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Review
. 2018 Jan 4:8:1853.
doi: 10.3389/fimmu.2017.01853. eCollection 2017.

Inhibiting the Ins and Outs of HIV Replication: Cell-Intrinsic Antiretroviral Restrictions at the Plasma Membrane

Toshana L Foster  1 , Suzanne Pickering  1 , Stuart J D Neil  1
Affiliations
Review

Inhibiting the Ins and Outs of HIV Replication: Cell-Intrinsic Antiretroviral Restrictions at the Plasma Membrane

Toshana L Foster et al. Front Immunol. .

Abstract

Like all viruses, human immunodeficiency viruses (HIVs) and their primate lentivirus relatives must enter cells in order to replicate and, once produced, new virions need to exit to spread to new _targets. These processes require the virus to cross the plasma membrane of the cell twice: once via fusion mediated by the envelope glycoprotein to deliver the viral core into the cytosol; and secondly by ESCRT-mediated scission of budding virions during release. This physical barrier thus presents a perfect location for host antiviral restrictions that _target enveloped viruses in general. In this review we will examine the current understanding of innate host antiviral defences that inhibit these essential replicative steps of primate lentiviruses associated with the plasma membrane, the mechanism by which these viruses have adapted to evade such defences, and the role that this virus/host battleground plays in the transmission and pathogenesis of HIV/AIDS.

Keywords: antiviral restriction; human immunodeficiency virus; interferon-induced transmembrane; plasma membrane; serine incorporator; tetherin/BST-2; type I interferons.

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Figures

Figure 1
Figure 1
Schematic representation of IFITMS, SERINC 3/5 and tetherin within a model membrane. (A) A model of the IFITM protein, which adopts a type II transmembrane protein topology in the membrane. The N-terminal domain lies within the cytoplasm and connects to two short intramembrane α-helices. IFITMs 2 and 3 possess a longer N-terminal domain that contains important trafficking motifs that determine protein localisation. The conserved intracellular loop (CIL) contains sites of palmitoylation that likely stabilise the conformation of the C-terminal transmembrane α-helix which spans the membrane, thus positioning the C-terminal domain within the extracellular space. (B) Very little information about the structures of SERINC proteins is currently known. SERINCs 3 and 5 are thought to possess between 10 and 12 transmembrane helices such that the N- and C-termini reside within the extracellular space. (C) Tetherin exists as a dimer anchored to the membrane via an N-terminal transmembrane domain and a C-terminal GPI anchor. The extracellular portion of tetherin is comprised of a coiled coil. The N terminal cytoplasmic tail contains a dual tyrosine motif that plays a role in both steady-state cycling of the protein and signal transduction following virus retention. Amino acid sequences of human and chimpanzee cytoplasmic tails are shown for comparison, highlighting the deletion of the DIWKK motif. The short isoform of human tetherin lacks the first 12 amino acids of the cytoplasmic tail.
Figure 2
Figure 2
Restriction of HIV-1 entry at the plasma membrane. (A) IFITMs. The antiviral restriction activity of the interferon induced transmembrane (IFITM) protein family appears to be linked to the site of viral fusion. The current general mechanism of action proposed, i.e. the physical fusion of the viral and host cell membranes is blocked, accounts for the diversity of viruses that IFITMs restrict. The influence of complex cellular trafficking pathways on this mechanism is yet to be determined. IFITMs 1, 2 and 3 are localised in different membrane compartments; IFITM1 primarily at the plasma membrane and IFITMs 2 and 3 in overlapping intracellular endocytic compartments-the sites of enveloped virus fusion. HIV-1 entry requires the CD4 receptor and co-receptors CCR5 or CXCR4 and it appears that HIV-1 sensitivity to IFITM restriction is influenced both by IFITM localisation and the site of fusion. Fusion that occurs at the plasma membrane is susceptible particularly to an IFITM1 mediated block. IFITMs 2 and 3 appear to restrict any fusion events that bypass the plasma membrane and occur within the intracellular compartments. IFITMs incorporated into viral particles during budding mediate their restriction on the _target cell as the virus progeny become increasingly less infectious due to IFITM incorporation. (B) SERINC 3 and 5. The transmembrane proteins SERINC3 and SERINC5 are incorporated into budding HIV-1 particles from the membrane of the infected cell. In the absence of the Nef protein, HIV-1 infectivity in the _target cell is restricted as delivery of the viral core is reduced due to a block to fusion. Conversely, in the presence of Nef, SERINC3/5 are relocalised from the plasma membrane through dynamin- and clathrin-dependent endocytosis, thus restoring viral infectivity and allowing for successful fusion of the progeny virions that lack SERINC3/5, with the _target cell. (C) Other lentiviral restrictions at the plasma membrane. The post-entry restriction activity of lentivirus susceptibility factors 2 and 3 (Lv2/3) is dependent on the fusion events at the plasma membrane. Both envelope and capsid are determinants of Lv2 mediated restriction that blocks reverse transcription and nuclear entry. Likewise, RNA-associated early stage antiviral factor (REAF) which has been identified as a potent effector of Lv2, blocks reverse transcription in a similar manner dependent on the route of entry. The Lv3 block is a TRIM5α-independent process that is dependent on envelope interactions with viral entry receptors. The cell specific restriction factor TRIM5α, binds to capsid and forms a lattice leading to premature disassembly of the core. In Langerhans cells, HIV-1 uptake by the C-type lectin Langerin leads to recruitment of TRIM5α and a post-fusion block that occurs prior to integration. Conversely, in other DC subsets, interaction with DC-SIGN, induces a signalling cascade that facilitates reverse transcription and prevents TRIM5α restriction.
Figure 3
Figure 3
Tetherin mediated restriction of HIV-1 assembly and release. (A) Tetherin resides in the plasma membrane and is constitutively recycled from the plasma membrane via endosomes and the trans-Golgi network (TGN). The antiviral activity of tetherin is counteracted by the Vpu and Nef proteins. During HIV-1 infection, Vpu binds to the transmembrane domain of tetherin in the endoplasmic reticulum and Golgi network and sequesters it in endosomal regions in a clathrin-dependent manner. This rerouting of tetherin from the plasma membrane leads to its degradation in lysosomes via the ESCRT pathway. SIV Nef, too, is able to antagonise tetherin activity by sequestering tetherin from the sites of virus assembly, leading to lysosomal degradation of the entrapped molecules. (B) In the absence of Vpu and Nef activity, tetherin accumulates at virus assembly sites and blocks virus release from the plasma membrane. This clustering of retained virions triggers a signalling cascade mediated by tetherin’s cytoplasmic tail that leads to NF-κB activation and release of proinflammatory cytokines. This sensing of retention is reliant on tetherin association with the actin cytoskeleton via the adaptor protein RICH2. (C) Signalling that ultimately leads to NF-κB activation triggered by the phosphorylation of tetherin monomers and recruitment of the Syk kinase. This in turn leads to recruitment of the E3 ligases TRAF2 and TRAF6, that with the E2 enzyme UBC13, and K63-ubiquitin-mediated activation of the kinase TAK1 to activate NF-κB (D) Virions tethered at the cell surface are also exposed to anti-Env antibodies that thereby sensitise the infected cell to anti-HIV antibody-dependent cell-mediated cytotoxicity (ADCC) responses from Fc-receptor expressing myeloid and NK cells. (E) Tetherin is able to further modulate the cell’s innate immunity through activation of the plasmacytoid dendritic cell specific leukocyte inhibitory receptor ILT7. Interaction with this ligand results in dampened TLR signals that thereby decrease type I interferon (IFN-I) production and enhancement of immune responses.
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