AIDS and Immunosuppression Program, Integrative Biology and Infectious Diseases Branch, DER, NIDCR
Objective
This initiative will support research to: 1) elucidate the structure, abundance, and distribution of glycans in HIV and persisting AIDS-related oral pathogens under antiretroviral therapy (HIV-OP/ART); and annotate glycans for HIV-OP/ART in a new electronic database, which will be publicly shared and implemented by investigator initiated strategic plans. The ultimate goal of this initiative is to create an AIDS-related, reference electronic database that contains glycoprofiles of HIV-OP/ART to serve as a comprehensive, centralized and public resource for future mechanistic and translational studies in which novel biomarkers and therapeutic targets against HIV-OP/ART could be analyzed.
Background
The spread of the HIV/AIDS pandemic and AIDS-related persisting oral diseases continues worldwide despite the availability of antiretroviral therapy (ART). There is an urgent global health need for more effective therapeutic approaches to halt this pandemic and to clinically manage HIV-OP/ART. It is known that glycans play a key role in infections and other diseases of the oral mucosa because they mediate interactions between hosts and oral pathogens as well as among oral pathogens. More specifically, the structure of glycan moieties on glycoproteins, glycolipids, and glycoconjugates of infectious pathogens plays an important role in determining the balance between health and disease such as AIDS and its persisting oral manifestations.
It is well-known that glycan moieties exert profound functional effects on glycoproteins and glycolipid conjugates as they regulate key biological processes. Examples of such effects include: control of three-dimensional folding of proteins central to multiple metabolic functions; regulation of cell-cell communication involved in maintenance of normal tissue homeostasis; regulation of early developmental processes such as embryogenesis; modulation of wound healing and tissue regeneration; and oral pathogen-host interactions through oral innate, mucosal and adaptive immune responses. Given this central role of glycans in a myriad of biological processes, it is important to apply emerging technologies of glycoprofiling1-10 to HIV-OP/ART. Elucidating glycan structure, their abundance, and their distribution on glycoproteins, glycolipids, and glycoconjugates of infectious pathogens has the potential to provide us with new strategies for identification of a new class of biomarkers and therapeutic targets in the future.
Despite growing recognition of the importance of glycans for oral health and disease, it is not well understood how different structures of glycans in oral pathogens, such as stereoisomers, chain bifurcations and modifications including phosphorylation, methylation, sulfation, and acetylation influence their ability to cause and/or modulate oral infections and diseases. It is also not known how the relative abundance and distribution of glycan moieties on glycoproteins and glycolipids influence oral infections and diseases. This lack of knowledge represents one of the key roadblocks for future development of effective therapeutic interventions against oral diseases. To move this field forward, it will be necessary to profile the structure, and determine the abundance and distribution of glycans in HIV-OP/ART.
Over the years, few glycomic resources have been developed, but overall there has been a scarcity of reagents, technologies, methodologies, databases, and shared resources to link glycans with oral diseases. This scarcity has prevented important glycoprofiling studies from going forward. Recently, the NIH Common Fund (CF) efforts in Glycoscience have been catalyzing this field by making reagents available, fostering the development of new technologies and methodologies, and attracting a critical mass of investigators to this field.
Findings from studies supported by this glycoprofiling initiative will help to create a centralized, publicly available, reference, electronic database that will contain annotated information about glycan structure, abundance, and distribution on HIV-OP/ART. This database will be publicly shared and implemented by investigator initiated strategic plans. The data and database produced will serve as a resource for future biological studies to:
- Delineate mechanisms that generate functional glycan diversity
- Define antigenicity and immunogenicity of glycan moieties
- Determine the impact on infection, pathogenicity, immune recognition, spread of infections to different cells and tissues, immune evasion, and immune clearance of HIV-OP/ART
- Define mechanisms of pathogen-host interactions
- Identify novel biomarkers for oral diseases
- Support the development of more effective therapies
- Expand the results of this work to other non-AIDS-related oral diseases
Examples of research topics supported by this initiative include but are not limited to the use of analytical methods and tools to:
- Determine, through high-throughput approaches such as glycan arrays or mass spectroscopy, the structure, abundance, and distribution of mono- and poly-saccharide chains on glycoproteins, glycolipids, and other glycoconjugates of HIV-OP/ART
- Elucidate the composition and diversity of polysaccharides formed by monosaccharide units interconnected through N/O-glycosidic linkages; define glycosylation points; determine the location and type of monosaccharide branch points, define sites for anomeric carbons, and elucidate stereoisomers for HIV-OP/ART
- Analyze existing glycan databases to annotate and predict the structure of glycans on HIV-OP/ART
Current Portfolio Overview
The NIH Common Fund efforts in Glycoscience have attracted many prominent investigators to catalyze the development of technologies, reagents and databases to allow linking glycosylation profiles of glycoproteins, glycolipids, and glycoconjugates with systemic diseases. As the glycoprofiling resources and infrastructure are now becoming more commonly available, it is timely and appropriate for NIDCR to capitalize on them and leverage this opportunity to address the structure, abundance, and distribution of glycans in HIV-OP/ART in the oral mucosa. The lack of research in this area represents a major gap in the NIDCR AIDS and Immunosuppression portfolio.
