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Structure and Assembly of Viruses

Award Number: R01CA013202
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/1975
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Structure and Assembly of Viruses - Summary The structure of a virus particle must conform to the mechanism by which it enters and infects a cell. We seek to relate structures of virus particles and viral surface proteins to mechanisms of the steps in cell attachment, uptake and penetration that initiate a productive infection. The proposed experiments take advantage of recent advances in electron cryomicroscopy (cryo-EM) and live-cell imaging to define these mechanisms for both non- enveloped and enveloped viruses, taking rotaviruses and flaviviruses (West Nile and dengue viruses, in particular) as specific examples. Previous live-cell imaging studies defined the cellular entry pathway for rhesus rotavirus (RRV). We can now relate structures we have determined for distinct conformations of the spike-like viral protein 4 (VP4), which mediates cell entry, to stages of plasma-membrane remodeling in the entry pathway. We will extend on-going analyses by cryo-EM of VP4 conformations at the membrane interface, both on cells and in an in vitro-reconstituted system for early steps, to determine how RRV deforms and then disrupts a membrane bilayer. A mechanism for RRV membrane perforation, suggested by preliminary data, may help unify observations made with several other RNA viruses. Proposed experiments will connect high- resolution structures with direct analyses (by electron cryotomography and potentially by high-resolution template matching) of VP4 conformations during cell entry and with sequences of events in time (by lattice- light-sheet microscopy). For the flavivirus fusion protein (the "E protein"), completing a structure for the postfusion conformation of the intact protein will enable design of experiments to trap fusion intermediates and thus to define the fusion mechanism more completely than hitherto possible. The intended outcomes of the studies, for both rotaviruses and flaviviruses, are structurally and mechanistically accurate "molecular movies" of viral entry.


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: 2024 ( Subtotal = $399,356 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	51	11/14/2023	NON-COMPETING CONTINUATION	$378,338
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	51	4/17/2024	NON-COMPETING CONTINUATION	$21,018
														Subtotal = $399,356

Issue Date FY: 2023 ( Subtotal = $420,375 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	50	3/15/2023	NON-COMPETING CONTINUATION	$42,037
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	50	11/29/2022	NON-COMPETING CONTINUATION	$378,338
														Subtotal = $420,375

Issue Date FY: 2022 ( Subtotal = $411,968 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	49	11/24/2021	NON-COMPETING CONTINUATION	$378,337
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	49	4/26/2022	NON-COMPETING CONTINUATION	$33,631
														Subtotal = $411,968

Issue Date FY: 2021 ( Subtotal = $420,375 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	48	11/18/2020	NON-COMPETING CONTINUATION	$399,356
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	48	1/21/2021	NON-COMPETING CONTINUATION	$21,019
														Subtotal = $420,375

Issue Date FY: 2020 ( Subtotal = $420,375 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	47	12/2/2019	COMPETING CONTINUATION	$420,375
														Subtotal = $420,375

Issue Date FY: 2019 ( Subtotal = -$2,285 )
2019	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	46	6/19/2019	NON-COMPETING CONTINUATION	-$2,285
														Subtotal = -$2,285

Issue Date FY: 2017 ( Subtotal = $384,600 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	46	3/13/2017	NON-COMPETING CONTINUATION	$346,139
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	46	6/7/2017	NON-COMPETING CONTINUATION	$38,461
														Subtotal = $384,600

Issue Date FY: 2016 ( Subtotal = $384,600 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	45	3/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$384,600
														Subtotal = $384,600

Issue Date FY: 2015 ( Subtotal = $383,513 )
2015	2015	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	44	2/25/2015	NON-COMPETING CONTINUATION	$383,513
														Subtotal = $383,513

Issue Date FY: 2014 ( Subtotal = $369,899 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	43	4/1/2014	NON-COMPETING CONTINUATION	$369,899
														Subtotal = $369,899

Issue Date FY: 2013 ( Subtotal = $380,254 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	42	9/12/2013	COMPETING CONTINUATION	-$380,254
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	42	6/28/2013	COMPETING CONTINUATION	$198,691
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	003	42	9/13/2013	COMPETING CONTINUATION	$380,254
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	42	3/27/2013	COMPETING CONTINUATION	$181,563
														Subtotal = $380,254

Issue Date FY: 2002 ( Subtotal = $330,478 )
2002	2002	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	31	4/25/2002	NON-COMPETING CONTINUATION	$330,478
														Subtotal = $330,478

Issue Date FY: 2001 ( Subtotal = $320,853 )
2001	2001	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	30	4/26/2001	NON-COMPETING CONTINUATION	$320,853
														Subtotal = $320,853

Issue Date FY: 2000 ( Subtotal = $223,653 )
2000	2000	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	29	4/26/2000	NON-COMPETING CONTINUATION	$223,653
														Subtotal = $223,653

Issue Date FY: 1999 ( Subtotal = $209,385 )
1999	1999	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	28	4/21/1999	NON-COMPETING CONTINUATION	$209,385
														Subtotal = $209,385

Issue Date FY: 1998 ( Subtotal = $203,286 )
1998	1998	HARVARD UNIVERSITY PRESIDENT & FELLOWS	HOLYOKE 466, 1350 MASS AVENUE	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	27	6/19/1998	COMPETING CONTINUATION	$203,286
														Subtotal = $203,286

Grand Total All Awards = $5,260,685

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Structure and Assembly of Viruses

Award Number: R01CA013202

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/1975

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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