Many of the pathogens that have properties that would be desirable to a would-be bioterrorist have been little-studied, in part because they cause a relatively limited toll in morbidity and mortality under natural circumstances. In other cases, such as for the North American hantaviruses, poor and medically underserved minority populations are disproportionately affected, making their toll even less visible. Two minority institutions in New Mexico, the University of New Mexico and New Mexico State University, have nevertheless devoted much attention to research on potential weapons of mass destruction (Sin Nombre virus or SNV, anthrax, tularemia, plague, etc) for years, with funding from at least four federal agencies. The hantavirus research portfolio at UNM, for example, has been funded at least $1 million direct/year essentially since its inception in 1994. The anthrax attacks of 2001 demonstrated the willingness and ability of terrorists to deploy bioweapons, which caused panic and severe economic damage. Countermeasures against WMD must be developed quickly to limit the damage exacted by future attacks. This application represents a concerted attack against SNV, a hantavirus that has killed over 100 Americans, including 26 New Mexicans, since its recognition in 1993. We have assembled an interdisciplinary team that pools its resources and skills in novel ways. We have developed interlocking, highly collaborative and cross-informing projects and cores involving project PIs who are genuine leaders in their fields, including several who have worked together productively in the past. The approaches that we have taken in this application will serve as a model that can be adapted successfully to a variety of pathogens other than hantaviruses. By pioneering new collaborative strategies using the SNV model, we will establish efficient, high-throughput methods that will work well against other agents. The core capabilities we describe herein will include high-throughput screening for antiviral effects of drugs, computer-assisted modeling that will be used to quickly refine and optimize lead compounds, and evaluation of the efficacy of drugs with sophisticated and quantitative animal model testing. The projects include (1) phage display to develop lead compounds that inhibit SNV entry into cells; (2) computational modeling of drugs; (3) development of RNA aptamer inhibitors of replication and/or packaging using SELEX; (4) development of potent human anti-SNV monoclonal antibodies; and (5) development of sophisticated mechanism-of-action assays to speed development of replicative inhibitors of SNV. Animal model, virology and structural analyses cores will each provide multiple projects with critical reagents or perform the molecular modeling services that are needed to improve lead compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI056618-01
Application #
6691949
Study Section
Special Emphasis Panel (ZAI1-ALR-M (M4))
Program Officer
Laughlin, Catherine A
Project Start
2003-09-15
Project End
2008-02-29
Budget Start
2003-09-15
Budget End
2004-02-29
Support Year
1
Fiscal Year
2003
Total Cost
$116,915
Indirect Cost
Name
University of New Mexico
Department
Pathology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Schountz, Tony; Acuña-Retamar, Mariana; Feinstein, Shira et al. (2012) Kinetics of immune responses in deer mice experimentally infected with Sin Nombre virus. J Virol 86:10015-27
Buranda, Tione; Wu, Yang; Perez, Dominique et al. (2010) Recognition of decay accelerating factor and alpha(v)beta(3) by inactivated hantaviruses: Toward the development of high-throughput screening flow cytometry assays. Anal Biochem 402:151-60
Torres-Perez, Fernando; Wilson, Linda; Collinge, Sharon K et al. (2010) Sin Nombre virus infection in field workers, Colorado, USA. Emerg Infect Dis 16:308-10
Prescott, Joseph; Hall, Pamela; Acuna-Retamar, Mariana et al. (2010) New World hantaviruses activate IFNlambda production in type I IFN-deficient vero E6 cells. PLoS One 5:e11159
Hall, Pamela R; Leitao, Andrei; Ye, Chunyan et al. (2010) Small molecule inhibitors of hantavirus infection. Bioorg Med Chem Lett 20:7085-91
Lordemann, Anja Grosse; Hjelle, Brian; Theegarten, Dirk et al. (2009) Young man with kidney failure and hemorrhagic interstitial nephritis. Am J Kidney Dis 54:1162-6
Medina, Rafael A; Torres-Perez, Fernando; Galeno, Hector et al. (2009) Ecology, genetic diversity, and phylogeographic structure of andes virus in humans and rodents in Chile. J Virol 83:2446-59
Hall, Pamela R; Hjelle, Brian; Njus, Hadya et al. (2009) Phage display selection of cyclic peptides that inhibit Andes virus infection. J Virol 83:8965-9
Bisoffi, M; Hjelle, B; Brown, D C et al. (2008) Detection of viral bioagents using a shear horizontal surface acoustic wave biosensor. Biosens Bioelectron 23:1397-403
Manigold, Tobias; Martinez, Jessica; Lazcano, Ximena et al. (2008) Case report: T-cell responses during clearance of Andes virus from blood cells 2 months after severe hantavirus cardiopulmonary syndrome. J Med Virol 80:1947-51

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