A bipartite structural organization defines the SERINC family of HIV-1 restriction factors

Pye, V.E.; Rosa, Annachiara; Bertelli, Cinzia; Struwe, Weston B.; Maslen, Sarah; Corey, Robin A.; Liko, Idlir; Hassall, Mark; Mattiuzzo, Giada; Ballandras-Colas, Allison; Nans, Andrea; Takeuchi, Yasuhiro; Stansfeld, Phillip J.; Skehel, J. Mark; Robinson, Carol V.; Pizzato, Massimo; Cherepanov, Peter

doi:10.1038/s41594-019-0357-0

Cited by 55 publications

(118 citation statements)

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“…A constant engagement of SERINC 5 by the host seem to have therefore acted as a driving force during the evolution of these retroviruses. Having found foamy envelope-dependent activity among coelacanth SERINC 2 is therefore not surprising and is in agreement with previous reports (41,42) suggesting an ability of envelope to interact with SERINC. As a result, an early challenge by this host factor leading to subsequent divergence of foamy envelope towards insensitivity to SERINC restriction.…”

Section: Discussionsupporting

confidence: 92%

“…This nevertheless is indicative of more SERINC -like restriction factors that display poor signatures of arms-race but are functionally active. The core function of SERINC s in eukaryotes awaits independent observations nevertheless, the most recent effort in providing structural insights into the fly and human ortholog (42) opens up avenues for structure-inspired biological perturbations.…”

Section: Discussionmentioning

confidence: 99%

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Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

Ramdas

Bhardwaj

Singh

et al. 2020

Preprint

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9The SERINC gene family comprises of five paralogs in humans of which SERINC3 and 10 SERINC5 inhibit HIV-1 infectivity and are counteracted by Nef. The origin of this anti-retroviral 11 activity, its prevalence among the remaining human paralogs, and its ability to target 12 retroviruses remain largely unknown. Here we show that despite their early divergence, the 13 anti-retroviral activity is functionally conserved among four human SERINC paralogs with 14 SERINC2 being an exception. The lack of activity in human SERINC2 is associated with its 15 post-whole genome duplication (WGD) divergence, as evidenced by the ability of pre-WGD 16 orthologs from yeast, fly, and a post-WGD-proximate SERINC2 from coelacanth to inhibit nef-17 defective HIV-1. Intriguingly, potent retroviral factors from HIV-1 and MLV are not able to relieve 18 the SERINC2-mediated particle infectivity inhibition, indicating that such activity was directed 19 towards other retroviruses that are found in coelacanth (like foamy viruses). However, foamy-20 derived vectors are intrinsically resistant to the action of SERINC2, and we show that a foamy 21 virus envelope confers this resistance. Despite the presence of weak arms-race signatures, the 22 functional reciprocal adaptation among SERINC2 and SERINC5 and, in response, the 23 emergence of antagonizing ability in foamy virus appears to have resulted from a long-term 24 conflict with the host. 25 26 27 28 Introduction 29Viruses have been exploiting the host machinery for their persistence, and, in response, the 30 host has continued to evolve increasingly intricate antiviral defense strategies. As part of this 31 ongoing arms-race, while viruses have relied on acquisition and fusion of diverse genes (1), 32 the host-defense mechanism has been made possible by the functional divergence of gene 33 copies following duplication of genes as well as whole-genomes (2-7). Restriction factors being 34 at the forefront of this long-term conflict (8-10), show clear molecular signatures of arms-race 35 (11,12). In fact, the presence of these signatures has been proposed to be a hallmark of 36 restriction factors (8,13), and has been used as a screening strategy to identify potential 37 candidates (2,14). In contrast, the recently identified anti-retroviral host inhibitors SERINC5 and 38 SERINC3 display an uneventful evolutionary history (15). This is counterintuitive, because 39 distant retroviruses, with wide host-range, encode anti-SERINC5 virulent factors (16)(17)(18). We, 40Ramdas et al.therefore, sought to trace the origins of this antiretroviral activity and its relevance for retroviral 41 inhibition. Our analysis to comprehend the evolutionary origins of the antiretroviral activity in 42 SERINCs, identifies an active SERINC2 with a hitherto unknown interaction with a foamy virus. 44 Results 45Antiretroviral activity among human SERINC paralogs 46 Analysis of sequence similarity and gene structure conservation reveals that SERINC5 and 47 SERINC4 share a recent ancestry (Fig-S1). Similarly, SERINC3 and...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

Ramdas

Bhardwaj

Singh

et al. 2020

Preprint

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“…SERINC Antagonism Assay. SERINC5 and SERINC3 expression vectors (pcDNA based) were gifted by Massimo Pizzato, University of Trento, Trento, Italy (54). SERINC proteins were HA tagged at the N terminus (intracellular tag) and FLAG tagged in the fourth extracellular loop.…”

