Can Sexually Transmitted Pathogens Impact the Efficacy of HIV-1 Microbicides?

性传播病原体会影响 HIV-1 杀菌剂的功效吗？

• 批准号: 8438517
• 负责人: Susana Noemi Asin
• 金额: --
• 依托单位: WHITE RIVER JUNCTION VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438517
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acyclovir; Adenoviruses; Adherence; Adult; Affect; Antiviral Agents; Antiviral Response; Binding; CD4 Positive T Lymphocytes; Candida albicans; Caring; Cell Communication; Cells; Clinical; Clinical Research; Clinical Trials; Clinical effectiveness; Coitus; Complex; Data; Development; Drug Formulations; Epidemic; Epidemiology; Experimental Models; Failure; Family; Female; Genital system; HIV; HIV-1; Health; Human; Human Herpesvirus 2; Immune; Immune Cell Activation; Immune response; Infection; Inflammatory; Inflammatory Response; Integrase Inhibitors; Interferon Type I; Lead; Lesion; Leukocytes; Life; Ligands; Military Personnel; Modeling; Mucous Membrane; Neisseria gonorrhoeae; Nucleotides; Participant; Patients; Pharmaceutical Preparations; Phase; Phosphorylation; Play; Population; Predisposition; Prevalence; Prevention; Preventive; Process; Production; Property; Provider; Receptor Activation; Receptor Signaling; Recombinants; Recruitment Activity; Reporting; Reverse Transcriptase Inhibitors; Risk; Role; SIV; Safety; Seroprevalences; Sexually Transmitted Diseases; Signal Pathway; Tenofovir; Testing; Tissues; Toll-like receptors; UC 781; United States; Vaccines; Vagina; Veterans; Viral; Woman; antimicrobial peptide; base; cervicovaginal; chemokine; clinical efficacy; cytokine; design; enhancing factor; global health; health care economics; human tissue; men; microbicide; nonhuman primate; novel; pathogen; preclinical evaluation; prevent; receptor; reproductive; research study; response; safety testing; sexually active; transmission process; vaccine candidate; vaccine development; vaginal transmission

DESCRIPTION (provided by applicant): Findings from the CAPRISA 004 Phase IIb clinical prevention trial in women who applied the HIV-1 nucleotide reverse transcriptase inhibitor (NRTI) Tenofovir (TFV) before and after sexual intercourse, illustrate the potential for microbicides as relevant strategies to prevent mucosal transmission of HIV-1. TFV reduced HIV-1 infection by an estimated 39% overall, and by 54% in women with a compliance rate of 80%. The reason(s) underlying the limited efficacy of TFV in this clinical trial are unknown but may reflect the lack of understanding of the interplay between co-factors that enhance mucosal transmission of HIV-1 and lead microbicides. Sexually transmitted pathogens (STP) highly prevalent in HIV-endemic populations enhance HIV-1 infection and transmission. It is well established that STP activate Toll Like Receptors (TLR), a family of pathogen recognition receptors to elicit a defense immune response, which includes cell activation and differentiation, secretion of type I interferon's and antimicrobial peptides, ad secretion of pro-inflammatory cytokines and chemokines that recruit and activate HIV-1 target cells. Thus, by activating TLR signaling pathways, STP may enhance pro-inflammatory innate immune responses that if dominant may override protective antiviral responses and decrease the anti-HIV-1 activity of microbicide candidates. As immune cell activation by Herpes Simplex Virus Type-2 (HSV-2) is associated with enhanced HIV-1 infection and replication, our proposal will test the hypothesis that TLR activation by STP modulates pro- inflammatory and antiviral innate immune responses to enhance HIV-1 infection, thereby compromising the efficacy of HIV-1 microbicides. Bacterial, fungal and viral pathogens highly prevalent in HIV-1-infected women bind to, and activate specific TLR. Thus, it is highly likely we will see a differential response according to the TLR signaling pathway activated by STP. Specific Aim 1 will define whether TLR activation by their cognate ligands modulates the anti-HIV-1 activity of lead microbicides by impacting innate pro-inflammatory and antiviral immune responses in the cervicovaginal mucosa. We will focus on TFV, the first NRTI vaginal formulation with demonstrated clinical effectiveness against HIV-1 infection, UC781 a non-nucleotide reverse transcriptase inhibitor with demonstrated clinical safety after vaginal application, and elvitegravr an integrase inhibitor with post-exposure profilaxis properties. Specific Aim 2 will explore TLR-dependent immunological mechanisms by which HSV-2, Neisseria gonorrhoeae, and Candida albicans modulate the efficacy of lead microbicides. These experiments will be conducted using human tissue explants from the cervicovaginal mucosa, and CD4+T cells isolated from lower female reproductive tract (FRT) tissues, infected ex vivo with primary isolates of HIV-1. Tissue explants truthfully reflect important aspects of cell-cell and cell-pathogen interactions that occu in the context of the complex tissue cytoarchitecture. Deciphering the mechanisms of these interactions is critical for understanding pathogenic processes caused by human pathogens such as HIV-1. Furthermore, tissue explants are a relevant experimental model for the preclinical evaluation of microbicide candidates that our group and leaders in the field have developed as a surrogate of microbicide efficacy. TLR play a significant role in activating immune responses triggered by STP with prevalence rates ranging from 40 to 80% in young sexually active adults living with HIV-1. Understanding the mechanisms by which TLR activation modulates the anti-HIV-1 activity of lead microbicides is relevant to developing adjunctive therapies that could enhance the efficacy of compounds aimed at preventing mucosal transmission of HIV-1. Furthermore, as the microenvironment of the FRT influences the risk of transmission in the absence of microbicides, our findings will lead to the development of approaches other than microbicides to prevent HIV-1 transmission to women under circumstances of co-infection by STP where they may be the most vulnerable.

