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MODULATION OF DENDRITIC CELLS AGAINST HIV-1

Award Number: SC3GM084802
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2012

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MODULATION OF DENDRITIC CELLS AGAINST HIV-1 - DESCRIPTION (provided by applicant): Currently, a vaccine for HIV/AIDS is not available. The antiretroviral therapies (ART) fail to eradicate HIV from infected individuals because of the existence of viral reservoirs and development of ART-resistant strains. Dendritic cells (DCs) are implicated in the development and spread of HIV reservoirs. Available data suggest that HIV particles are captured by DC-SIGN and routed in endosomes with milder pHs to evade lysosomal degradation. Internalized particles are subsequently transmitted to T-cells in trans. A few labs have reported using siRNA against DC-SIGN to diminish HIV infection in DCs. But the intracellular molecules participating in trafficking of HIV within DCs are not clear. Tetraspanins such as CD9, CD63 and CD81 colocalize with HIV-1 particles in endosomes, but their exact role in this milieu has not been fully elucidated. Therefore, the goals of this project are to modulate DCs by priming with an HIV-DNA vaccine and evaluate roles of DC-SIGN, CD63, CD81, and CD9 in intracellular trafficking within DCs. The central hypothesis is that, since DC-SIGN, CD63, CD81 and CD9 participate during capture, internalization and transmission of HIV to susceptible T cells, RNAi interference of these molecules will help to elucidate their roles. The central hypothesis will be tested by three specific aims. Aim 1 will evaluate modulation of DCs with HIV-DNA vaccine priming on capture and destruction of virus. Aim 2 will evaluate RNAi interference of DC-SIGN on transmission of HIV virions to T-cells. Aim 3 will evaluate the roles of CD9, CD63 and CD81 in internal trafficking of HIV within DCs. The approach is to prime DCs by HIV DNA transfection, and knock down expressions of DC-SIGN, CD9, CD63 and CD81 by RNAi interference to elucidate their exact roles in, internalization, intracellular localization and trans infection of T-cells. We will employ immunofluorescent confocal microscopy, electron microscopy, gp120 Env ELISA, Western blot, RT PCR and coculture assays to obtain our results. We expect that HIV- DNA priming will activate DCs to capture and process HIV via antigen processing and presentation pathways. It is also expected that RNAi silencing of tetraspanins will divert HIV to lysosomal degradation. We anticipate that this strategy will prevent creation and transmission of HIV reservoirs. These outcomes could have a profound and significant impact on understanding the pathogenesis and spread of HIV.


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: 2011 ( Subtotal = $93,358 )
2011	2011	WINSTON SALEM STATE UNIVERSITY	601 MARTIN LUTHER KING JR DR	WINSTON-SALEM	NC	27110		USA	Biomedical Research and Research Training	002	6	5/25/2011	NON-COMPETING CONTINUATION	$98,129
2011	2010	WINSTON SALEM STATE UNIVERSITY	601 MARTIN LUTHER KING JR DR	WINSTON-SALEM	NC	27110		USA	Biomedical Research and Research Training	001	5	1/21/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$61,106
2011	2010	NORFOLK STATE UNIVERSITY	2401 CORPREW AVE	NORFOLK	VA	23504	NORFOLK CITY	USA	Biomedical Research and Research Training	000	4	1/20/2011	NON-COMPETING CONTINUATION	-$65,877
														Subtotal = $93,358

Issue Date FY: 2010 ( Subtotal = $102,876 )
2010	2010	NORFOLK STATE UNIVERSITY	2401 CORPREW AVE	NORFOLK	VA	23504	NORFOLK CITY	USA	Biomedical Research and Research Training	002	4	7/6/2010	NON-COMPETING CONTINUATION	$102,750
2010	2009	WINSTON SALEM STATE UNIVERSITY	601 MARTIN LUTHER KING JR DR	WINSTON-SALEM	NC	27110		USA	Biomedical Research and Research Training	000	2	2/19/2010	NON-COMPETING CONTINUATION	-$102,624
2010	2009	NORFOLK STATE UNIVERSITY	2401 CORPREW AVE	NORFOLK	VA	23504	NORFOLK CITY	USA	Biomedical Research and Research Training	001	3	3/9/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$102,750
														Subtotal = $102,876

Issue Date FY: 2009 ( Subtotal = $102,625 )
2009	2009	WINSTON SALEM STATE UNIVERSITY	601 MARTIN LUTHER KING JR DR	WINSTON-SALEM	NC	27110		USA	Biomedical Research and Research Training	000	2	5/19/2009	NON-COMPETING CONTINUATION	$102,625
														Subtotal = $102,625

Issue Date FY: 2008 ( Subtotal = $101,820 )
2008	2008	WINSTON SALEM STATE UNIVERSITY	601 MARTIN LUTHER KING JR DR	WINSTON-SALEM	NC	27110		USA	Biomedical Research and Research Training	000	1	8/1/2008	NEW	$101,820
														Subtotal = $101,820

Grand Total All Awards = $400,679

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MODULATION OF DENDRITIC CELLS AGAINST HIV-1

Award Number: SC3GM084802

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2012

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