ZCM:A NOVEL BROAD-SPECTRUM MICROBICIDE FOR SEXUALLY TRANSMITTED INFECTIONS

ZCM：一种治疗性传播感染的新型广谱杀菌剂

• 批准号: 8172989
• 负责人: Melissa J Robbiani
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172989
• 关键词: Animals; Computer Retrieval of Information on Scientific Projects Database; Depo Provera; Detection; Development; Epithelium; Funding; Gel; Grant; HIV-1 Reverse Transcriptase; Infection; Institution; Macaca mulatta; Mediating; Methylcellulose; Mus; Peripheral Blood Mononuclear Cell; Placebos; Plasma; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Sexually Transmitted Diseases; Source; T cell response; Testing; Time; United States National Institutes of Health; Vagina; Zinc; Zinc Acetate; follow-up; improved; microbicide; non-nucleoside reverse transcriptase inhibitors; novel; response; simian human immunodeficiency virus; viral DNA; viral RNA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We recently demonstrated partial efficacy of PC-815, a microbicide gel consisting of the NNRTI MIV-150 and Carraguard (CG) against vaginal challenge of rhesus macaques with SHIV-RT (SIVmac239 expressing HIV-1 reverse transcriptase). Here, we aimed to further improve the potency of the gels by adding zinc, which enhances the anti-HSV-2 activity of CG in mice. We tested two candidate microbicides: PC-707 (14mM zinc acetate in CG) and PC-1005 (50mM MIV-150 and 14mM zinc acetate in CG). Treatment gels PC-707 (n=14) and PC-1005 (n=21), or methyl cellulose (MC) placebo (n=14), were applied daily (2ml/day) for 14 days to the vaginal epithelium of Depo-Provera-treated rhesus macaques. Animals were vaginally challenged with 103 TCID50 SHIV-RT at 4, 8, or 24h after the last gel application. Follow-up included detection of plasma virus RNA and PBMC virus DNA, seroconversion, and IFN-¿ responses. Statistical significance was determined with Fisher's exact test. In the MC group, 12 of 14 animals (85.7%) became infected. Among the PC-707 treatment groups, 1 of 7 (14.3%) and 2 of 7 animals (28.6%), became infected when challenged 8 and 24h after final gel application, respectively. None of the animals treated with PC-1005 became infected with SHIV-RT after challenge at any time point. This contrasts findings from separate studies where we found that in animals treated with CG, 8 (5 of 7 animals or 71.4% infected) or 24h (4 of 7 animals or 57.1% infected) and PC-815 (50 M MIV-150 in CG) in animals challenged 8 (2 of 7 animals or 28.6% infected) or 24h (5 of 7 animals or 71.4% infected) after the last gel application. PC-1005 was significantly more protective than CG (p0.0003). Infection typically correlated with the development of SIV-specific Ab and T cell responses. Repeated daily application of PC-1005, a microbicide containing MIV-150 and zinc acetate delivered in CG, provided complete protection for up to 24h against vaginal SHIV-RT challenge. The enhanced protection mediated by PC-1005 (compared to the partial activity seen when either MIV-150 or zinc acetate alone were delivered in CG) is promising for the development of an effective, coitally-independent gel.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 最近，我们证明了PC-815的部分效率，PC-815是由NNRTI MIV-150和Carraguard（CG）组成的菌心凝胶（CG），以针对带有SHIV-RT（SIVMAC239表达HIV-1反向转录酶）的恒河猕猴的阴道挑战。在这里，我们旨在通过添加锌进一步提高凝胶的效力，从而增强了小鼠CG的抗HSV-2活性。我们测试了两种候选菌皮：PC-707（CG中的14mm乙酸锌）和PC-1005（50mm MIV-150和CG中的14mm乙酸锌）。处理凝胶PC-707（n = 14）和PC-1005（n = 21），或甲基纤维素（MC）安慰剂（n = 14），每天（2ml/天）14天应用于Depo-Provera处理的鼠王麦片的阴道上皮。上次凝胶施用后4、8或24小时，动物用103 TCID50 SHIV-RT进行了阴道挑战。随访包括检测等离子体病毒RNA和PBMC病毒DNA，血清转化和IFN- - 反应。通过Fisher的精确检验确定统计显着性。在MC组中，14只动物中有12只（85.7％）被感染。在PC-707治疗组中，有7只动物中有1个（14.3％）和2个动物（28.6％），分别在最终凝胶施用后挑战8和24h时被感染。在任何时间点，用PC-1005处理的动物都没有被Shiv-RT感染。 contrasts findings from separate studies where we found that in animals treated with CG, 8 (5 of 7 animals or 71.4% infected) or 24h (4 of 7 animals or 57.1% infected) and PC-815 (50 M MIV-150 in CG) in animals challenged 8 (2 of 7 animals or 28.6% infected) or 24h (5 of 7 animals or 71.4% infected) after the last gel application. PC-1005比CG更受保护（P0.0003）。感染通常与SIV特异性AB和T细胞反应的发展相关。在CG中递送的含有MIV-150和乙酸锌的菌心PC-1005的重复应用，可为阴道SHIV-RT挑战提供最多24小时的完全保护。 PC-1005介导的增强保护（与单独使用MIV-150或单独乙酸锌在CG中传递的部分活性相比）是有望开发有效的，具有coIt污染的凝胶的。