Human immunodeficiency virus type 1 (HIV-1) is a member of the retroviridae that causes Acquired Immunodeficiency Syndome (AIDS), which affects over 33.3 million people worldwide. Like many viruses, retroviruses require access to the host nucleus in order to replicate yet the processes and factors involved remain poorly understood. After entry into the cell, viral particles transit the cytoplasm to the nucleus on host microtubules, long filamentous transport networks that arrange around the microtubule organizing centre (MTOC) located near the nucleus. Our recent work has identified a neuronal protein, FEZ1 that localizes to the MTOC and suppress infection by a number of retroviruses, including HIV-1, by blocking the entry of viral DNA into the nucleus. Our preliminary data also suggests that the FEZ1 interacting protein, NEK1 has a similar neuronal expression pattern and inhibitory effect on HIV-1 infection, suggesting that FEZ1 and at least some of its interacting proteins may form part of a neuronal complex that impairs retroviral infection. Our additional preliminary data shows that FEZ1 also suppresses infection by another clinically important neurotropic DNA virus, Herpes Simplex Virus type 1 (HSV-1), suggesting that FEZ1 expression in neurons may limit their susceptibility to infection by a number of distinct viruses. Finally, ectopic expression of FEZ1 in microglia, another brain cell type, causes changes in nuclear architecture, called multi-lobulation, which may contribute to its antiviral properties and which suggests that FEZ1 and its interacting proteins may regulate important, poorly understood functions of the nucleus itself. In this proposal, we aim to characterize the antiviral and nuclear regulatory functions of FEZ1 in detail, defining the domains involved in regulating infection as well as those involved in the formation of multi-lobulated nuclei, and determining the regulation of FEZ1 function by host signaling pathways. By also examining the contribution of additional FEZ1- and NEK1-interacting factors to the phenotypes observed, we hope to build a picture of how these proteins regulate viral infection and nuclear architecture or movement, which will provide important insights into how factors associated with the MTOC communicate with and regulate nuclear functions important for viral infection and the broader movement of large cargoes, such as viral capsids, into the nucleus. As such, these studies are also likely to contribute to our broader understanding of the control of nuclear transport and architecture.
HIV-1 infects 33.3 million people worldwide while HSV-1 has established lifelong infections in an estimated 80% of the world population, causing periodic cold sores, corneal blindness and encephalitis. Understanding how FEZ1/NEK1 inhibits these viruses could identify important new avenues for therapeutic intervention.
|Naghavi, Mojgan H (2014) Stable microtubule subsets facilitate early HIV-1 infection. AIDS Res Hum Retroviruses 30:211-2|
|Naghavi, Mojgan H; Gundersen, Gregg G; Walsh, Derek (2013) Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread. Proc Natl Acad Sci U S A 110:18268-73|