The parent grant Role of Dendritic Cells in HIV Pathogenesis addresses two important areas. (1) What cellular pathways contribution to viral replication particularly in the early subclinical stages of diseases, what cells are infected at mucosal surface, how is virus transmitted to T-cells, and why does viral replication precede chronically at substantial levels even in asymptomatic individuals. (2) What are the mechanisms whereby CD4+ T cells are lost, particularly T cells that mediate immunologic memory. Why is the loss of CD4 T cells like viral replication apparently a chronic process such that HIV-1 infected individuals may lose greater than 1 billion T cells each day? The overall hypothesis is that dendritic cells play an important role in both areas of pathogenesis because of the capacity of dendritic cells to express CD4 and to interact with CD4+ memory T cells in mucosal sites. The principal investigator has found, using skin leukocytes as a model for the cells in keratinized mucosal surfaces through HIV-1 is transmitted, that mixtures of dendritic cells and T cells lead to extensive HIV-1 replication and T cell death, and the apparent absence of exogenous mitogous stimuli. They have visualized production infection of dendritic cells, including syncytia derived from dendritic cells in the tonsil and adenoid mucosia of 13 of 13 specimens from HIV-1 infected individuals, most of them asymptomatic. They propose that these organs are lymphoepithelia in which dendritic cells and T cells can chronically interact in an analogous fashion to their skin culture results. In this Fogarty application, a collaboration with Paul Race and Klara Tenner Race in Hamburg will extend the study of mucosal dendritic cells to the SIV macaque model and to other lymphepithelia in HIV-1 infected individuals. The Race s have access to SIV infected macaques as well as an array of incentive morphoragicalic approaches for SIV-1 and HIV-1. By providing expertise in mucosal leukocyte isolate and dendritic cell isolation, the principal investigator will be able to work with the Race s to carry out a unique set of experiments that will extend area #1 above.
| Breton, Gaëlle; Yassine-Diab, Bader; Cohn, Lillian et al. (2009) siRNA knockdown of PD-L1 and PD-L2 in monocyte-derived dendritic cells only modestly improves proliferative responses to Gag by CD8(+) T cells from HIV-1-infected individuals. J Clin Immunol 29:637-45 |
