Research
Regulation of innate immune responses
The complex transcriptional circuitry that regulates innate immune responses is difficult to understand using traditional approaches. To unravel this complexity, we have collaborated with several groups around the world (including the laboratories of Michael Menager, Institut Imagine; Nicolas Manel, Institut Curie; Dan Littman, NYU; Richard Bonneau, Simons Foundation; and Alan Aderem, Seattle Children’s), and together, we profiled genome-wide epigenetic and transcriptional responses in monocyte-derived dendritic cells infected with HIV-1 (Johnson et al., Cell Reports 2020). We inferred a gene regulatory network that maps thousands of possible connections between transcription factors and their gene targets. We are now exploring this network to understand new modes of innate immune control during virus infection.
Unmasking interferon responses
The interferon system is one of our most potent antiviral defense mechanisms. However, viruses like HIV-1 have evolved many strategies to hide from the immune system! Antiviral responses in the host are often too late and too dysregulated to be fully protective. In many cases, innate immune cell activation and robust interferon responses are not engaged until HIV-1 integrates into the host genome (see Figure). So it is critical that we determine how HIV-1 avoids being “sensed” during entry and identify parameters that lead to robust antiviral immune responses. Reverse transcription products can be sensed through the cGAS-STING prior to integration, but this happens at low efficiency and does not trigger a strong interferon response (Johnson et al., Cell Host Microbe 2018). We’re now determining the mechanisms that control these responses and testing ways to “boost” interferon activation at early stages of virus infection.
Host-virus interactions
Cells are crowded places. It can be challenging to study host-virus interactions deep within the confines of a cell during infection, especially when looking for rare events. When possible, we seek to reconstitute infectious processes and host-virus interactions in purified, cell-free systems. We recently collaborated with the laboratories of Wes Sundquist, Barbie Ganser-Pornillos, and Owen Pornillos (University of Utah, Department of Biochemistry) to reconstitute the processes of reverse transcription and integration in vitro (Christensen et al., Science 2020). We are now extending this system to study additional host-virus interactions that impact virus infection. Although we incorporate functional genomics and high-throughput approaches into our work, our goal is to gain mechanistic insight into how cellular components regulate infection and detection of HIV-1.
