Projects and Grants
- Mechanisms of HIV cell-cell transmission
Recent studies have revealed that the efficiency of HIV dissemination is greatly facilitated by cell contact between infected and uninfected T cells. Infected T cells have been found to form adhesive contacts with uninfected CD4+ T cells. These contacts are called virological synapses (VS) because of some similarity to other adhesive structures in the immune system call immunological synapses. These structures require viral Env proteins to be expressed on the cell surface where they interact with CD4 on target cells. Using infectious fluorescent virus systems we are able to quantify and visualize the amount of viral transfer that occurs through VS. In vitro we find that these can be over 10,000-fold more efficient at transferring viral antigen from cell to cell. High resolution, real-time confocal microscopy allows us to directly visualize the changes in cellular distribution of viral protein that occur during VS formation. We find that the VS causes the massive transfer of viral particles into target T cells through an endocytic route that is still largely uncharacterized. The VS-mediated viral transfer can be resistant to patient antibodies that are capable of neutralizing homologous cell free virus. Our ongoing studies are directed at understanding the cellular mechanisms that regulate VS transfer. We are also working to understand how transfer may provide an important mechanism to evade humoral immune responses. The work will help us understand how this mode of efficient viral dissemination may allow HIV to spread efficiently in vivo.
- Examining the role of cell-cell transmission of HIV in vivo
HIV researchers have long sought a genetically tractable, economical alternative to the costly primate models for HIV infection. In a recent breakthrough in the field, investigators are using mice with humanized immune systems as in vivo models for HIV infection. These mouse systems transplant human hematopoietic stem cells into immunodeficient mice and support the development of diverse lineages of human immunocytes. Importantly, the human immune systems are highly susceptible to HIV and can support sustained HIV viral loads in animals that are challenged. In humanized mouse systems, we plan to study the T cell dynamics that allow HIV to spread within a living organism. To understand the dynamics of T cells in an organism we will investigate the trafficking, interactions and viral propagation of HIV infected T cells. Our aim is to understand how T cell migration and interactions contribute to HIV dissemination in vivo.
- Role of host factors in regulating HIV assembly and virological synapse function
We are interested in understanding how the viral Gag protein is targeted to specific membranes where viral assembly occurs as well as the endocytic process by which HIV is internalized by virological synapses. We are examining the role of active cytoskeletal remodeling in both the donor and target cells that may participate in these processes. Using molecular and biochemical approaches we plan to characterize the endocytic process that results in productive HIV infection.