MARCH Proteins, Members of a Host Protein Family that Targets HIV-1

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Project Summary/ Abstract Membrane Associated RING CH (MARCH) proteins are RING E3 ubiquitin ligases that are implicated in the regulation of membrane receptors. This family of ubiquitin ligases emerged after the discovery of K3 and K5, two viral MARCH-homologues in Kaposi’s sarcoma associated herpesvirus (KSHV), which are critical in evading the host’s immune response by ubiquitinating and subsequently removing the major histocompatibility complex class II (MHC-II) receptors from the surface of the cells and therefore blocking antigen presentation. The cellular MARCH family of proteins consists of 11 members that share structural similarity and contain a RING-CH domain that is essential for the removal and internalization of target membrane receptors (e.g. MHC-II). Recent reports showed that MARCH proteins can also potently restrict human immunodeficiency virus 1 (HIV-1) infection. MARCH1, 2 and 8 restrict HIV-1 and other retroviruses by blocking the incorporation of the viral envelope in the budding virions. This proposal explores aspects of the MARCH-mediated antiretroviral mechanism that have never been previously studied. Currently, there is no information concerning a viral protein that counteracts MARCH proteins. The first aim of this research plan examines the mechanism by which an HIV encoded factor counteracts MARCH8 during infection. The second aim examines the susceptibility of HIV-1 envelopes from different subtypes to MARCH-mediated restriction as well as the ability of HIV-1 proteins from different subtypes to counteract MARCH8. Preliminary studies show that HIV-1 over time becomes resistant to MARCH restriction. The third aim will determine the changes in the HIV-1 genome that render it resistant to MARCH inhibition. Finally, the fourth aim will address the role of the other MARCH proteins on HIV-1 infection. In summary, these studies will shed new light on the anti-retroviral role of MARCH proteins and will address aspects of MARCH- mediated HIV-1 inhibition that have not been previously determined. Finally, these proteins have strong potential as clinical targets for the development of antiretroviral therapeutics.