Hematopoiesis is highly regulated by complex interactions between numerous intracellular pathways that control the fundamental processes of self-renewal, quiescence, proliferation, differentiation, and apoptosis. Many viruses, including HCMV, KSHV, and HTLV-1 have evolved to manipulate hematopoiesis and specifically drive differentiation towards a virus-favorable outcome. Uniquely, however, each of these viruses manipulates different cellular pathways that drive HPC differentiation to specific lineages, i.e. HTLV-1 promotes T-cell differentiation, KSHV promotes endothelial cell differentiation, and HCMV promotes myeloid differentiation, all through multiple mechanisms.
HCMV infection of HPCs provides a reservoir for infected cells and results in dramatically altered patterns of hematopoiesis. While recent research has begun to describe some viral gene products involved in latency and reactivation, much remains to be understood about how these, and other viral genes, cooperate and manipulate the host cell system. Using novel and tractable model systems of viral latency and reactivation, and human hematopoiesis, our lab will elucidate the role of HCMV in controlling hematopoietic cell fate. Determining how HCMV exploits cellular traits to establish latency, maintain a viral reservoir, and manipulate hematopoiesis will help develop novel targeted treatments, a more detailed understanding of hematopoietic mechanisms, and an improved understanding of immune cell fate during viral infection. We will explore a variety of projects to understand viral manipulation of the hematopoietic system via dual control of cellular hematopoiesis and viral latency.
1. How do the HCMV RL11 genes contribute to latency & reactivation?
2. What is the link between HPC subsets and cellular regulation with viral latency?
3. How does an infrequent HCMV infection of a minor subset of HPCs result in global effects in the bone marrow and on immune responses?
4. Which cellular pathways are controlling (or controlled by) the HCMV lifecycle?
(1) Recombinant BAC-derived HCMV
(3) in vitro latency and reactivation models for HCMV
(4) in vitro human hematopoiesis models
(5) in vivo humanized mouse models: Latency / Immune Response / Transplant