HIV-1 encounters many obstacles to viral replication in the host cell, which is armed with an intrinsic immune system of antiviral factors with direct antiviral activity, including APOBEC3G, TRIM5alpha, Tetherin, SAMHD1, and Mx2. Our understanding of the mechanism by which these factors inhibit retroviral replication, and how they are evaded by certain viruses has accrued significantly, but is far from complete. Such knowledge could greatly aid the development of new animal models of human disease and novel therapeutic intervention. The goal of this project is to investigate the mechanistic basis fo inhibition of HIV-1 infection by the newly identified factor, Mx2.
The first aim of this project is to identify the cellular requirements for the localization and antviral activity of Mx2. It is unknown how Mx2 interacts with the nuclear pore complex, how it may be involved in regulation of nuclear import, or how the localization of Mx2 at the nuclear pore drives its antiviral activity. Both targeted and non-biased approaches will be employed to precisely identify cellular factors important for the antiviral activity of Mx2.
The second aim i s to determie the nature of the interaction between Mx2 and the HIV-1 capsid. It is known that the capsid is the determinant of sensitivity or resistance to inhibition by Mx2, but the mechanistic basis for this interaction remains unknown. Independent but complementary biochemical and genetic approaches will be utilized to define the precise interface that determines the antiviral specificiy of Mx2. The knowledge gained by this project will provide an enhanced understanding of how Mx2 inhibits the early stages of HIV-1 infection and can be utilized to develop new, targeted anti-retroviral therapies.
Human immunodeficiency virus-1 (HIV-1) remains a major global health threat, and there is a pressing need for the development of new therapies. This requires a better understanding of the natural defenses employed by the host. I propose to investigate in detail the mechanism of inhibition of HIV-1 by the antiviral factor Mx2, which can form the basis of new, targeted inhibitors against the virus.
| Kane, Melissa; Deiss, Felicity; Chervonsky, Alexander et al. (2018) A Single Locus Controls Interferon Gamma-Independent Antiretroviral Neutralizing Antibody Responses. J Virol 92: |
