Deficient production of interferon-a (IFN-a) by natural IFN-producing cells (NIPC) is observed in patients with advanced HIV-1 infection. This deficient IFN-a production was found to be associated with, and predictive of, susceptibility to opportunistic infections. Although long-suspected to be a dendritic cell, progress was somewhat hampered by the lack of a definitive phenotype for the NIPC. NIPC have now been demonstrated to be identical to the plasmacytoid dendritic cell (PDC). PDC's are believed to be important not only as professional IPC but also as vital links between innate and adaptive immunity. Deficient IFN-a production in HIV infection results from both decreases in numbers of circulating PDC as well as dysfunction in those cells present. This current study is organized in five specific aims; the first three involve studies of the basic biology of the PDC and the last two apply what has been learned about the function of PDC's to understand how they become deficient in HIV infected patients. Peripheral blood PDC's express very high constitutive levels of the transcription factor, IRF-7. These observations will be extended to evaluate the expression and function of the IRF-7 in PDC's in different anatomical sites and determine the roles of IRF-7 vs. IRF-3 and IRF- 5 in these cells. Cross-linking of receptors on the surface of PDC leads to down-regulation of their ability to produce IFN-a, a phenomenon that may also have physiological relevance in the HIV-infected patients. Studies are proposed to understand the mechanisms of this down-regulation and determine whether other functions carried out by PDC such as production of TNF-a and chemokines is similarly affected by the receptor crosslinking. Production of IFN-a by PDC's does not require infection of the cells with virus; rather uptake of material by endocytosis appears to trigger the generation of IFN-a. Using fluorescent labeled infected cells or virus and confocal microscopy, the fate of the endocytosed material in vivo will be determined. In studies to better understand the mechanisms of deficiency in PDC in HIV-infected patients, studies will be undertaken to determine whether PDC's are infected with HIV in vivo and whether they traffick from the blood to sites in the tissues. Finally studies are proposed to evaluate other functions of the PDC in HIV-1 infected patients including cytokine and chemokine production and activation of T cells as well evaluation of the IRF-7 function in these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI026806-12
Application #
7151193
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Finzi, Diana
Project Start
1991-06-15
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
12
Fiscal Year
2007
Total Cost
$368,605
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pathology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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Maldonado, Samuel; Fitzgerald-Bocarsly, Patricia (2017) Antifungal Activity of Plasmacytoid Dendritic Cells and the Impact of Chronic HIV Infection. Front Immunol 8:1705
Li, You; Dai, Jihong; Song, Mangen et al. (2012) Dcp2 decapping protein modulates mRNA stability of the critical interferon regulatory factor (IRF) IRF-7. Mol Cell Biol 32:1164-72
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Fitzgerald-Bocarsly, Patricia (2011) Gutward, ho! pDCs in SIV infection. Blood 118:2643-4
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Fitzgerald-Bocarsly, Patricia; Jacobs, Evan S (2010) Plasmacytoid dendritic cells in HIV infection: striking a delicate balance. J Leukoc Biol 87:609-20
Jyonouchi, Harumi; Cui, Chongwei; Geng, Lee et al. (2010) Age-dependent changes in peripheral blood dendritic cell subsets in normal children and children with specific polysaccharide antibody deficiency (SPAD). Eur J Pediatr 169:1233-9
Fitzgerald-Bocarsly, Patricia; Dai, Jihong; Singh, Sukhwinder (2008) Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. Cytokine Growth Factor Rev 19:3-19
Fitzgerald-Bocarsly, P; Feng, D (2007) The role of type I interferon production by dendritic cells in host defense. Biochimie 89:843-55

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