Vaginal Product Formulation Alters the Innate Antiviral Activity and Glycome of Cervicovaginal Fluids with Implications for Viral Susceptibility,ACS Infectious Diseases

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Vaginal Product Formulation Alters the Innate Antiviral Activity and Glycome of Cervicovaginal Fluids with Implications for Viral Susceptibility
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-09-05 00:00:00 , DOI: 10.1021/acsinfecdis.8b00157
Sujeethraj Koppolu ₁ , Linlin Wang ₁ , Ayushi Mathur ₁ , Jayeshwar A. Nigam ₁ , Charlene S. Dezzutti _{2,

3} , Charles Isaacs ₄ , Leslie Meyn _{2,

3} , Katherine E. Bunge _{2,

3} , Bernard J. Moncla _{2,

3} , Sharon L. Hillier _{2,

3} , Lisa C. Rohan _{2,

5} , Lara K. Mahal ₁

Affiliation

Glycosylated proteins (i.e., mucins, IgG) are important mediators of innate antiviral immunity in the vagina; however, our current knowledge of the role that glycan themselves play in genital immunity is relatively low. Herein, we evaluate the relationship between innate antiviral immunity and glycomic composition in cervicovaginal lavage fluid (CVL) collected as part of a Phase I clinical trial testing the impact of two distinct formulations of the antiretroviral drug dapivirine. Using lectin microarray technology, we discovered that formulation (hydrogel- versus film-based delivery) impacted the CVL glycome, with hydrogel formulations inducing more changes, including a loss of high-mannose. The loss of this epitope correlated to a loss of anti-HIV-1 activity. Glycoproteomic identification of high-mannose proteins revealed a cohort of antiproteases shown to be important in HIV-1 resistance, whose expression covaried with the high-mannose signature. Our data strongly suggests high-mannose as a marker for secreted proteins mediating innate antiviral immunity in vaginal fluids and that drug formulation may impact this activity as reflected in the glycome.

中文翻译：

阴道产品配方改变了子宫颈阴道液的先天抗病毒活性和糖原，对病毒易感性有影响

糖基化蛋白（即粘蛋白，IgG）是阴道先天抗病毒免疫的重要介质。但是，我们目前对聚糖自身在生殖器免疫中的作用的了解还相对较少。在本文中，我们评估了子宫颈阴道灌洗液（CVL）中固有的抗病毒免疫力与糖组学组成之间的关系，该抗体是作为I期临床试验的一部分进行测试的，该试验测试了抗逆转录病毒药物dapivirine的两种不同配方的影响。使用凝集素微阵列技术，我们发现制剂（基于水凝胶的与基于膜的递送）影响了CVL糖原，水凝胶制剂诱导了更多的变化，包括高甘露糖的损失。该表位的丧失与抗HIV-1活性的丧失相关。高甘露糖蛋白的糖代谢组学鉴定揭示了一组抗蛋白酶被证明对HIV-1抵抗很重要，其表达与高甘露糖签名共变。我们的数据强烈表明，高甘露糖可作为分泌蛋白的标志物，介导阴道液中固有的抗病毒免疫力，而药物制剂可能会影响这种活性，如糖蛋白所反映。

更新日期：2018-09-05

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