Role of Transportin-SR2 in HIV-1 Nuclear Import

Abstract

The HIV replication cycle depends on the interaction of viral proteins with proteins of the host. Unraveling host-pathogen interactions during the infection is of great importance for understanding the pathogenesis and the development of antiviral therapies. To date HIV uncoating and nuclear import are the most debated steps of the HIV-1 replication cycle. Despite numerous studies during past decades, there is still much controversy with respect to the identity and the role of viral and host factors involved in these processes. In this review, we provide a comprehensive overview on the role of transportin-SR2 as a host cell factor during active nuclear transport.

Keywords: CPSF6; HIV-1; TNPO3; TRN-SR2; capsid; integrase; nuclear import; transportin-SR2.

Figure 1

The nuclear transport cycle. In the cytoplasm, cargo/importin complex formation is mediated by the nuclear localization signal (NLS) of the cargo (upper left). In the nucleus the cargo is released upon binding of RanGTP to the importin (lower panel). Next, the importin/RanGTP complex is exported to the cytoplasm where the GTPase activating protein (GAP) hydrolyses GTP to GDP, which subsequently leads to release of importin (upper right). Ran guanine nucleotide exchange factor (GEF) phosphorylates Ran/GDP in the nucleus. The figure is created by https://app.biorender.com (accessed on 22 March 2021).

Figure 2

Models of HIV-1 uncoating. To date three potential models for HIV-1 uncoating are proposed. “Immediate uncoating” points to the early disassembly of the HIV-1 core inside the cytoplasm during the first hour of infection and prior to NPC docking (A). Uncoating at the NE is supported by imaging experiments showing that uncoating occurs when the core is stalled at the NPC. (B). Recent studies are claiming a “nuclear uncoating” mechanism and represent the third model of HIV-1 uncoating (C). In the third model, intact HIV-1 cones enter into the cell nucleus, reverse transcription is completed, and uncoating and integration are all completed inside the nucleus and close to the integration site.

Figure 3

HIV-1 nuclear import. Interaction between Nup358 and viral CA results in docking of HIV-1 cones to the NE. Depending on the model chosen (see Figure 2) capsid uncoating occurs in the cytoplasm, at the NE, or in the nucleus. Interaction between Nup153 and CA results in docking to the nuclear basket of the NPC. CPSF6 bound to CA proteins may recruit TRN-SR2 to the PICs. After capsid uncoating the triple complex of transportin-SR2/HIV-1 IN/CPSF6 may subsequently translocate the viral integration complex into the nucleus. Binding of nuclear CPSF6 molecules to CA remnants may release these remnants into the nucleoplasm.