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Defensins in STI-Mediated Enhanced HIV Infectivity

防御素在性传播感染介导的艾滋病毒感染性增强中的作用

基本信息

批准号：
8607109
负责人：
Theresa L Chang
金额：
$ 45.53万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607109
关键词：
AIDS prevention Accounting Acute Antibodies Binding Biological Assay Charge Clinical Research Complex Defensins Development Epidemiologic Studies Epithelial Epithelial Cells Epithelium Exocervix Gene Expression Gene Expression Regulation Genital system Glycoproteins Glycosaminoglycans Goals Gonorrhea HDAC5 gene HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Heparin Host Defense Human Indium Individual Infection Intestines Lead Ligands Male urethral structure Mediating Molecular Mucosal Immunity Mucous Membrane Mutation Neisseria gonorrhoeae Nucleotides Paneth Cells Pathogenesis Peptides Phage Display Play Polysaccharides Predisposition Prevention strategy Probability Publications Publishing Reporting Research Role Route Series Sexual Transmission Sexually Transmitted Diseases Signal Pathway Site Structure Surface Plasmon Resonance System TLR4 gene Technology Time Toll-Like Receptor 2 Transcriptional Regulation Up-Regulation V3 Loop Vaccines Vagina Variant Viral Virus Woman analog antimicrobial peptide base cervicovaginal clinically significant cytokine insight microbicide mutant neutralizing antibody novel promoter response tissue culture transmission process

项目摘要

PROJECT SUMMARY Sexual transmission is the most common route of HIV infection and women account for nearly half of those infected worldwide. Prevention strategies employing different approaches are needed to reduce the probability of transmission. Epidemiological and clinical studies strongly indicate that sexually transmitted infections (STIs) increase the likelihood of HIV transmission. Although the contribution of STIs to the increase in HIV transmission is likely to be multifaceted, understanding how STIs enhance HIV infection is vital to the development of new strategies for the prevention of HIV. Mammalian defensins are antimicrobial peptides important to innate host defense and play a role in mucosal immunity. Human defensins 5 and 6 (HD5 and HD6), the most abundant antimicrobial peptides in intestine, are constitutively expressed in Paneth cells but also found in the epithelium of the vagina and ectocervix. Induction of HD5 has been reported in the male urethra during C. trachomatis and N. gonorrhoeae infectioN, further supporting the role of defensins in the mucosal immunity against STIs. However, our recent publication indicates that HD5 and HD6 significantly enhance HIV infection at the step of viral entry. Using a cervicovaginal epithelial tissue culture system, we demonstrate that, for the first time, induction of HD5 and HD6 in response to gonococcal (GC) infection increases HIV infectivity. The HIV enhancing effect of HD5 and HD6 is more pronounced with R5 virus compared to X4 virus, suggesting its clinical significance as R5 viruses are almost exclusively detected upon sexual transmission. We hypothesize that STIs may contribute to increased HIV transmission by up-regulation of innate effectors that in turn promote HIV infectivity in the genital mucosa. The consequence of defensin-mediated enhancement of HIV infectivity may result in reduction of efficacy of potential microbicides and neutralizing antibodies. The goal of this proposal is to dissect the molecular basis of defensin-mediated enhanced HIV infectivity and to assess transcriptional regulation of HD5 and HD6 in cervicovaginal epithelial cells in response to GC infection. We will define the role of HIV glycoprotein gp120 in defensin-mediated enhancement of HIV infectivity. We will investigate the molecular determinants for the HIV enhancing effect of HD5 and HD6. We will elucidate the mechanism underlying gene regulation of HD5 and HD6 by GC infection. This study will provide a better understanding of the complex function of defensins in HIV-1 pathogenesis and mucosal transmission and offer insight into the development of novel prevention strategies, especially in the setting of STIs.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Differential profiles of immune mediators and in vitro HIV infectivity between endocervical and vaginal secretions from women with Chlamydia trachomatis infection: a pilot study.

沙眼衣原体感染女性宫颈内膜和阴道分泌物之间免疫介质和体外 HIV 感染性的差异：一项初步研究。

DOI：
10.1016/j.jri.2013.07.003
发表时间：
2013
期刊：
Journal of reproductive immunology
影响因子：
3.4
作者：
Sperling,Rhoda;Kraus,ThomasA;Ding,Jian;Veretennikova,Alina;Lorde-Rollins,Elizabeth;Singh,Tricia;Lo,Yungtai;Quayle,AlisonJ;Chang,TheresaL
通讯作者：
Chang,TheresaL

TLR2 activation enhances HIV nuclear import and infection through T cell activation-independent and -dependent pathways.

DOI：
10.4049/jimmunol.1102098
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Ding J;Chang TL
通讯作者：
Chang TL

Integrin α4β7 Expression Increases HIV Susceptibility in Activated Cervical CD4+ T Cells by an HIV Attachment-Independent Mechanism.

DOI：
10.1097/qai.0000000000000676
发表时间：
2015-08-15
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
0
作者：
Ding J;Tasker C;Lespinasse P;Dai J;Fitzgerald-Bocarsly P;Lu W;Heller D;Chang TL
通讯作者：
Chang TL

Chlamydia trachomatis Enhances HIV Infection of Non-Activated PBMCs.

沙眼衣原体增强非激活 PBMC 的 HIV 感染。