Lymphocytes bearing high levels of FasL are known to suppress cell-mediated immunity and destroy the efficacy of DNA vaccines. Their ability to kill the antigen-presenting cells can be eliminated by several different mechanisms and we are exploring a number of these mechanisms to find one optimal for promoting cell- mediated responses to SIVGag vaccination. It is our hypothesis that treatment with small molecules that block Fas/FasL signaling could prevent the destruction of antigen-presenting-cells (APC), and allow the development of vigorous anti-retroviral immunity. High levels of CD4+FasL+ cells during AIDS also reduce immunity against opportunistic infections and neoplastic events. Therefore, treatments to block signals delivered by these cells could boost resistance to opportunistic infections and to AIDS-associated cancers. The experimental plan is to develop novel small-molecule inhibitors of Fas/FasL signaling to prevent APC lysis after vaccination. We identified three different strategies for Fas/FasL inhibition which will be compared in mouse immunization studies to identify the strategy, or combination of strategies, most suitable for promoting cell-mediated immunity to a common SIV vaccine antigen, p27Gag. Among our approaches we are investigating the use of pre-ligand assembly domains (PLAD) that are critical for function in TNF receptor superfamily proteins. PLAD represent a novel class of TNF and Fas receptor inhibitors with important advantages for use during DNA vaccination and prime-boost strategies. We propose structural biology studies to address key questions about PLAD structural/functional elements critical for inhibiting Fas/FasL. Our studies will compare inhibitors of FasL signaling that should have short-term effects and highly-specific targets, yet should not interfere with the development of strong functional responses to vaccine antigens

Public Health Relevance

People with AIDS carry a subset of white blood cells that destroy their ability to fight opportunistic infections and to prevent cancer. Attempts to fix this problem with long-lasting solutions would endanger the normal balance of blood cells. Our studies propose to test inhibitors of cell-death signals that would have short-term effects and highly-specific targets, yet would not interfere with the development of strong responses against cancers or infections.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
1RC2CA149001-01
Application #
7853033
Study Section
Special Emphasis Panel (ZCA1-GRB-I (O9))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2009-09-29
Project End
2011-08-31
Budget Start
2009-09-29
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$492,788
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Zapata, Juan C; Cox, Dermot; Salvato, Maria S (2014) The role of platelets in the pathogenesis of viral hemorrhagic fevers. PLoS Negl Trop Dis 8:e2858
GarcĂ­a, C C; Topisirovic, I; Djavani, M et al. (2010) An antiviral disulfide compound blocks interaction between arenavirus Z protein and cellular promyelocytic leukemia protein. Biochem Biophys Res Commun 393:625-30