Research in our lab combines our curiosity about the biological processes that viruses exploit to infect a host cell and about the fundamental workings of proteins and nucleic acids as building blocks of life. We emphasize interdisciplinary approaches, and integrate structural biology (NMR, X-ray crystallography, cryoEM, cryoET), biophysics, biochemistry, and molecular virology techniques in our projects. We strive to maintain a lab culture founded on openness and inclusivity, wherein members are mutually accountable to each other, are invested in each other’s success, and freely share and respect each other’s knowledge and expertise.

Currently active projects in the lab focus on HIV and retroviruses, briefly summarized below:

We have previously defined the structures of the immature and mature capsids of HIV-1 in order to delineate the boundary conditions of a process called virion maturation, which is an essential stage of HIV-1 replication. In the past few years, we have built on this knowledge by assembling virus-like particles in the test tube, starting from purified protein and nucleic acid reagents. Such biochemical reconstitutions provide us with novel experimental platforms for hypothesis-testing and discovery, and serve as abundant sources of samples for structural analyses using cryo-EM and cryotomography. For example, our recent studies with these systems have led to atomic-level understanding of two molecular switches, which control multiple aspects of the virus replication process – from assembly and proteolytic maturation of the immature virion, to subsequent re-assembly of the mature viral capsid, through targeting of the virus to the host cell nucleus. Molecular switches are a fascinating case of functional regulation through protein conformational change, and are proven targets of inhibitors that can be developed as anti-viral drugs.

Another set of projects have the goal of understanding the so-called cell-intrinsic (or innate) anti-viral response mechanisms, which have evolved as the first line of defense against invading pathogens such as HIV. One of these defense mechanisms is an anti-viral protein called TRIM5, which forms a cage that surrounds incoming HIV-1 capsids. The TRIM5 cage not only disables the capacity of the virus to replicate, but also signals the presence of an invader. We are still trying to figure out exactly how the cage accomplishes these two outcomes. From these naturally-evolved defense systems, we can learn about previously unrecognized viral vulnerabilities and develop new ways to fight viruses.

We are always open to new questions and ways to answer these questions. Currently, we are reconstituting the process of HIV nuclear import from purified viral capsids and cell nuclei, learning how to apply fluorescence microscopy and new approaches of virus imaging in our studies, and figuring out novel delivery systems based on what we have learned from HIV.