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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 对于中心来说，它不一定是研究者的机构。 我们最近证明了 PC-815（一种由 NNRTI MIV-150 和 Carraguard (CG) 组成的杀菌剂凝胶）对恒河猴 SHIV-RT（表达 HIV-1 逆转录酶的 SIVmac239）阴道攻击的部分功效。通过添加锌进一步提高凝胶的效力，从而增强 CG 在小鼠中的抗 HSV-2 活性。我们测试了两种候选杀菌剂：PC-707。 （CG 中含有 14mM 醋酸锌）和 PC-1005（CG 中含有 50mM MIV-150 和 14mM 醋酸锌）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）施用到阴道上皮，持续 14 天。在最后一次凝胶应用后 4、8 或 24 小时，对经 Depo-Provera 处理的恒河猴进行阴道攻击，随访包括血浆病毒 RNA 和 PBMC 病毒 DNA、血清转化和 IFN-的检测。 ¿统计显着性通过 Fisher 精确检验确定。在 MC 组中，14 只动物中有 12 只（85.7%）被感染，而在 PC-707 治疗组中，7 只动物中有 1 只（14.3%）被感染，7 只动物中有 2 只（28.6%）被感染。 )，分别在最后一次凝胶应用后8小时和24小时攻击时被感染，用PC-1005治疗的动物在攻击后的任何时间都没有感染SHIV-RT。这与单独研究的结果形成对比，我们发现在用 CG 治疗的动物中，8 只（7 只动物中的 5 只或 71.4% 感染）或 24 小时（7 只动物中的 4 只或 57.1% 感染）和 PC-815（50 M MIV-）。 CG 中为 150），在动物受到攻击 8 小时（7 只动物中的 2 只或 28.6% 感染）或 24 小时（7 只动物中的 5 只或 71.4% 感染）后最后一次凝胶应用的保护性明显高于 CG（p0.0003），感染通常与 SIV 特异性抗体和 T 细胞反应的发展相关。 CG 中递送的醋酸锌，提供长达 24 小时的针对阴道 SHIV-RT 攻击的完全保护 PC-1005 介导的增强保护（与部分保护相比）。当 MIV-150 或醋酸锌单独在 CG 中递送时所观察到的活性）有望开发出一种有效的、独立于性交的凝胶。