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CONTROL OF PARAMYXOVIRUS RNA SYNTHESIS

Award Number: R01AI042023
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/1998
PERIOD OF PERFORMANCE END DATE: 11/30/2010

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CONTROL OF PARAMYXOVIRUS RNA SYNTHESIS - DESCRIPTION (provided by applicant): Our recent work has led to the overall hypothesis that following infection, paramyxoviruses delay abundant RNA synthesis to provide time for virus-mediated suppression of host anti-virus responses. This hypothesis emerged from our results with variants of the prototype paramyxovirus Simian Virus 5 (SV5) that have either accelerated or delayed kinetics of RNA synthesis. A remarkable result from this work was our finding that mutations in the P/V gene that accelerate viral RNA synthesis also convert SV5 from a noncytopathic virus into a virus that activates type I interferon (IFN) and kills cells by apoptosis. Thus, the overall goal of our work is to understand mechanisms that can accelerate or delay paramyxovirus RNA synthesis and how changes in the timing of viral gene expression affect key virus:host cell interactions. We have isolated a naturally-occurring SV5 variant (WF-CPIV) that shows a remarkable delay in viral gene expression compared to WT SV5. In Aim 1, we will determine the basis for the delay in WF-CPIV gene expression. Real-time PCR assays will be used to test the hypotheses that delayed WF-CPIV gene expression is due to a defect in either primary or secondary transcription. Recombinant SV5 viruses containing exchanges of polymerase-associate genes will identify WF-CPIV component(s) responsible for delayed gene expression. Aim 2 addresses our finding that an rSV5 with substitutions in the P/V gene expresses viral mRNA and proteins earlier and to higher levels than WT rSV5. Novel rSV5 viruses will be generated that express WT or mutant P and V proteins from separate transcription units. Biochemical and minigenome replication assays will be used to test the hypotheses that P/V substitutions either decrease the ability of V to inhibit SV5 genome replication or confer higher RNA synthesis activity on the P protein. In Aim 3, we will test the hypothesis that the cytopathic rSV5 variant containing P/V substitutions induces interferon (IFN) synthesis and apoptosis due to premature expression of viral gene products. Cell lines with inducible expression of WT and mutant P and V proteins, and new rSV5 P/V mutants will be used to test a two-step model for the role of accelerated and delayed SV5 RNA synthesis in the induction of IFN and apoptosis. We hypothesize that paramyxoviruses have evolved to optimize the timing of the onset of viral gene expression to avoid host antiviral responses, and changes that accelerate or significantly delay RNA synthesis can activate IFN and/or apoptotic pathways. Our work will increase our understanding of important virus-host cell interactions, as well as provide new approaches to improve the safety and potency of vaccine vectors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2008	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	10	9/7/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $233,588 )
2008	2008	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	10	11/26/2007	NON-COMPETING CONTINUATION	$233,588
														Subtotal = $233,588

Issue Date FY: 2007 ( Subtotal = $238,112 )
2007	2007	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	9	11/15/2006	NON-COMPETING CONTINUATION	$238,112
														Subtotal = $238,112

Issue Date FY: 2006 ( Subtotal = $245,224 )
2006	2006	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Allergy and Infectious Diseases Research	000	8	12/1/2005	NON-COMPETING CONTINUATION	$245,224
														Subtotal = $245,224

Issue Date FY: 2005 ( Subtotal = $251,125 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Microbiology and Infectious Diseases Research	000	7	11/25/2004	NON-COMPETING CONTINUATION	$251,125
														Subtotal = $251,125

Issue Date FY: 2004 ( Subtotal = $257,189 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Indicates awards funded from multiple programs	000	6	12/5/2003	COMPETING CONTINUATION	$257,189
														Subtotal = $257,189

Issue Date FY: 2002 ( Subtotal = $173,729 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Microbiology and Infectious Diseases Research	000	5	6/17/2002	NON-COMPETING CONTINUATION	$173,729
														Subtotal = $173,729

Issue Date FY: 2001 ( Subtotal = $168,671 )
2001	2001	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Microbiology and Infectious Diseases Research	000	4	6/22/2001	NON-COMPETING CONTINUATION	$168,671
														Subtotal = $168,671

Issue Date FY: 2000 ( Subtotal = $170,091 )
2000	2000	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Microbiology and Infectious Diseases Research	000	3	7/5/2000	NON-COMPETING CONTINUATION	$170,091
														Subtotal = $170,091

Issue Date FY: 1999 ( Subtotal = $166,772 )
1999	1999	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Microbiology and Infectious Diseases Research	000	2	6/25/1999	NON-COMPETING CONTINUATION	$166,772
														Subtotal = $166,772

Issue Date FY: 1998 ( Subtotal = $166,132 )
1998	1998	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Microbiology and Infectious Diseases Research	000	1	6/16/1998	NEW	$166,132
														Subtotal = $166,132

Grand Total All Awards = $2,070,633

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CONTROL OF PARAMYXOVIRUS RNA SYNTHESIS

Award Number: R01AI042023

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/1998

PERIOD OF PERFORMANCE END DATE: 11/30/2010

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