Manipulation of the host cell by viral auxiliary proteins

Editorial

23 February 2015

Shaping of the host cell by viral accessory proteins

Nadine Laguette

and

Monsef Benkirane

5,096 views

6 citations

Editors

Nadine Laguette

Centre National de la Recherche Scientifique (CNRS)

Monsef Benkirane

Centre National de la Recherche Scientifique (CNRS)

Impact

Structure of Vif and host interacting partners. (A) Domain organization of Vif. Vif uses specific motifs to interact with A3G (magenta, 40YRHHY44), A3F/A3C/A3D (red, 11WQxDRMR17 and 74TGERxW79), and A3H (orange, 39F and 48H). In conjunction with these specific motifs, there are shared interaction motifs for A3F and A3G with Vif (pink, 21WKSLVK26 and 69YWxL72). CBFβ interacts with Vif through two adjacent motifs (cyan, 84GxSIEW89 and 102LADQLI107). The Zinc finger region (green, amino acids 108-139) coordinates the Zinc through an 108H114C133C139H motif and stabilizes the Vif structure, which indirectly enables an interaction with Cullin 5 (Cul5). Direct interaction of Vif with Cul5 is through amino acids 120IRxxL124. The BC box mediates an interaction with Elongin C (green 144SLQYLA149). Vif oligomerizes through a PPLP motif (gray, 163PPLPx4L169). Slanted lines are used to indicate intervening amino acids between the domains. (B) The crystal structure of Vif (PDB: 4N9F) shows that it has two domains on either side of a bound Zinc (blue). The N-terminal α/β-domain consists of a five stranded β-sheet, a discontinuous β-strand and three α-helices. The α/β-domain contains the binding interface for CBFβ (cyan, 102LADQLI107, 84GxSIEW89) and A3 enzymes. The 11WQxDRMR17 motif (red) is used to interact with A3F, A3C, and A3D, the 40YRHHY44 motif (magenta) is used to interact with A3G, and residues 39F and 48H (orange) are used to interact with A3H. The α-domain contains two alpha helices that mediate two separate interactions with EloC (green, 144SLQYLA149) and Cul5 (green, 120IRxxL124). (C) Structure HIV Vif (red) in complex with CBFβ (cyan), Elongin C (EloC, yellow), and the N-terminal domain of Cullin 5 (nCul5, amino acids 12–386, orange, PDB: 4N9F). Elongin B (EloB, magenta) dimerizes with EloC. Figures were made using PyMOL (The PyMOL Molecular Graphics System, Version 1.5.05, Shrödinger, LLC.).

Review

26 August 2014

Suppression of APOBEC3-mediated restriction of HIV-1 by Vif

Yuqing Feng

, 2 more and

Linda Chelico

The APOBEC3 restriction factors are a family of deoxycytidine deaminases that are able to suppress replication of viruses with a single-stranded DNA intermediate by inducing mutagenesis and functional inactivation of the virus. Of the seven human APOBEC3 enzymes, only APOBEC3-D, -F, -G, and -H appear relevant to restriction of HIV-1 in CD4+ T cells and will be the focus of this review. The restriction of HIV-1 occurs most potently in the absence of HIV-1 Vif that induces polyubiquitination and degradation of APOBEC3 enzymes through the proteasome pathway. To restrict HIV-1, APOBEC3 enzymes must be encapsidated into budding virions. Upon infection of the target cell during reverse transcription of the HIV-1 RNA into (-)DNA, APOBEC3 enzymes deaminate cytosines to form uracils in single-stranded (-)DNA regions. Upon replication of the (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite to the uracils thereby inducing C/G to T/A mutations that can functionally inactivate HIV-1. APOBEC3G is the most studied APOBEC3 enzyme and it is known that Vif attempts to thwart APOBEC3 function not only by inducing its proteasomal degradation but also by several degradation-independent mechanisms, such as inhibiting APOBEC3G virion encapsidation, mRNA translation, and for those APOBEC3G molecules that still become virion encapsidated, Vif can inhibit APOBEC3G mutagenic activity. Although most Vif variants can induce efficient degradation of APOBEC3-D, -F, and -G, there appears to be differential sensitivity to Vif-mediated degradation for APOBEC3H. This review examines APOBEC3-mediated HIV restriction mechanisms, how Vif acts as a substrate receptor for a Cullin5 ubiquitin ligase complex to induce degradation of APOBEC3s, and the determinants and functional consequences of the APOBEC3 and Vif interaction from a biological and biochemical perspective.