Alignment with Institute Goals, Strategies and Implementation Plan
This initiative is aligned with the following NIH Overarching AIDS Research Priorities: #2 “Next generation of HIV therapies with better safety and ease of use”; and #4: “HIV-associated comorbidities and co-infections”. Specifically, this initiative is aligned with the FY 2016 Trans-NIH Plan for HIV-related Research (PDF - 2,986 KB) in the scientific areas of emphasis on “Treatment” and “Pathogenesis”. This initiative is equally aligned with the NIDCR Strategic Plan 2014–2019: Goal I, Objective 1-1: Enable basic research to advance knowledge of dental, oral, and craniofacial health; Objective 1-2: Promote development and use of comprehensive, interoperable databases and informatics resources to advance prevention, diagnosis, and treatment of dental, oral, and craniofacial diseases; and Goal 2, Objective 2-1: Support research toward precise classification, prevention, and treatment of dental, oral, and craniofacial health and disease.
This initiative embraces the continued NIDCR sponsored research efforts in “pathogenesis and treatment” for HIV-OP/ART in the oral mucosa using glycomics as a novel research approach.
References
Geissner, A., Anish, C., and Seeberger, P.H. Glycan arrays as tools for infectious disease research. Curr Opin Chem Biol. 2014 Feb; 18: 38-45.
Arthur, C.M., Cummings, R.D., Stowell, S.R. Using glycan microarrays to understand immunity. Curr Opin Chem Biol. 2014 Feb; 18: 55-61.
Hagan A.K., Wang, M., and Liu, L. Current approaches to glycoprotein analysis. Protein Pept Lett. 2014; 21(10): 986-99.
Cummings, R.D., and Pierce, J.M. The challenge and promise of glycomics. Chem Biol. 2014 Jan 16;21(1):1-15
Frost, D.C., and Li, L. Recent advances in mass spectrometry-based glycoproteomics. Adv Protein Chem Struct Biol. 2014; 95: 71-123.
Wang, T., and Voglmeir, J. PNGases as valuable tools in glycoprotein analysis. Protein Pept Lett. 2014; 21(10): 976-85.
Thaysen-Andersen, M., and Packer, N.H. Advances in LC-MS/MS-based glycoproteomics: getting closer to system-wide site-specific mapping of the N- and O-glycoproteome. Biochim Biophys Acta. 2014 Sep; 1844(9): 1437-52.
Muthana, S.M., Gildersleeve, J.C. Glycan microarrays: powerful tools for biomarker discovery. Cancer Biomark. 2014 Jan 1; 14(1): 29-41.
Campbell, M.P., Ranzinger, R., Lütteke, T., Mariethoz, J., Hayes, C.A., Zhang, J., Akune, Y., Aoki- Kinoshita, K.F., Damerell, D., Carta, G., York, W.S., Haslam, S.M., Narimatsu, H., Rudd, P.M., Karlsson, N.G., Packer, N.H., and Lisacek, F. Toolboxes for a standardised and systematic study of glycans. BMC Bioinformatics. 2014; 15 Suppl 1: S9.
Song, X., Heimburg-Molinaro, J., Cummings, R.D., Smith, D.F. Chemistry of natural glycan microarrays. Curr Opin Chem Biol. 2014 Feb; 18: 70-7.