Dendritic cells (DCs) comprise a multivariate family of cell types whose principal function is in the primary initiation of immune responses. Blood dendritic cells patrol areas of the body that are susceptible to invasion by pathogens and engulf antigens for later processing and presentation to T lymphocytes. HIV has apparently appropriated this feature of the immune system to better establish and maintain infection of its primary target--CD4 positive T cells. DCs can efficiently bind and transfer HIV infection without themselves becoming infected and can in fact greatly enhance the infection of target cells. DCs are therefore potentially important both in primary infection and in the persistence of viral reservoirs in infected individuals, making them an attractive target for new therapies aimed at prevention and treatment of HIV infection. My lab tracks the movement of HIV within and between living DCs and T-cells by tagging virions with the green fluorescent protein (GFP). We have previously reported that DCs effect enhancement of HIV infection by concentrating the virus to sites of intimate contact with CD4 T cells at the same time that the HIV receptors (CD4 and CXCR4/CCR5) are concentrated on the surface of the T cell. Because this structure bears similarities to the antigen signaling structure known as the immunological synapse, we refer to it as the infectious synapse. The experiments proposed here will explore the dynamics of formation the infectious synapse in living cells and examine the molecular events responsible for its formation. In addition, the molecular machinery responsible for HIV trafficking within DCs and delivery to target T cells will be evaluated by specific inhibition of individual effectors. Understanding the mechanisms of cell-to-cell transmission of HIV is crucial to understanding how the virus persists in the face of the human immune response. Undermining the very cells that should protect the body from infection is yet another example of how a relatively simple virus can outsmart the human immune system. The knowledge gained from this study will be useful in devising new strategies for the prevention and treatment of HIV infections. 7. Project Narrative Dendritic cells (DCs) are essential players in immune defense that patrol the gut and other tissues, picking up bacteria and viruses and destroying them in order to help T cells recognize the foreign invaders. When a dendritic cell picks up HIV, however, some of the virus survives inside the DC and is efficiently passed on to the T cell, causing the infections that eventually leads to AIDS. This project aims to identify the way that HIV avoids degradation and is passed into the T cell by direct observation of HIV particles in living cells using high resolution microscopy. We will identify the key players in the routing of the virus inside the DCs with the goal of devising new treatment strategies to prevent DC mediated infections. ? ? ?
| Reuter, Morgan A; Pecora, Nicole D; Harding, Clifford V et al. (2010) Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells. J Virol 84:8549-60 |
| Yu, Hyun Jae; Reuter, Morgan A; McDonald, David (2008) HIV traffics through a specialized, surface-accessible intracellular compartment during trans-infection of T cells by mature dendritic cells. PLoS Pathog 4:e1000134 |