17,181 views

105 citations

APOBEC3G links innate/intrinsic immunity with adaptive cellular immunity. A3G is expressed at various levels in human immunodeficiency virus (HIV) infected cells and can be induced upon viral sensing by Toll-like receptors (TLR), triggering of CD40 or CCR5 and IFN production (left). A3G is incorporated in budding virions and exerts its antiviral activities in newly infected cells (right). During reverse transcription, A3G catalyzes cytosine to uracil deaminations on the nascent minus DNA strand of HIV. The presence of uracil and the expression of HIV Vpr recruit the cellular DNA repair machinery (UNG2, right middle) leading to either HIV DNA restoration or degradation, the latter reducing viral replication. The cellular DNA-repair machinery trying to cope with uracil-rich HIV DNA also activates the DNA-damage- and stress–response pathways leading to the up-regulation of activating natural killer (NK) cell ligands (NKG2D ligands) and killing of infected cells (right middle). In addition, deaminations lead to G to A transitions in HIV DNA leading to the integration of proviruses with a high frequency of amino acid substitutions and/or premature STOP codons. These proviruses express aberrant viral proteins that are unable to produce infectious particles. Infected cells can use these misfolded or truncated viral proteins (called DRiPs, defective ribosomal products) to generate MHC-I epitopes leading to activation of anti-HIV cytotoxic T lymphocyte (CTL) responses (right upper). However, in infected cells, Vif counteracts the antiviral functions of A3G by targeting newly synthetized A3G for proteasomal degradation, thus reducing the amount of A3G incorporated into budding virions (left) and facilitating HIV replication in newly infected cells (right bottom). Viral replication is therefore the result of a balance between anti-viral innate and adaptive (cellular) immunity promoted by A3G and Vif-mediated escape mechanisms developed by HIV.

Review

13 October 2014

AID and APOBECs span the gap between innate and adaptive immunity

Arnaud Moris

, 1 more and

Sylvain Cardinaud

14,517 views

70 citations

Review

20 May 2014

The activity of Nef on HIV-1 infectivity

Stéphane Basmaciogullari

and

Massimo Pizzato

The replication and pathogenicity of lentiviruses is crucially modulated by “auxiliary proteins” which are expressed in addition to the canonical retroviral ORFs gag, pol, and env. Strategies to inhibit the activity of such proteins are often sought and proposed as possible additions to increase efficacy of the traditional antiretroviral therapy. This requires the acquisition of an in-depth knowledge of the molecular mechanisms underlying their function. The Nef auxiliary protein is expressed uniquely by primate lentiviruses and plays an important role in virus replication in vivo and in the onset of AIDS. Among its several activities Nef enhances the intrinsic infectivity of progeny virions through a mechanism which remains today enigmatic. Here we review the current knowledge surrounding such activity and we discuss its possible role in HIV biology.

19,680 views

72 citations

$Vpu subverts the host cell trafficking and ubiquitin machineries to counteract BST2 antiviral activity. BST2 physically tethers HIV-1 particles on the surface of infected cells preventing their release and further dissemination. The accessory protein Vpu counteracts this restriction by hijacking the host machineries involved in BST2 trafficking and turnover. BST2 cycles between the plasma membrane, the TGN and the endosomes, with a fraction sorted for lysosomal degradation through an ESCRT-mediated pathway (left panel). Vpu counteracts BST2 restriction activity through (i) displacing it from viral assembly sites by a yet-to-be-determined mechanism involving a “dileucine”-like motif located in its cytoplasmic tail and (ii) down-regulating BST2 cell surface expression level and as such restores viral release. Vpu down-regulates cell surface BST2 by slowing down the PM access of internalized and newly synthesized BST2. Vpu-induced BST2 cell surface down regulation is associated with targeting of the restriction factor for lysosomal degradation through an ubiquitin-dependent mechanism that involves the recruitment of SCFβ-TrCP E3 ubiquitin ligase complex and the ESCRT machinery. Indeed, through binding to HRS, Vpu enhances the affinity of BST2 for HRS thus accelerating its sorting by the ESCRT machinery for lysosomal degradation. One might propose that through binding with the ESCRT machinery, Vpu may favor the sorting of BST2 at the level of endosomes, thereby reducing its recycling to the plasma membrane (right panel). This figure is adapted from Janvier et al. (2012).$

