BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 单纯疱疹病毒2型(HSV-2)感染可促进人类免疫缺陷病毒(HIV)的传播和感染。这发生在HSV-2感染的症状和无症状阶段，这表明明显的疱疹病变不是增加艾滋病毒传播所必需的。目前还没有一个动物模型来研究这两种病毒协同作用的根本原因，以及在这种复杂的生理条件下可以测试预防策略的动物模型。我们开始建立恒河猴模型，在该模型中，HSV-2感染增加了对模式免疫缺陷病毒(SIV-人类免疫缺陷病毒，SHIV-RT)阴道感染的易感性，并更严格地测试有前景的杀菌剂。HSV-2暴露显著增加阴道SHV-RT感染的频率(n=6)。虽然只在大约10%的动物身上检测到宫颈病变，但长期的HSV-2DNA脱落被检测到(在50%的动物中随访2年)。经阴道暴露HSV-2可在所有动物中诱导局部细胞因子/趋化因子(n=12)和系统低水平的HSV-2特异性适应性反应(n=8)，涉及CD4(+)和CD8(+)HSV特异性T细胞(n=5)。混合感染动物的局部细胞因子/趋化因子反应较低，而新城疫和单纯疱疹病毒2型感染动物(n=6)的猴免疫缺陷病毒(SIV)特异性适应性反应相似。尽管SHV-RT感染的频率增加，但由CarraGuard(R)和非核苷类逆转录酶抑制剂MIV-150(PC-817)组成的新一代杀微生物凝胶可以阻止暴露于HSV-2的动物(n=8)的阴道SHV-RT感染，就像在自然动物中一样。我们建立了一个独特的HSV-2猕猴模型，这可能有助于研究HSV-2如何增加艾滋病毒的传播，并能够在体内对候选的抗病毒方法进行更严格的评估。

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. Herpes simplex virus type-2 (HSV-2) infection enhances the transmission and acquisition of human immunodeficiency virus (HIV). This occurs in symptomatic and asymptomatic stages of HSV-2 infection, suggesting that obvious herpetic lesions are not required to increase HIV spread. An animal model to investigate the underlying causes of the synergistic action of the two viruses and where preventative strategies can be tested under such complex physiological conditions is currently unavailable. We set out to establish a rhesus macaque model in which HSV-2 infection increases the susceptibility to vaginal infection with a model immunodeficiency virus (simian-human immunodeficiency virus, SHIV-RT), and to more stringently test promising microbicides. HSV-2 exposure significantly increased the frequency of vaginal SHIV-RT infection (n = 6). Although cervical lesions were detected in only approximately 10% of the animals, long term HSV-2 DNA shedding was detected (in 50% of animals followed for 2 years). Vaginal HSV-2 exposure elicited local cytokine/chemokine (n = 12) and systemic low-level HSV-2-specific adaptive responses in all animals (n = 8), involving CD4(+) and CD8(+) HSV-specific T cells (n = 5). Local cytokine/chemokine responses were lower in co-infected animals, while simian immunodeficiency virus (SIV)-specific adaptive responses were comparable in na¿ve and HSV-2-infected animals (n = 6). Despite the increased frequency of SHIV-RT infection, a new generation microbicide gel, comprised of Carraguard(R) and a non-nucleoside reverse transcriptase inhibitor MIV-150 (PC-817), blocked vaginal SHIV-RT infection in HSV-2-exposed animals (n = 8), just as in na¿ve animals. We established a unique HSV-2 macaque model that will likely facilitate research to define how HSV-2 increases HIV transmission, and enable more rigorous evaluation of candidate anti-viral approaches in vivo.