REFINEMENT OF THE SHIV/MACAQUE MODEL FOR ASSESSMENT OF CANDIDATE MICROBICIDES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 背景：非人灵长类动物模型在局部杀微生物剂的临床前评价中起着关键作用。我们已经证明，6%硫酸纤维素（CS）凝胶可防止每周用100 TCID 50的R5和X4 SHIV（3：1比例）（R5+X4）攻毒的恒河猴发生病毒血症和血清转化。本研究旨在比较经300 TCID 50 R5+X4 SHIV单次给药的Depo-Provera处理动物中的CS疗效。 研究方法：用2 ml活性或安慰剂凝胶（使用其临床制剂）阴道内处理动物（n=30），30 min后用300 TCID 50的R5+X4 SHIV攻毒。通过测量血浆病毒血症、抗体血清转化和前病毒DNA来监测感染。采用Fisher精确检验分析结果。 结果/结论：本研究分为两个实验，每个实验12只猴子（每组n=6）。综合结果显示，与安慰剂相比，CS凝胶具有统计学显著性保护作用（安慰剂组和CS组分别有1/12和7/12只动物无全身感染; P = 0.0272）。 与低剂量重复攻毒模型一样，偶尔在病毒血症动物的PBMC和淋巴细胞中检出前病毒DNA。第二项实验中包含的PRO 2000（0.5%）凝胶保护了该模型中的4/6只动物（P=0.0217）。CS预防了每周用100 TCID 50 R5+X4 SHIV攻毒的所有动物中的全身性病毒血症，以及约60%用300 TCID 50单次剂量攻毒的Depo处理动物中的全身性病毒血症。 PRO2000还保护了大约60%的这些动物。考虑到模型的差异，这些结果是一致的，并证明了这些凝胶的临床前疗效。这些结果不能预测临床试验结果的事实可能与多种原因有关，包括保护的定义、预测值的截止值以及与人类一致和正确使用凝胶相关的问题。

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. Background: Nonhuman primate models play critical role in preclinical evaluation of topical microbicides. We have shown that 6% cellulose sulfate (CS) gel prevents the development of viremia and seroconversion in rhesus macaques challenged weekly with 100 TCID50 of R5 and X4 SHIV (3:1 ratio) (R5+X4). The current study was aimed at comparing CS efficacy in Depo-Provera treated animals infected by a single dose of 300 TCID50 of R5+X4 SHIV. Methods: Animals (n=30) were treated intravaginally with 2 ml of active or placebo gel (using their clinical formulations) and challenged 30 min later with 300 TCID50 of R5+X4 SHIV. Infection was monitored by measuring plasma viremia, antibody seroconversion and proviral DNA. Results were analyzed with Fisher's exact test. Results/Dsicussion: The study was undertaken as two experiments of 12 monkeys each (n=6 per group). The combined outcome showed a statistically significant protection of CS gel compared to placebo (1/12 vs 7/12 animals were free of systemic infection in the placebo and CS group, respectively; P = 0.0272). As in the low-dose repeated challenge model, proviral DNA was occasionally detected in PBMC and lymphoid cells of the aviremic animals. PRO2000 (0.5%) gel, included in the second experiment, protected 4/6 animals in this model (P=0.0217). CS prevented systemic viremia in all animals challenged weekly with 100 TCID50 R5+X4 SHIV and in about 60% of Depo-treated animals challenged with a single dose of 300 TCID50. PRO2000 also protected about 60% of these animals. Given the differences in the models, these results are consistent and demonstrate the preclinical efficacy of these gels. The fact that these results do not predict the outcome of clinical trials may be related to multiple reasons including definition of protection, cutoff for predictive value and issues related to consistent and proper use of the gels by humans.