Barnable Patrick, Calenda Giulia, Bonnaire Thierry, Menon Radhika, Levendosky Keith, Gettie Agegnehu, Blanchard James, Cooney Michael L, Fernández-Romero José A, Zydowsky Thomas M, Teleshova Natalia
Population Council, New York, New York, USA.
Aaron Diamond AIDS Research Center, Rockefeller University, New York, New York, USA.
Antimicrob Agents Chemother. 2015 Jul;59(7):3829-37. doi: 10.1128/AAC.00073-15. Epub 2015 Apr 13.
The transmission of both cell-free and cell-associated immunodeficiency viruses has been demonstrated directly in multiple animal species and possibly occurs in humans, as suggested by genotyping of the infecting human immunodeficiency virus (HIV) in acutely infected women and in semen from their partners. Therefore, a microbicide may need to block both mechanisms of HIV transmission to achieve maximum efficacy. To date, most of the preclinical evaluation of candidate microbicides has been performed using cell-free HIV. New models of mucosal transmission of cell-associated HIV are needed to evaluate candidate microbicide performance. The MIV-150/zinc acetate/carrageenan (MZC) gel protects Depo-Provera-treated macaques against cell-free simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) infection when applied vaginally up to 8 h before challenge. We recently demonstrated the potent activity of MZC gel against cell-free SHIV-RT in macaque vaginal explants. In the current study, we established a cell-associated SHIV-RT infection model of macaque vaginal tissues and tested the activity of MZC gel in this model. MZC gel protected tissues against cell-associated SHIV-RT infection when present at the time of viral exposure or when applied up to 4 days prior to viral challenge. These data support clinical testing of the MZC gel. Overall, our ex vivo model of cell-associated SHIV-RT infection in macaque vaginal mucosa complements the cell-free infection models, providing tools for prioritization of products that block both modes of HIV transmission.
无细胞和细胞相关免疫缺陷病毒的传播已在多种动物物种中得到直接证实，并且在人类中可能也会发生，急性感染女性及其伴侣精液中感染的人类免疫缺陷病毒（HIV）基因分型表明了这一点。因此，一种杀微生物剂可能需要阻断HIV传播的两种机制才能实现最大疗效。迄今为止，大多数候选杀微生物剂的临床前评估都是使用无细胞HIV进行的。需要新的细胞相关HIV黏膜传播模型来评估候选杀微生物剂的性能。MIV-150/醋酸锌/角叉菜胶（MZC）凝胶在攻击前长达8小时经阴道给药时，可保护接受醋酸甲羟孕酮治疗的猕猴免受无细胞猿猴-人类免疫缺陷病毒逆转录酶（SHIV-RT）感染。我们最近证明了MZC凝胶在猕猴阴道外植体中对无细胞SHIV-RT具有强大活性。在本研究中，我们建立了猕猴阴道组织的细胞相关SHIV-RT感染模型，并在该模型中测试了MZC凝胶的活性。当在病毒暴露时存在或在病毒攻击前长达4天应用时，MZC凝胶可保护组织免受细胞相关SHIV-RT感染。这些数据支持对MZC凝胶进行临床试验。总体而言，我们在猕猴阴道黏膜中建立的细胞相关SHIV-RT感染的体外模型补充了无细胞感染模型，为筛选能阻断两种HIV传播模式的产品提供了工具。
