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？

基本信息

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
项目类别：
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

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

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项目摘要

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）：在性交发生之前和之后，使用HIV-1核苷酸逆转录酶抑制剂（NRTI）Tenofovir（NRTI）Tenofovir（TFV）的女性中CAPRISA 004期IIB临床预防试验的发现，说明了微生物剂作为相关策略以防止HIV-1的粘膜传播。 TFV估计将HIV-1感染降低了39％，依从性率为80％的女性为54％。 TFV在这项临床试验中的有限疗效的原因尚不清楚，但可能反映出对辅助因素之间相互作用的了解不足，从而增强了HIV-1和铅杀菌剂的粘膜传播。性传播病原体（STP）在HIV-流行种群中高度普遍增强HIV-1感染和传播。众所周知，STP激活像受体（TLR）一样激活Toll，这是一个病原体识别受体家族，以引起防御免疫反应，其中包括细胞激活和分化，I型干扰素的分泌和抗菌肽的分泌，AD促炎细胞因子和促促炎细胞因子和趋化因子的分泌，这些因子和趋化的HIV和actikate HIV HIV-1靶细胞。因此，通过激活TLR信号通路，STP可能会增强促炎的先天免疫反应，如果显性可能会覆盖保护性抗病毒药反应并降低杀菌剂候选物的抗HIV-1活性。由于单纯疱疹病毒类型2（HSV-2）的免疫细胞激活与HIV-1感染和复制增强有关，因此我们的建议将检验以下假说，即STP通过STP激活调节促炎性和抗病毒的先天性免疫反应，以增强HIV HIV HIV HIV HIV HIV HIV HIV HIV HIV-1的感染，从而使HIV-1 Microbiciesders canmancy and Imiv-1 Microbicides造成了影响。在HIV-1感染的女性中高度普遍的细菌，真菌和病毒病原体与特定的TLR结合并激活特定的TLR。因此，根据STP激活的TLR信号通路，我们很可能会看到差异响应。具体的目标1将通过影响宫颈阴道粘膜中先天促炎和抗病毒免疫反应来定义TLR的同源配体激活是否通过影响先天的促炎和抗病毒免疫反应来调节铅微生物的抗HIV-1活性。我们将专注于TFV，这是第一个具有针对HIV-1感染的临床有效性的NRTI阴道配方，UC781 A非核苷酸逆转录酶抑制剂具有阴道施用后具有临床安全性，Elvitegravr具有eLVITEGRAVR，具有侵蚀后特性的整合酶抑制剂。特定的目标2将探索依赖于TLR的免疫机制，通过这种机制，HSV-2，淋病奈瑟氏菌和白色念珠菌调节铅杀菌剂的功效。这些实验将使用来自子宫颈阴道粘膜的人体组织外植体，以及从雌性下部生殖道（FRT）组织分离的CD4+T细胞，这些组织被感染了HIV-1的主要分离株。组织外植体如实反映出在复杂组织细胞结构的背景下发生的细胞细胞和细胞病原体相互作用的重要方面。解读这些相互作用的机制对于理解由HIV-1等人类病原体引起的致病过程至关重要。此外，组织外植体是对我们的小组和该领域的临床前候选临床前评估的相关实验模型，该模型已发展为菌心疗效的替代物。 TLR在激活由STP触发的免疫反应中起着重要作用，患病率在40％至80％的年轻性活跃成年人中，患有HIV-1的年轻人。了解TLR激活调节铅杀菌剂的抗HIV-1活性的机制与开发辅助疗法有关，该疗法可以增强旨在防止HIV-1的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生液剂的情况下传播的风险，因此我们的发现将导致在STP通过STP共同感染的情况下，以防止HIV-1向妇女传播以外的方法，而这些方法可能是最容易受到影响的。