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Exploring the Role of Semen Amyloids in Promoting HIV Infection and Fertilization

探索精液淀粉样蛋白在促进 HIV 感染和受精中的作用

基本信息

批准号：
8986150
负责人：
Nadia R Roan
金额：
$ 24.36万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2013-05-15 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986150
关键词：
AIDS prevention Accounting Acquired Immunodeficiency Syndrome Address Advisory Committees Amyloid Amyloid Fibrils Antiviral Agents Applied Skills Artificial Insemination Atomic Force Microscopy Biochemical Biological Biological Assay Cell physiology Cells Characteristics Chemotaxis Data Development Enhancers Epidemic Epithelial Event Female Fertility Rates Fertilization Fertilization in Vitro Funding Future Genetic Transcription Genital system Germ Cells Goals HIV HIV Infections HIV-1 Human Immune In Situ In Vitro Inflammation Inflammatory Integration Host Factors Knowledge Local Microbicides Macaca mulatta Measures Mentors Microscopy Molecular Molecular Conformation Mouse Strains Mucous Membrane Mus Neurobiology Oocytes Pattern recognition receptor Persons Pharmaceutical Preparations Phase Physiological Process Production Property Proteins Recruitment Activity Reproduction Reproductive Biology Research Role SIV Seminal Plasma Seminal fluid Sexual Transmission Signal Pathway Signal Transduction Technical Expertise Techniques Testing Tissues Translating Viral Virus Virus Diseases Work abstracting anti-HIV microbicide antimicrobial cellular targeting chemokine conformer cytokine design egg fertility improvement improved in vivo inhibitor/antagonist insight killings male microbicide prevent prophylactic research study response sexual HIV transmission sperm cell transmission process vector

项目摘要

7. PROJECT SUMMARY/ABSTRACT: HIV is most frequently transmitted following sexual contact, and semen is the vehicle fueling the global spread of this deadly virus. Far from being a passive vector for HIV, our research revealed that semen drastically enhances HIV infection in vitro, and we have further identified and characterized amyloid fibrils from human semen that increase HIV-1 fusion to its cellular targets. These fibrils can enhance HIV infection by over several orders of magnitude, and therefore serve as good targets for the development of a topical HIV microbicide. The first two aims of this proposal focus on better characterizing the mechanisms by which these semen fibrils enhance HIV infectivity and their influence on cells present within the genital mucosa. In Aim 1, I propose to use techniques from the field of neurobiology to characterize the morphological characteristics of semen fibrils that most effectively enhance HIV infectivity. This information will reveal the types of amyloid conformations in semen that should be targeted in efforts to design specific inhibitors against host factors in semen. In Aim 2, I will determine whether semen fibrils induce inflammation in host cells, and what role this may have in promoting HIV infection. It is known that inflammation generally facilitates HIV transmission by recruiting susceptible target cells and promoting HIV gene transcription. Understanding the extent to which semen fibrils contribute to host inflammation during transmission will be vital for developing microbicides that are effective in preventing sexual transmission of the virus. Lastly, Aim 3 of the proposal focuses on better understanding the fundamental physiological function of semen fibrils. Semen fibrils did not evolve to promote HIV infection, and may have a biological purpose in humans. Intriguingly, HIV fusion to its cellular target shares many properties with the fusion of a spermatozoon to an egg, raising the possibility for a role for these fibrils in fertilization. In this aim, I propose in vitro fertilization (IVF) and in vivo artificial insemination experiments to determine if the semen fibrils we have characterized promote the fusion of murine gametes. Understanding whether these fibrils serve to promote fertilization is vital information for the development of an HIV microbicide, and could also have a significant impact in the field of reproduction. Substantial efforts have been invested into developing an effective HIV microbicide. However, the field still lacks a drug that is highly effective at preventing the sexual spread of HIV, in part due to our lack of basic understanding of the molecular events surrounding mucosal HIV transmission. This proposal focuses on better understanding one aspect of HIV transmission, namely the effect of naturally-occurring semen fibrils that enhance HIV infectivity. Although the proposal is limited to in vitro analysis of these fibrils, we are initiating experiments in parallel in rhesus macaques to examine the effect of these fibrils in vivo. My plan during the mentored phase of the K99/R00, were it to get funded, is to develop new technical skills in amyloid and reproductive biology and to apply these skills towards understanding HIV transmission. This will be accomplished by working closely with my K99 mentors and advisory committee. My long-term goal is to advance our understanding of the molecular events surrounding HIV transmission in the genital mucosa, and to translate this knowledge into the development of new classes of HIV preventatives.

7. 项目总结/文摘: