Inhibition of HIV Infection by Oral Bacterial Component

描述(申请人提供)：HIV-1感染与获得性免疫缺陷综合征(艾滋病)的发展有关，艾滋病是一种毁灭性的疾病，影响着全球4000多万人。与经阴道和直肠传播的风险高得多相比，经口传播艾滋病毒似乎是一种罕见的事件。为了寻找这一现象的解释，密集的研究集中在确定负责抑制艾滋病毒口头传播的口腔成分。在我们正在进行的研究中，我们已经证明牙龈卟啉单胞菌具有抑制HIV诱导的膜融合的能力，这种牙周病原体在牙周炎患者的大多数病变部位都能检测到。我们的长期目标是充分了解口腔细菌在HIV口腔传播中的作用，并为开发有效的抗HIV疗法提供基础。这一提议的假设是牙龈假单胞菌是一种有效的HIV传播口服抑制剂，这种抑制的主要机制是牙龈假单胞菌的一个成分特异性地干扰艾滋病毒感染早期的关键步骤之一。为了验证这一假设，我们将从鉴定和纯化抑制分子开始。抑制分子将从功能和遗传结构方面进行表征。我们还将试图阐明牙龈假单胞菌抑制成分的分子靶点。实验旨在检查细菌介入并导致病毒入侵流产的每一种可能的事件。还将做出特别努力，通过测定其抗病毒光谱来评估该抑制分子的临床潜力。最后，将启动研究，以调查艾滋病毒和牙龈假单胞菌混合感染对这些微生物的病原学的影响。该提案的成功完成将是理解牙龈假单胞菌在艾滋病毒口头传播中的作用方面的一个重大进步。此外，对牙龈假单胞菌抑制蛋白的研究可能会导致发现一个额外的靶点，以补充目前的抗HIV靶点，即逆转录酶或蛋白酶。

DESCRIPTION (provided by applicant): HIV-1 infection is associated with the development of acquired immunodeficiency syndrome (AIDS), a devastating disease affecting over 40 million people worldwide. Oral transmission of HIV appears to be a rare event, compared to a much higher risk of vaginal and rectal transmission. In search for the explanations for this phenomenon, intensive studies have focused on identification of oral components that are responsible for inhibition of HIV oral transmission. In our ongoing studies, we have demonstrated that Porphyromonas gingivalis, a periodontopathogen detected in most disease sites of periodontitis patients, possesses the ability to inhibit HIV induced membrane fusion. Our long-range goal is to fully understand the involvement of oral bacteria in the oral transmission of HIV and to provide the basis for development of effective anti-HIV therapies. The hypothesis for this proposal is that P. gingivalis is a potent oral inhibitor of HIV transmission, and that the primary mechanism of the inhibition is that a P. gingivalis component specifically interferes with one of the key steps in the early stage of HIV infection. To test the hypothesis, we will start with identification and purification of the inhibitory molecule. The inhibitory molecule will be characterized in the term of functional and genetic structures. We will also attempt to elucidate the molecular target of the P. gingivalis inhibitory component. Experiments are designed to examine every possible event where the bacterium steps in and leads to an aborted viral entry. Special effort will also be made to evaluate the clinical potential of the inhibitory molecule by determining its anti-viral spectra. Finally, studies will be initiated to investigate the effect of co-infection of HIV and P. gingivalis on the pathogenicites of the organisms. The successful completion of the proposal will be a significant advance in the understanding of the role of P. gingivalis in HIV oral transmission. Furthermore, the study of P. gingivalis inhibitory protein may lead to a discovery of an additional target to complement the current anti-HIV targets which are either reverse transcriptase or protease.