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.
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