The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild

Heigele, Anke; Kmieć, Dorota; Regensburger, Kerstin; Langer, Simon; Peiffer, Lukas; Stürzel, Christina M.; Sauter, Daniel; Peeters, Martine; Pizzato, Massimo; Learn, Gerald H.; Hahn, Beatrice H.; Kirchhoff, Frank

doi:10.1016/j.chom.2016.08.004

Cited by 85 publications

(105 citation statements)

References 51 publications

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“…Because the ability to counteract SERINC5 is conserved among all primate lentiviral lineages (Heigele et al, 2016), we additionally examined the effects of simian immunodeficiency virus (SIV) Nefs. SIV mac239 Nef increased the specific infectivity of Nef − HIV-1 produced in the presence of frog SERINC5 or of the fS5/hS5-ICL4 chimera 17- or 27-fold, respectively (Figure S1D).…”

Section: Resultsmentioning

confidence: 99%

A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef

Dai

Usami

et al. 2018

Cell Reports

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SUMMARY We recently identified the multipass transmembrane protein SERINC5 as an antiviral protein that can potently inhibit HIV-1 infectivity and is counteracted by HIV-1 Nef. We now report that the anti-HIV-1 activity, but not the sensitivity to Nef, is conserved among vertebrate SERINC5 proteins. However, a Nef-resistant SERINC5 became Nef sensitive when its intracellular loop 4 (ICL4) was replaced by that of Nef-sensitive human SERINC5. Conversely, human SERINC5 became resistant to Nef when its ICL4 was replaced by that of a Nef-resistant SERINC5. In general, ICL4 regions from SERINCs that exhibited resistance to a given Nef conferred resistance to the same Nef when transferred to a sensitive SERINC, and vice versa. Our results establish that human SERINC5 can be modified to restrict HIV-1 infectivity even in the presence of Nef.

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Section: Resultsmentioning

confidence: 99%

A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef

Dai

Usami

et al. 2018

Cell Reports

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“…The antiviral activity of SER5 is antagonized by HIV/simian immunodeficiency virus Nef and by the unrelated glycoGag protein of murine leukemia virus (MLV), 3 which are thought to diminish SER5 incorporation into virions by removing it from the plasma membrane (10,11). The importance of SER5 as a restriction factor is strongly supported by the observation that the potency with which Nef antagonizes this protein correlates with the prevalence of primate lentiviruses in the wild (12).…”

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confidence: 99%

SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins

Sood

Marin

Chande

et al. 2017

Journal of Biological Chemistry

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Edited by Charles E. SamuelThe host proteins, SERINC3 and SERINC5, have been recently shown to incorporate into HIV-1 particles and compromise their ability to fuse with target cells, an effect that is antagonized by the viral Nef protein. Envelope (Env) glycoproteins from different HIV-1 isolates exhibit a broad range of sensitivity to SERINC-mediated restriction, and the mechanism by which SERINCs interfere with HIV-1 fusion remains unclear. Here, we show that incorporation of SERINC5 into virions in the absence of Nef inhibits the formation of small fusion pores between viruses and cells. Strikingly, we found that SERINC5 promotes spontaneous functional inactivation of sensitive but not resistant Env glycoproteins. Although SERINC5-Env interaction was not detected by co-immunoprecipitation, incorporation of this protein enhanced the exposure of the conserved gp41 domains and sensitized the virus to neutralizing antibodies and gp41-derived inhibitory peptides. These results imply that SERINC5 restricts HIV-1 fusion at a step prior to small pore formation by selectively inactivating sensitive Env glycoproteins, likely through altering their conformation. The increased HIV-1 sensitivity to anti-gp41 antibodies and peptides suggests that SER5 also delays refolding of the remaining fusion-competent Env trimers.

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“…HIV-1 is not the only virus inhibited by SERINC5. SIVs lacking nef are also inhibited by SERINC5 and SIV nefs counteract this inhibition (17) with a potency that is proportional to the prevalence of SIV in wild primate populations (21). Two examples of convergent evolution of anti-SERINC function by virally encoded proteins are found outside of primate immunodeficiency viruses.…”

Section: Introductionmentioning

confidence: 99%

Influence of different glycoproteins and of the virion core on SERINC5 antiviral activity

Diehl

Guney

Kyawe

et al. 2019

Preprint

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Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three accessory proteins encoded by diverse retroviruses, HIV-1 Nef, EIAV S2, and MLV Glycogag, each independently disrupt SERINC5 antiviral activity, by redirecting SERINC5 from the site of virion assembly on the plasma membrane to an internal RAB7 + endosomal compartment. Pseudotyping retroviruses with particular glycoproteins, e.g., the vesicular stomatitis glycoprotein (VSV G), renders the infectivity of particles resistant to inhibition by virion-associated SERINC5. To better understand viral determinants for SERINC5-sensitivity, the effect of SERINC5 was assessed using HIV-1, MLV, and M-PMV virion cores, pseudotyped with glycoproteins from Arenavirus, Coronavirus, Filovirus, Rhabdovirus, Paramyxovirus, and Orthomyxovirus genera. Infectivity of particles, pseudotyped with HIV-1, amphotropic-MLV, or influenza virus glycoproteins, was decreased by SERINC5, whether the core was provided by HIV-1, MLV, or M-PMV. Particles generated by all three cores, and pseudotyped with glycoproteins from either avian leukosis virus-A, human endogenous retrovirus K (HERV-K), ecotropic-MLV, HTLV-1, Measles morbillivirus, lymphocytic choriomeningitis mammarenavirus (LCMV), Marburg virus, Ebola virus, severe acute respiratory syndrome-related coronavirus (SARS-CoV), or VSV, were insensitive to SERINC5. In contrast, particles pseudotyped with M-PMV, RD114, or rabies virus (RABV)glycoproteins were sensitive to SERINC5, but only with particular retroviral cores. Resistance to SERINC5 by particular glycoproteins did not correlate with reduced SERINC5 incorporation into particles or with the route of viral entry. These findings indicate that some non-retroviruses may be sensitive to SERINC5 and that, in addition to the viral glycoprotein, the retroviral core influences sensitivity to SERINC5.

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The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild

Cited by 85 publications

References 51 publications

A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef

A Long Cytoplasmic Loop Governs the Sensitivity of the Anti-viral Host Protein SERINC5 to HIV-1 Nef

SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins

Influence of different glycoproteins and of the virion core on SERINC5 antiviral activity

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