Human host cell responses to viral pathogens are complex processes of immense importance to society. These processes also play a crucial role in viral vector-based gene therapy. My research interest is to use quantitative, systems-oriented approaches to understand how viruses alter the host cell signaling networks that control cell function. Here I describe investigations of two key problems in viral pathogenesis: induction of cell death by adenoviral vectors and the establishment of latency in HIV infection.

Recombinant adenoviruses are used extensively as delivery vectors in clinical gene therapy and in molecular biology, but little is known about how the viral carrier itself contributes to cellular responses. I previously demonstrated that adenoviral vectors (Adv), by “rewiring” intracellular signaling networks, alter human epithelial cell death responses to the inflammatory cytokine tumor necrosis factor alpha (TNF-α). Based on multivariate experimental measurements of kinase signaling pathways, we constructed a partial least squares regression model that describes how Adv alters TNF-induced apoptosis and cytokine secretion as a function of kinase signaling activity data. Importantly, the same functional model predicts Adv-TNF-induced phenotypic behavior in multiple epithelial cell types, given each cell types' unique set of signaling inputs. We demonstrate that cell-specific signal activation is a mechanism for achieving different phenotypes from the same initial stimulus. This property, which we call common effector processing, offers an important general biological principle for understanding and predicting cell-specific responses to non-viral treatments, such as rational drug therapies.

In addition to perturbing the upstream signaling pathways that regulate apoptosis, viruses hijack host cell transcriptional machinery to control viral replication and–in some cases–establish latent infections. In the case of the lentivirus HIV, viral replication causes host cell death, but latent infections can persist for decades and represent the most significant obstacle to eliminating HIV from a patient. I am currently studying how the availability of transcription factors within the host cell contributes to the replication-versus-latency decision. We have previously shown that, for some integration positions, HIV promoter activity can result in a bifurcating expression pattern in an infected clonal population, where some cells have high promoter activity while others have low activity. We are now exploring how the host transcription factor NF-κB and the viral transactivator of transcription Tat affect expression from the HIV promoter at fixed integration positions. Using both computational modeling and experimental measurements, we show that clonal populations will transition between specific expression profiles if the concentration of either of these factors is systematically varied. By quantitatively understanding how transcription factors affect the HIV fate decision, we hope to improve therapeutic strategies to counteract viral latency.