BLOCKING VIRUS SPREAD BY DCS WITH CARRAGEENAN-BASED COMPOUNDS

用卡拉胶基化合物阻断 DCS 传播的病毒

• 批准号: 8172934
• 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/8172934
• 关键词: Animal Model; Animals; CD8B1 gene; Carrageenan; Cervical; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; Evaluation; Frequencies; Funding; Gel; Generations; Grant; HIV; Human Herpesvirus 2; Immunologic Deficiency Syndromes; Infection; Institution; Lesion; Macaca; Macaca mulatta; Modeling; Physiological; Predisposition; Research; Research Personnel; Resources; SIV; Source; Staging; T-Lymphocyte; Testing; United States National Institutes of Health; Vagina; Viral; Virus; base; chemokine; cytokine; in vivo; microbicide; non-nucleoside reverse transcriptase inhibitors; response; simian human immunodeficiency virus; transmission process

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.

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。 单纯疱疹病毒2型（HSV-2）感染可促进人类免疫缺陷病毒（HIV）的传播和获得。这发生在HSV-2感染的有症状和无症状阶段，表明明显的疱疹病变并不需要增加HIV传播。目前还没有一种动物模型来研究这两种病毒协同作用的根本原因，并在这种复杂的生理条件下测试预防策略。 我们着手建立一个恒河猴模型，其中HSV-2感染增加阴道感染模型免疫缺陷病毒（猴-人免疫缺陷病毒，SHIV-RT）的易感性，并更严格地测试有前途的杀微生物剂。HSV-2暴露显著增加阴道SHIV-RT感染的频率（n = 6）。虽然仅在约10%的动物中检测到宫颈病变，但检测到长期HSV-2 DNA脱落（在50%的动物中随访2年）。阴道HSV-2暴露在所有动物中引起局部细胞因子/趋化因子（n = 12）和全身低水平HSV-2特异性适应性应答（n = 8），涉及CD 4（+）和CD 8（+）HSV特异性T细胞（n = 5）。局部细胞因子/趋化因子反应在共感染动物中较低，而猴免疫缺陷病毒（SIV）特异性适应性反应在未感染和HSV-2感染动物中相当（n = 6）。尽管SHIV-RT感染的频率增加，但由Carraguard（R）和非核苷逆转录酶抑制剂MIV-150（PC-817）组成的新一代杀微生物剂凝胶阻断了HSV-2暴露动物（n = 8）的阴道SHIV-RT感染，就像在未处理动物中一样。 我们建立了一种独特的HSV-2猕猴模型，这可能有助于研究HSV-2如何增加HIV传播，并能够更严格地评估体内候选抗病毒方法。