靶向除PR、RT和Env之外的病毒组分，并且其可以被开发为安全有效的杀微生物剂。我们鉴定了一种称为杀病毒剂的短线性肽，其在nM范围内中和HIV。几条证据表明，即使每天两次以上级阻断HIV感染的浓度20-200倍的浓度施用于细胞，杀病毒剂也不会伤害每天两次静脉注射高肽浓度的小鼠（0.5mg）持续3天;和iv）杀病毒剂显然不会在人源化小鼠的阴道上皮中产生损伤，因为肽，而不是促进传播，完全阻断阴道内传播杀病毒剂代表了一种有吸引力的杀微生物剂候选物，原因如下：i）杀病毒剂抑制各种原代人细胞类型中的广泛的原代分离物的感染; ii）它干扰HIV传播中涉及的三种机制：生殖器上皮细胞迁移、树突细胞介导的传播和粘膜靶细胞的感染; iii）杀病毒剂非常有效，因为少于15分钟的暴露足以中和HIV; iv）在向细胞中加入HIV之前和之后两小时都是有效的，探讨Virocide的体外抗HIV效果及其体内毒性和免疫原性。如果这些研究明确表明，杀病毒剂代表一个有吸引力的抗艾滋病毒杀微生物剂的候选人，我们将能够测试其作为局部杀微生物剂在体内的功效。

DESCRIPTION (provided by applicant): Topical microbicides are defined as vaginally applied products that prevent male-to-female or female-to-male HIV transmission. The high error rate of the HIV reverse transcriptase (RT) drives the development of resistance and genomic diversity in HIV. The current pan-resistance to all classes of HIV inhibitors, such as those found in O group virus for non-nucleoside RT and protease (PR) inhibitors, raises an important question with regard to the development of microbicides targeting RT or PR. These concerns may be extended to inhibitors of HIV entry due to rapid emergence of mutations in the envelope (Env) glycoprotein under selective pressure. There is thus an urgent need to identify new anti-HIV compounds, which target viral components other than PR, RT and Env, and which may be developed as safe and effective microbicides. We identified a short linear peptide called Virocide, which neutralizes HIV at an nM range. Several lines of evidence s cells even when applied twice daily to cells at a concentration 20-200-fold superior to that which blocks HIV infection; iii) Virocide does not harm mice injected i.v. twice daily with high peptide concentrations (0.5 mg) for a period of 3 days; and iv) Virocide apparently does not create lesions in the vaginal epithelium of humanized mice since the peptide, rather than promoting transmission, completely blocks intravaginal transmission. Virocide represents an attractive microbicide candidate for several reasons: i) Virocide inhibits infection of a broad range of primary isolates in various primary human cell types; ii) it interferes with the three mechanisms involved in HIV transmission: genital epithelial transmigration, dendritic cell-mediated transmission, and infection of mucosal target cells; iii) Virocide is extremely efficacious since less than 15 min of exposure suffices to neutralize HIV; iv) it is potent for two hours both prior to and after addition of HIV to cells, suggze the anti-HIV efficacy of Virocide in vitro as well as its toxicity and immunogenicity in vivo. If these studies unambiguously demonstrate that Virocide represents an attractive anti-HIV microbicide candidate, we will be in a position to test its efficacy as a topical microbicide in vivo.