描述（由申请人提供）： CAPRISA 004 IIb 期临床预防试验的结果显示，在性交前后使用 HIV-1 核苷酸逆转录酶抑制剂 (NRTI) 替诺福韦 (TFV) 的女性，杀菌剂具有作为预防 HIV 粘膜传播相关策略的潜力。 1. TFV 总体上减少了 HIV-1 感染 39%，女性的 HIV-1 感染减少了 54%，依从率为 80%。该临床试验中 TFV 功效有限的原因尚不清楚，但可能反映出对增强 HIV-1 粘膜传播的辅助因子和主要杀菌剂之间的相互作用缺乏了解。 HIV 流行人群中高度流行的性传播病原体 (STP) 会增强 HIV-1 的感染和传播。众所周知，STP 激活 Toll 样受体 (TLR)，这是一个病原体识别受体家族，可引发防御免疫反应，包括细胞活化和分化、I 型干扰素和抗菌肽的分泌、促炎细胞因子的分泌以及招募和激活 HIV-1 靶细胞的趋化因子。因此，通过激活 TLR 信号通路，STP 可能会增强促炎性先天免疫反应，如果该反应占主导地位，可能会超越保护性抗病毒反应并降低候选杀菌剂的抗 HIV-1 活性。由于 2 型单纯疱疹病毒 (HSV-2) 激活免疫细胞与增强 HIV-1 感染和复制相关，因此我们的提案将检验以下假设：STP 激活 TLR 调节促炎和抗病毒先天免疫反应，从而增强 HIV -1 感染，从而损害 HIV-1 杀菌剂的功效。 HIV-1 感染女性中普遍存在的细菌、真菌和病毒病原体会结合并激活特定的 TLR。因此，我们很可能会根据 STP 激活的 TLR 信号通路看到不同的反应。 具体目标 1 将确定 TLR 的同源配体激活是否通过影响宫颈阴道粘膜的先天促炎和抗病毒免疫反应来调节先导杀菌剂的抗 HIV-1 活性。我们将重点关注 TFV，这是第一个已证明对 HIV-1 感染具有临床有效性的 NRTI 阴道制剂，UC781 是一种非核苷酸逆转录酶抑制剂，在阴道应用后已证明具有临床安全性，而 elvitegravr 是一种具有暴露后分布特性的整合酶抑制剂。具体目标 2 将探索 TLR 依赖性免疫机制，HSV-2、淋病奈瑟菌和白色念珠菌通过该机制调节先导杀菌剂的功效。这些实验将使用来自子宫颈阴道粘膜的人体组织外植体和从女性下生殖道 (FRT) 组织中分离的 CD4+T 细胞进行，这些细胞在体外感染了 HIV-1 的初级分离株。组织外植体真实地反映了在复杂的组织细胞结构中发生的细胞-细胞和细胞-病原体相互作用的重要方面。破译这些相互作用的机制对于理解 HIV-1 等人类病原体引起的致病过程至关重要。此外，组织外植体是用于候选杀菌剂临床前评估的相关实验模型，我们的小组和该领域的领导者已将其开发为杀菌剂功效的替代品。 TLR 在激活 STP 引发的免疫反应中发挥着重要作用，在性活跃的年轻 HIV-1 感染者中，TLR 的患病率在 40% 至 80% 之间。了解 TLR 激活调节先导杀菌剂的抗 HIV-1 活性的机制与开发辅助疗法相关，这些疗法可以增强旨在预防 HIV-1 粘膜传播的化合物的功效。此外，由于 FRT 的微环境会影响在没有杀微生物剂的情况下传播的风险，我们的研究结果将导致开发除杀微生物剂之外的方法，以防止在 STP 合并感染的情况下 HIV-1 传播给女性。成为最脆弱的。