Actions of Vif and APOBEC3 Proteins in HIV-1 Replication

Michigan State University, East Lansing MI

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Abstract

The mammalian APOBEC3 (A3) cytidine deaminases have emerged as key players in the host intrinsic immunity to retroviruses. They exhibit different levels of antiretroviral activity against various types of retroviruses. In particular, A3B, A3DE, A3F, A3G, and A3H inhibit HIV-1 replication, with A3G having the most potent anti-HIV activity. A3G is packaged into virions via an interaction with HIV-1 nucleocapsid in a RNAdependent manner. Virion incorporation allows A3G inhibit viral replication by two mechanisms. The first is the cytidine deamination-dependent mechanism, where A3G catalyzes dC-to-dU deamination of the de novo synthesized minus-strand viral cDNAs during reverse transcription (RT), converting them into non-functional viral genomes. The second is the cytidine deamination-independent mechanism, where A3G directly inhibits viral RT at multiple stages or modifies viral cDNAs improperly to block their integration. In spite of this potent intrinsic antiretroviral immunity, HIV-1 still infects its hosts because of the viral protein Vif. Vif binds to A3G and a Cul5/EloB/EloC E3 ubiquitin ligase, leading A3G to proteasome for degradation. In addition, Vif may inhibit A3G activity via other proteasome-independent mechanisms. Vif also neutralizes A3DE and A3F, but not A3B and A3H (which are poorly expressed in vivo). Thus, the A3 family constitutes a potent antiretroviral apparatus that, if fully engaged, would be a dominant weapon in the fight against HIV-1. In this proposal, we will address critical questions regarding the antiviral mechanism of A3 proteins and the counteractive mechanism of Vif. We will pursue three specific aims. First, we will investigate A3 antiretroviral mechanism. We will identify other unknown determinants for A3 anti-HIV-1 activity, compare the activity of CDDs in different A3 proteins, and study how A3H expression is regulated in vivo. Second, we will investigate MOV10 antiretroviral mechanism. MOV10 is a newly identified antiretroviral host factor, and it interacts with A3G. We will characterize MOV10 biochemical property, study how it inhibits HIV-1, and determine whether it contributes to A3G antiretroviral activity. Third, we will investigate Vif counteractive mechanism. We will study how Vif activity is regulated by those twelve discontinuous motifs and identify other critical residues, understand why it cannot neutralize A3B and A3H, and determine whether Vif is a proteasomal adaptor protein to bring A3G into proteasomes and initiate degradation. We expect that from these studies, we will be able to potentiate A3 anti- HIV activity and suppress Vif counteractive activity, and thus mobilize this powerful host innate antiretroviral apparatus into new HIV therapies.