Mini Review

01 May 2014

Mechanisms underlying HIV-1 Vpu-mediated viral egress

Nicolas Roy

, 2 more and

Katy Janvier

8,316 views

32 citations

HIV-1 subversion of innate immune DNA sensing. (A) A schematic diagram of early stages of HIV-1 life cycle. HIV-1 capsid (CA) and associated host factors, CypA and CPSF6, regulate HIV DNA access to innate immune sensing. TREX1 and SAMHD1 regulate HIV DNA quantity. IN, integrase. (B) HIV-1 DNA sensing by cGAS in many target cells activates a STING-mediated IFN response, whereas HIV-1 DNA sensing by IFI16 in “bystander” quiescent CD4+ T cells trigger IFN signaling, caspase-1 activation, IL-1β secretion and pyroptosis.

Review

30 April 2014

Safeguard against DNA sensing: the role of TREX1 in HIV-1 infection and autoimmune diseases

Maroof Hasan

and

Nan Yan

7,440 views

23 citations

Vpr-induced SLX4 complex activation promotes escape from innate immune sensing. (1) Premature delivery of viral genomes in the cytoplasm of host cells may lead to recognition by nucleic acid sensors. (2) Editing by APOBEC3G and dNTP hydrolysis by SAMHD1 induce viral DNA instability and impair reverse transcription. Of note, a nuclease activity has been described for SAMHD1 which may target viral nucleic acids. (3) APOBEC3G and SAMHD1 contribute to generate abortive RT by-products which are taken care of by cellular exonucleases: RNaseH2 degrades DNA:RNA hybrids while TREX1 degrades ssDNA preferentially. (3′) Abortive nucleic acid intermediates may also be directly degraded by RNaseH2 and TREX1. (4) The SLX4 structure specific endonuclease complex is activated by Vpr and likely cleaves dsDNA. Whether these dsDNA fragments are further degraded by cellular exonucleases or may be recognized by nucleic acid sensors remains questioned. (1′) When uncoating is correctly orchestrated, viral nucleic acids are protected from mechanisms described in 1–4, and ensures delivery of viral genomes in the nucleus.

Review

22 April 2014

DNA damage repair machinery and HIV escape from innate immune sensing

Christelle Brégnard

, 1 more and

Nadine Laguette

12,456 views

48 citations

Review

10 April 2014

Counteraction of the multifunctional restriction factor tetherin

Daniel Sauter

Viral antagonists of tetherin. Schematic structure and mode of action are shown for (A) SIV Nef, (B) HIV-1 Vpu, (C) HIV-2 Env, (D) HHV-8 K5, (E) Ebolavirus Gp. Tetherin is indicated in blue, the viral antagonists are shown in red. SIV Nef and HIV-2 Env sequester tetherin to intracellular compartments without affecting total cellular tetherin levels. In contrast HIV-1 Vpu and HHV-8 K5 induce the ubiquitination and subsequent degradation of the restriction factor. The mechanism of Ebola Gp-mediated tetherin antagonism is still unclear. Interactions between domains of tetherin and its antagonists are indicated by red arrows.