Section: Methodsmentioning

confidence: 99%

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Mesner

Hotter

Kirchhoff

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Nef is an accessory protein of primate lentiviruses that is essential for efficient replication and pathogenesis of HIV-1. A conserved feature of Nef proteins from different lentiviral lineages is the ability to modulate host protein trafficking and down-regulate a number of cell surface receptors to enhance replication and promote immune evasion. Notably, the inability of Nef to down-regulate CD3 from infected T cells distinguishes HIV-1 Nef and its direct simian precursors from other primate lentiviruses. Why HIV-1 does not employ this potential immune evasion strategy is not fully understood. Using chimeric HIV-1 constructs expressing lentiviral Nef proteins that differ in their ability to down-modulate CD3, we show that retaining CD3 on the surface of infected primary T cells results in increased viral replication and cell-to-cell spread. We identified increased expression of envelope (Env) trimers at the cell surface and increased Env incorporation into virions as the determinants for the Nef-and CD3-dependent enhancement of viral infectivity. Importantly, this was independent of Nef-mediated antagonism of the host restriction factor SERINC5. CD3 retention on the surface of infected primary T cells also correlated with increased T cell signaling, activation, and cell death during cell-tocell spread. Taken together, our results show that loss of an otherwise conserved function of Nef has a positive effect on HIV-1 replication, allowing for more efficient replication while potentially contributing to HIV-1 pathogenesis by triggering T cell activation and cell death during viral spread.HIV | CD3 | Nef | T cell | Env

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“…The SARS-CoV-2 RBD and S1 constructs, spanning SARS-CoV-2 S (UniProt ID P59594) residues 319-541 (RVQPT…KCVNF) and 1-530 (MFVFL…GPKKS), respectively, were produced with C-terminal twin Strep tags. To this end, the corresponding codon-optimised DNA fragments were cloned into mammalian expression vector pQ-3C-2xStrep 38 . A signal peptide from immunoglobulin kappa gene product (METDTLLLWVLLLWVPGSTGD) was used to direct secretion of the RBD construct.…”

Section: Recombinant Protein Productionmentioning

confidence: 99%

Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

Ng¹,

Faulkner²,

Cornish³

et al. 2020

Preprint

Self Cite

126

170

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Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections 1 . Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 , is a recent zoonotic infection that has quickly reached pandemic spread 2,3 . Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 Spike (S) glycoprotein, we demonstrate the presence of pre-existing immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies, exclusively of the IgG class, were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals with recent HCoV infection and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 Sreactive IgG antibodies, as well as concomitant IgM and IgA antibodies throughout the observation period of 6 weeks since symptoms onset. HCoV patient sera also variably reacted with SARS-CoV-2 S and nucleocapsid (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, HCoV patient sera exhibited specific neutralising activity against SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for serology, seroprevalence and vaccine studies, as well as for our understanding of susceptibility to and natural course of SARS-CoV-2 infection. ResultsImmune cross-reactivity among seasonally spreading human coronaviruses (HCoVs) has long been hypothesised to provide cross-protection, albeit transient, against infection with distinct HCoV types 1,4,5 . To determine the degree of cross-reactivity between HCoVs and the recently introduced zoonotic coronavirus SARS-CoV-2, we developed a sensitive flow cytometry-based assay for detection of SARS-CoV-2-binding antibodies. Sera from COVID-19 patients at University College London Hospitals (UCLH) (Table S1), contained high levels of IgG, IgM and IgA antibodies recognising the wild-type Spike (S) glycoprotein of SARS-CoV-2 expressed on the surface of HEK293T cells, whereas control sera did not (Fig. 1a). Notably, sera from a proportion patients with confirmed HCoV infection collected before or during the early spread of SARS-CoV-2 in the UK (Table S1), also contained SARS-CoV-2 S-specific antibodies (Fig. 1a). However, the latter sera contained only lower levels of S-specific IgG and no IgM or IgA antibodies, which clearly distinguished them from COVID-19 patient sera (Fig. 1a). The SARS-CoV-2 S protein is proteolytically processed into the S1 and S2 subunits that mediate target cell attachment and entry, respectively 6,7 . S2 exhibits a higher degree of homology among coronaviruses than S1 (Extended data Fig. 1...

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A bipartite structural organization defines the SERINC family of HIV-1 restriction factors

Cited by 55 publications

References 59 publications

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

Loss of Nef-mediated CD3 down-regulation in the HIV-1 lineage increases viral infectivity and spread

Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

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