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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sakalian, Michael
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Medicine
United States
Zip Code
Meade, Nathan; Furey, Colleen; Li, Hua et al. (2018) Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit. Cell 174:1143-1157.e17
Naghavi, Mojgan H; Walsh, Derek (2017) Microtubule Regulation and Function during Virus Infection. J Virol 91:
Delaney, Michael Keegan; Malikov, Viacheslav; Chai, Qingqing et al. (2017) Distinct functions of diaphanous-related formins regulate HIV-1 uncoating and transport. Proc Natl Acad Sci U S A 114:E6932-E6941
Chai, Qingqing; Jovasevic, Vladimir; Malikov, Viacheslav et al. (2017) HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration. Nat Commun 8:1522
Malikov, Viacheslav; Naghavi, Mojgan H (2017) Localized Phosphorylation of a Kinesin-1 Adaptor by a Capsid-Associated Kinase Regulates HIV-1 Motility and Uncoating. Cell Rep 20:2792-2799
Jovasevic, Vladimir; Naghavi, Mojgan H; Walsh, Derek (2015) Microtubule plus end-associated CLIP-170 initiates HSV-1 retrograde transport in primary human cells. J Cell Biol 211:323-37
Malikov, Viacheslav; da Silva, Eveline Santos; Jovasevic, Vladimir et al. (2015) HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. Nat Commun 6:6660
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
Sabo, Yosef; Walsh, Derek; Barry, Denis S et al. (2013) HIV-1 induces the formation of stable microtubules to enhance early infection. Cell Host Microbe 14:535-46