Cervical/Vaginal Mucus and Microbicides

宫颈/阴道粘液和杀菌剂

• 批准号: 8649479
• 负责人: Thomas Hope
• 金额: $ 46.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649479
• 关键词: Antibodies; Binding; Biological; Carbopol; Cellulose; Cervical; Cervix Mucus; Characteristics; Clinical Trials; Clinical Trials Design; Collaborations; Complex; Development; Dose; Environment; Failure; Female; Fertilization; Gel; Genital system; HIV; HIV Antibodies; Hour; Imagery; In Vitro; Intervention; Laboratories; Lactobacillus; Lead; Liquid substance; Macaca mulatta; Male Genital Organs; Methods; Modeling; Movement; Mucins; Mucous body substance; Neuraminidase; Pharmacodynamics; Phase; Primates; Process; Production; Publishing; Relative (related person); Research; Role; SIV; Seminal Plasma; Seminal fluid; Sexual Transmission; System; Vagina; Virus; Viscosity; Water; cervicovaginal; design; genital secretion; in vivo; microbicide; particle; prevent; protein complex; public health relevance; sperm cell; transmission process

DESCRIPTION (Provided by the Applicant): To develop a functional microbicide it is critical to know how it will interact within HIV in the context of the female genital tract. This is a critical issue as previous clinical trials have indicated that microbicides do not function as expected in the presence of semen. Likewise, other factors, such as cervical/vaginal mucus, might also modulate microbicide function. To date, little is known about how HIV interacts with these fluids and how the interaction of these fluids changes the local environment. Even less is known about how microbicides interact with HIV within this milieu. For example, the vehicle delivering the microbicide might interact with the biological fluids of sexual transmission to either increase or inhibit HIV acquisition or microbicide potency. The Hope laboratory has recently developed methods that allow the transport of HIV with cervical and cervical/vaginal mucus to be analyzed and quantified. These studies have revealed that mucus can perturb HIV transport and is pH sensitive. At acidic pH, as is found in the lactobacilli influenced environment of the vaginal vault, HIV transport is greatly reduced. At neutral pH, such as when semen is introduced into the system, HIV transport is reduced 10-15 fold relative to what is observed in media (water). Additionally, we have found, but not yet published, that virus-binding antibodies can further reduce transport in neutral pH cervical mucus. These antibodies do not need to be neutralizing as any antibody binding to the virus can decrease virus transport. Semen also contains mucins and other components that have the potential to alter HIV transport as we have observed in cervical mucus. How HIV is transported within semen and how this changes when mixed with mucus or microbicides is not defined. How this process influences HIV transport and interaction with mucosal barriers is not understood. In the first phase (R21) of this proposal we will define how HIV is transported in semen alone and mixed with mucus and/or microbicide vehicles such as carbopol gel and hydroxy ethyl cellulose (HEC). In the second phase (R33) of this proposal we will extend our studies into the environment of the rhesus macaque female genital tract to determine how biological fluids and microbicide vehicles alter the way that virus interacts with the mucosal barriers of this environment and how these changes can increase or decrease SIV acquisition. These studies will lead to a better understanding of how virus interacts with biological fluids and how these interactions might alter microbicide efficacy.

描述（由申请人提供）：要开发一种功能性微生物，至关重要的是要知道在女性生殖道的背景下它将如何在HIV中相互作用。这是一个关键问题，因为先前的临床试验表明，在精液存在下，菌皮不如预期的。同样，其他因素（例如宫颈/阴道粘液）也可能调节杀生型功能。迄今为止，关于艾滋病毒如何与这些液体相互作用以及这些流体的相互作用如何改变当地环境，知之甚少。关于微生物在这个环境中如何与HIV相互作用的知之甚少。例如，输送菌心的车辆可能会与性传播的生物流体相互作用，以增加或抑制HIV的获取或杀菌剂效力。 Hope Laboratory最近开发了允许对HIV运输的方法，可以分析和量化宫颈和宫颈/阴道粘液。这些研究表明，粘液可以扰动HIV转运并且对pH敏感。在酸性pH值中，正如乳酸杆菌影响阴道穹顶环境的那样，HIV转运大大降低。在中性pH值（例如将精液引入系统中时），相对于培养基（水）观察到的相比，HIV转运降低了10-15倍。此外，我们发现但尚未发表，病毒结合抗体可以进一步降低中性pH宫颈粘液中的转运。这些抗体不需要中和，因为与病毒结合的任何抗体都可以降低病毒的转运。精液还含有粘蛋白和其他成分，它们具有改变HIV转运的潜力，如我们在宫颈粘液中所观察到的那样。未定义与粘液或菌皮混合时，如何在精液中运输HIV以及如何变化。该过程如何影响艾滋病毒的运输和与粘膜屏障的相互作用。在该提案的第一阶段（R21）中，我们将定义如何仅在精液中运输HIV，并与粘液和/或杀菌糖型（例如Carbopol凝胶和羟基乙基纤维素（HEC））混合。在该提案的第二阶段（R33）中，我们将我们的研究扩展到恒河猕猴女性生殖道的环境，以确定生物体液体和微生物型如何改变病毒与该环境的粘膜障碍的相互作用的方式以及这些变化如何变化可以增加或减少SIV获取。这些研究将使人们更好地了解病毒如何与生物液相互作用以及这些相互作用如何改变菌心疗效。