HIV infection is characterized by immune activation long before advanced loss of CD4+ T cells occurs. While the underlying pathophysiology is unclear, many clinical studies have observed, among other defects, elevated levels of inflammatory cytokines and chronic T cell activation. Despite studies showing that HIV protein binding to or ligation of CD4 on T cells results in cell signaling defects and unresponsiveness, the direct infection of CD4+ T cells by HIV is unlikely to explain generalized immune dysfunction. It will be important to determine the effects of HIV on other immune cells. Our understanding of the interaction of HIV and antigen presenting cells (APCs) in vivo remains incomplete, related to the difficulties of performing these studies in humans: the APCs may be rarely found in peripheral blood, APCs are infected by HIV at a low rate, and some APCs, such as monocyte-derived dendritic cells and macrophages, traditionally require in vitro differentiation before study. We have recently employed phospho-specific monoclonal antibodies in conjunction with multiparameter (up to 11-color) flow cytometry to study cell signaling pathways in response to stereotyped stimuli within highly characterized cell populations. It is our central hypothesis that HIV perturbs cell signaling pathways in APCs, leading to deregulated cytokine secretion and immune activation. This hypothesis will be tested by pursuing the following specific aims: 1) to evaluate the effect of HIV infection in vitro on signaling networks within antigen presenting cells (APCs), 2) to identify alterations in APC signaling within HIV-infected individuals, and 3) to determine if detected alterations in signaling correlate with elevated inflammatory cytokine levels. The proposed work is an innovative, translational approach to a clinically important question, to be performed in a dynamic research setting with extensive intellectual and technical support. Thus, the candidate will acquire the experience and skills required to become a faculty-level physician-scientist.
| Lee, Andrew W; Sharp, Elizabeth R; O'Mahony, Alison et al. (2008) Single-cell, phosphoepitope-specific analysis demonstrates cell type- and pathway-specific dysregulation of Jak/STAT and MAPK signaling associated with in vivo human immunodeficiency virus type 1 infection. J Virol 82:3702-12 |
