Our research focuses on infection by Human Immunodeficiency Virus type 1 (HIV-1), a retrovirus and causative agent of acquired immunodeficiency syndrome (AIDS). In addition to suppressing the immune system, rendering victims susceptible to opportunistic infections, HIV-1 can cross the blood-brain barrier and cause serious damage to the central nervous system, ultimately leading to HIV-associated dementia.
We are interested in how HIV-1 particles move within infected cells, including brain cell types such as microglia. Our work focuses on how the virus exploits host microtubules, the intracellular filaments that mediate cargo trafficking to different subcellular sites within the cell.
Employing a variety of screening approaches, our lab identified a number of host proteins involved in cytoskeletal regulation and motor function as playing key roles in the early stages of HIV-1 infection. This includes Ezrin-Radixin-Moesin (ERM) proteins, which cross-link the actin and microtubule cytoskeletons. In exploring their role in HIV-1 infection, we identified the first biological function for the host protein, PDZD8, demonstrating that it binds ERMs to control microtubule stability. Furthermore, we uncovered that PDZD8 is a direct target for the HIV-1 protein, Gag.
Work in our laboratory has shown that HIV-1 can induce the formation of highly stable microtubule subsets to facilitate early HIV-1 trafficking to the nucleus. We are interested in:
- The role played in this process by proteins such as PDZD8, as well as a family of specialized microtubule regulatory proteins called +TIPs, which accumulate at the ends of dynamically growing microtubule filaments to control their growth and stability
- The function of microtubule motors and cargo adaptor proteins in HIV-1 infection. In particular, we are exploring how Fasiculation and Elongation factor Zeta-1 (FEZ-1), a kinesin-1 adaptor protein that is highly expressed in neurons, functions to control HIV-1 infection
Our work employs a range of approaches, including biochemical characterization of protein-protein interactions as well as live imaging of fluorescently-labeled HIV-1 particles as they move within infected cells.
We look to understand the molecular basis behind how microtubules, regulators of microtubule dynamics and microtubule motor proteins function to enable HIV-1 movement to and from the nucleus.