Determinates of anti-HIV nucleic acid aptamer potency and resistance

University Of Missouri-Columbia, Columbia MO

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Abstract

Principal Investigator/Program Director (Last, first, middle): Burke, Donald, H. RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? m Yes l No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes m No IACUC Approval Date: Animal Welfare Assurance Number 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 7830-Abstract_NIH07fRT-Aptamers.pdf Mime Type: application/pdf 7. * Project Narrative 1671-Narrative_NIH07fRT-Aptamers.pdfMime Type: application/pdf 8. Bibliography &References Cited 5133-LIT-CITED_NIH07fRT-Aptamers.pdMf ime Type: application/pdf 9. Facilities &Other Resources 4129-resources_NIH07fRT-Aptamers.pdfMime Type: application/pdf 10. Equipment 5363-equipment_NIH07fRT-Aptamers.pdMf ime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Burke, Donald, H. Abstract New therapeutic strategies are needed to circumvent the rapid selection of drug- resistant virus and the toxicity of current anti-HIV drugs. RNA aptamers targeted to the reverse transcriptase (RT) inhibit viral replication when expressed inside cells, and they offer great potential in future therapies against HIV/AIDS. There is little known about how the virus might evolve in the face of continual selection pressure, or about how the aptamers can be improved to circumvent potential resistance. The long-term goal of this project is to develop RNA aptamers as gene therapy agents that provide long-term anti- viral protection against a rapidly-evolving virus. Our emphasis is on defining the influence of RT amino acid sequence variations on inhibition by aptamers, and on identifying new aptamer sequences and structures with improved inhibition, both in vitro and in cells. Aim 1 will determine the biophysical and structural basis for aptamer recognition and for differential inhibition by aptamers across phylogenetically diverse lentiviral RT's. Aim 2 will identify new aptamers with broad recognition and improved potency, and delineate the secondary structures associated with cross-clade enzymatic inhibition. Aim 3 examines inhibition of pseudotyped and replication-competent HIV-1 by intracellularly expressed aptamers, moving from optimization of the design elements that control expression, localization and inhibition to high throughput screens of aptamer and RT libraries. Aim 4 evaluates the de novo evolution of aptamer resistance with emphasis on establishing genetic threshold, resistance loci, and the molecular basis of resistance. Project Description Page 6