The interferon-inducible restriction factor tetherin (also known as CD317, BST-2 or HM1.24) has emerged as a key component of the antiviral immune response. Initially, tetherin was shown to restrict replication of various enveloped viruses by inhibiting the release of budding virions from infected cells. More recently, it has become clear that tetherin also acts as a pattern recognition receptor inducing NF-κB-dependent proinflammatory gene expression in virus infected cells. Whereas the ability to restrict virion release is highly conserved among mammalian tetherin orthologs and thus probably an ancient function of this protein, innate sensing seems to be an evolutionarily recent activity. The potent and broad antiviral activity of tetherin is reflected by the fact that many viruses evolved means to counteract this restriction factor. A continuous arms race with viruses has apparently driven the evolution of different isoforms of tetherin with different functional properties. Interestingly, tetherin has also been implicated in cellular processes that are unrelated to immunity, such as the organization of the apical actin network and membrane microdomains or stabilization of the Golgi apparatus. In this review, I summarize our current knowledge of the different functions of tetherin and describe the molecular strategies that viruses have evolved to antagonize or evade this multifunctional host restriction factor.

8,157 views

84 citations

Maximum likelihood phylogeny of primate lentiviruses vpr and vpx genes. vpr are represented in blue and vpx in red. Branch lengths represent nucleotide substitutions per site, as indicated in the scale. Branch supports are indicated by one asterisk (≥90% confidence) or two asterisks (≥99%). The tree was rooted using the midpoint rooting method. Abbreviations: HIV, human immunodeficiency virus; SIV, simian immunodeficiency virus; cpz, chimpanzee (Pan troglodytes); gor, gorilla (Gorilla gorilla); stm, stump-tailed macaque (Macaca arctoides); smm, sooty mangabey monkey (Cercocebus atys); mac, rhesus macaque (Macaca mulatta); mne, pig-tailed macaque (Macaca nemestrina); rcm, red-capped mangabey (Cercocebus torquatus); drl, drill monkey (Mandrillus leucophaeus); mnd, mandrill (Mandrillus sphinx); lst, L'Hoest's monkey (Cercopithecus lhoesti); sun, sun-tailed monkey (Cercopithecus solatus); olc, olive Colobus (Procolobus verus); gsn, greater spot-nosed monkey (Cercopithecus nictitans); mus, mustached monkey (Cercopithecus cephus); mon, mona monkey (Cercopithecus mona); tal, northern talapoins (Miopithecus ogouensis); deb, De Brazza's monkey (Cercopithecus neglectus); syk, Sykes' monkey (Cercopithecus mitis); agm TAN, tantalus African green monkey (Chlorocebus tantalus); agm VER, vervet African green monkey (Chlorocebus pygerythrus); agm GRV, grivet African green monkey (Chlorocebus aethiops); agm SAB, sabaeus African green monkey (Chlorocebus aethiops sabaeus); col, guereza colobus monkey (Colobus guereza).

Review

08 April 2014

New insights into an X-traordinary viral protein

Torsten Schaller

, 3 more and

Caroline Goujon

5,456 views

26 citations

Review

31 March 2014

HIV-1 Vpr—a still “enigmatic multitasker”

Carolin A. Guenzel

, 1 more and

Serge Benichou

Like other HIV-1 auxiliary proteins, Vpr is conserved within all the human (HIV-1, HIV-2) and simian (SIV) immunodeficiency viruses. However, Vpr and homologous HIV-2, and SIV Vpx are the only viral auxiliary proteins specifically incorporated into virus particles through direct interaction with the Gag precursor, indicating that this presence in the core of the mature virions is mainly required for optimal establishment of the early steps of the virus life cycle in the newly infected cell. In spite of its small size, a plethora of effects and functions have been attributed to Vpr, including induction of cell cycle arrest and apoptosis, modulation of the fidelity of reverse transcription, nuclear import of viral DNA in macrophages and other non-dividing cells, and transcriptional modulation of viral and host cell genes. Even if some more recent studies identified a few cellular targets that HIV-1 Vpr may utilize in order to perform its different tasks, the real role and functions of Vpr during the course of natural infection are still enigmatic. In this review, we will summarize the main reported functions of HIV-1 Vpr and their significance in the context of the viral life cycle.

12,642 views

97 citations