Benjamin K Chen, MD, PhD

Current Students: MD/PhD: Chati Zony, Graduate: Natasha Durham, Kenneth Law, Hongru Li

Postdoctoral Fellows: Ray Alvarez, Anthony Esposito, Lili Wang

Research Faculty: Ping Chen, Talia Swartz                    

Summary of Research Studies:

Mechanisms of HIV cell-cell transmission

The efficiency of HIV spread in culture is greatly facilitated by cell contact between infected and uninfected CD4+ T cells. Infected T cells form adhesive contacts with uninfected CD4+ T cells. These contacts are called virological synapses (VS) because of similarity to other adhesive structures in the immune system call immunological synapses. VS require viral Env proteins to be expressed on the cell surface where they interact with CD4 on target cells.  Using infectious, fluorescent virus clones we are able to quantify and visualize the amount of viral transfer that occurs through VS.  Live, video rate confocal microscopy allowed us to visualize the changes in cellular distribution of the viral protein Gag that occurs during VS formation. We found that the VS causes the efficient transfer of viral particles into target T cells through an endocytic route that is still being characterized.  We are working to understand the viral signals that allow virus assembly to be recruited to the VS and the cellular signaling pathways the work in both the VS donor and target cells.

Neutralization Resistance of VS

The VS-mediated viral infection can be resistant to patient antibodies that are capable of neutralizing homologous cell free virus. We are working to understand how the VS provides a mechanism for HIV to evade humoral immune responses.  We found that the cytoplasmic tail of the Env glycoprotein, which is plays an important role in regulating fusion activity of Env, plays a role in the resistance of cell-cell infection to neutralization.  We are testing a model whereby the conformational regulation of Env during VS formation is what makes cell-cell transmission more resistant to neutralization.  We are studying patient neutralizing responses, and cloning B cells from patients to characterize potent cell-cell neutralizing activities.

Role of cell-cell transmission in vivo

We have been studying humanized mouse models to better understand how this mode of efficient viral dissemination contributes to viral spread in vivo. To overcome the inability of HIV to replicate in mouse cells, researchers have exploited mouse xenograft models that engraft human immune systems into immunocompromised mice. These mouse systems transplant human hematopoietic stem cells into immunodeficient mice and allow diverse lineages of human immune cells to develop.  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 are using whole animal imaging and intravital microscopy to understand how T cell migration and synapse formation contribute to HIV spread within a living organism.

For more information, please visit the Benjamin K. Chen Laboratory.