Microbicide Effects on Efficacy, Safety, Innate Immunity

异性性传播艾滋病毒是妇女的主要途径，目前妇女占感染者的50%。 在缺乏有效疫苗的情况下，需要其他预防方式。安全有效的外用 杀微生物剂将使妇女和男子在自我保护方面发挥更直接的作用。作为治疗 艾滋病毒的方法，一种结合了不同作用模式的化合物的局部杀微生物剂， 在阻断传播时在粘膜中发生的复杂相互作用方面具有优势。 许多将使用这些化合物的高危妇女将不知道自己的艾滋病毒状况。因此，杀微生物剂 一种方法必须考虑感染妇女暴露于化合物的影响，因此局部用药 不代表主要的治疗性抗逆转录病毒药物可能是一个优势。有证据表明， 此外，如果一种药物能增加艾滋病毒的传播，那么对其他性传播感染也有影响的药物将有额外的好处。这种方法 必须是安全的，不干扰感染的天然屏障。提高妇女地位的办法 本计划中提出的候选杀微生物剂考虑到了这些问题中的每一个。我们提议 推进新型化合物SAMMA的开发，使其成为含有酸的配方产品， 缓冲液，以将SAMMA的进入抑制活性与酸性pH对病毒的直接影响结合起来。 我们还将探索其他化合物的潜力，如新型过硫酸化分子伞（PMU） 以及CDK抑制剂。这两类化合物都具有抗HIV和HSV的活性。这一切成功都 将仔细研究各种方法，不仅关注候选化合物的进展， 我们对关键宿主防御和局部杀微生物剂之间相互作用的理解。仔细 已在临床试验中的化合物（硫酸纤维素、酸式和 泰诺福韦）以及拟议的制定SAMMA将集中在这些化合物的影响， 先天免疫以及效力的替代标志物的开发。

Heterosexual transmission of HIV is the primary route in women, who now account for 50% of those infected. In the absence of an effective vaccine, other modes of prevention are needed. A safe and effective topical microbicide will allow women and men to play a more direct role in their own protection. As with therapeutic approaches to HIV, a topical microbicide that combines compounds with differing modes of action will have an advantage in blocking the complex interactions that occur in the mucosa at the time of transmission. Many women at risk who will use the compounds will not know their HIV status. Therefore, a microbicide approach must consider the impact of exposure of infected women to the compound and therefore topicals that do not represent major therapeutic antiretrovirals might be an advantage. Given the evidence that HSV enhances HIV transmission, agents that also impact on other STI will have an added benefit. This approach must be safe and not interfere with natural barriers to infection. The approach to the advancement of candidate microbicides proposed in this program takes into account each of these issues. We are proposing to advance the development of the novel compound SAMMA to formulated product that will include an acid buffer to combine the entry inhibitory activity of SAMMA with the direct effects of an acid pH on the virus. We will also explore the potential of other compounds such as novel persulfated molecular umbrellas (pmu) as well as cdk inhibitors. Both classes of compounds have activity against HIV and HSV. Each of these approaches will be carefully studied focusing not only on advancing candidate compounds but broadening our understanding of the interaction between critical host defenses and topical microbicides. Carefully planned pilot clinical evaluation of compounds already in clinical trials (cellulose sulfate, acidform and tenofovir) as well as the proposed formulated SAMMA will focus on the effects of these compounds on innate immunity as well as the development of surrogate markers for efficacy.