The central hypothesis to be tested i this application is that differences in the function of antigen-presenting cells, notably dendritic cells (DC's), may be age-dependent. Little direct evidence exists for this in the prior literature, however in recent years DC function has been recognized as being closely related to functional maturation state which, in turn, is regulated by an interplay between various cytokines. The cytokine milieu of the neonate may differ from that of the more mature infant and the fully developed individual, particularly in response to repeate exposure to exogenous agents, and this change in cytokine milieu may impact on DC differentiation and maturation. Because DC's represent a potential first target for mucosal transmission of HIV-1 and have been shown to be a potent reservoir for viral infection in adults, the Investigator postulates that the age-dependent differences in DC function may account for the more aggressive course of HIV-1 infection in vertically-infected infants compared to adults.
The aims of the application are to determine chemokine receptor expression on DC's at well-defined stages of differentiation and test co-receptor usage by different HIV-1 strains for entry into neonatal or adult DC's, to compare neonatal DC function at well defined stages of maturation to that of adult cells, and to determine the influence of infectious HIV-1 or isolated virus gene products on the function of neonatal and adult DC's. The overall approach is designed to shed light on the basic biology of how DC generate immune responses in neonates to viral infections generally, and to dissemination of HIV-1 in particular.
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| Popov, Sergei; Chenine, Agnes-Laurence; Gruber, Andreas et al. (2005) Long-term productive human immunodeficiency virus infection of CD1a-sorted myeloid dendritic cells. J Virol 79:602-8 |
| Gruber, Andreas; Chalmers, Alistair S; Popov, Sergei et al. (2002) Functional aspects of binding of monoclonal antibody DCN46 to DC-SIGN on dendritic cells. Immunol Lett 84:103-8 |
