{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T20:53:01Z","timestamp":1780519981983,"version":"3.54.1"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009750","name":"University of Rochester Medical Center","doi-asserted-by":"publisher","award":["OP212337"],"award-info":[{"award-number":["OP212337"]}],"id":[{"id":"10.13039\/100009750","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SERINC5 is a restriction factor that becomes incorporated into nascent retroviral particles, impairing their ability to infect target cells. In turn, retroviruses have evolved countermeasures against SERINC5. For instance, the primate lentiviruses (HIV and SIV) use Nef, Moloney Murine Leukemia Virus (MLV) uses GlycoGag, and Equine Infectious Anemia Virus (EIAV) uses S2 to remove SERINC5 from the plasma membrane, preventing its incorporation into progeny virions. Recent studies have shown that SERINC5 also restricts other viruses, such as Hepatitis B Virus (HBV) and Classical Swine Fever Virus (CSFV), although through a different mechanism, suggesting that SERINC5 can interfere with multiple stages of the virus life cycle. To investigate whether SERINC5 can also impact other steps of the replication cycle of HIV, the effects of SERINC5 on viral transcripts, proteins, and virus progeny size were studied. Here, we report that SERINC5 causes significant defects in HIV gene expression, which impacts virion production. While the underlying mechanism is still unknown, we found that the restriction occurs at the transcriptional level and similarly affects plasmid and non-integrated proviral DNA (ectopic or non-self-DNA). However, SERINC5 causes no defects in the expression of viral RNA, host genes, or proviral DNA that is integrated in the cellular genome. Hence, our findings reveal that SERINC5\u2019s actions in host defense extend beyond blocking virus entry.<\/jats:p>","DOI":"10.3390\/v15091961","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T21:47:03Z","timestamp":1695246423000},"page":"1961","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Antiviral Factor SERINC5 Impairs the Expression of Non-Self-DNA"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8533-846X","authenticated-orcid":false,"given":"Yuhang","family":"Shi","sequence":"first","affiliation":[{"name":"Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Simpson","sequence":"additional","affiliation":[{"name":"QuidelOrtho, Rochester, NY 14626, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahad K.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidin","family":"Tavakoli-Tameh","sequence":"additional","affiliation":[{"name":"Pharmaceutical Product Development, Middleton, WI 53562, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2341-1526","authenticated-orcid":false,"given":"Sanath Kumar","family":"Janaka","sequence":"additional","affiliation":[{"name":"Kelonia Therapeutics, Boston, MA 02210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-6292","authenticated-orcid":false,"given":"David T.","family":"Evans","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53792, USA"},{"name":"Wisconsin National Primate Research Center, Madison, WI 53715, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-6414","authenticated-orcid":false,"given":"Ruth","family":"Serra-Moreno","sequence":"additional","affiliation":[{"name":"Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature15399","article-title":"HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation","volume":"526","author":"Rosa","year":"2015","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature15400","article-title":"SERINC3 and SERINC5 restrict HIV-1 infectivity and are counteracted by Nef","volume":"526","author":"Usami","year":"2015","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35776","DOI":"10.1074\/jbc.M505712200","article-title":"Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis","volume":"280","author":"Inuzuka","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6014","DOI":"10.1074\/jbc.M117.777714","article-title":"SERINC5 protein inhibits HIV-1 fusion pore formation by promoting functional inactivation of envelope glycoproteins","volume":"292","author":"Sood","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e02214-16","DOI":"10.1128\/JVI.02214-16","article-title":"Effect of HIV-1 Env on SERINC5 Antagonism","volume":"91","author":"Beitari","year":"2017","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10929","DOI":"10.1021\/acsnano.0c02699","article-title":"Super-Resolution Fluorescence Imaging Reveals That Serine Incorporator Protein 5 Inhibits Human Immunodeficiency Virus Fusion by Disrupting Envelope Glycoprotein Clusters","volume":"14","author":"Chen","year":"2020","journal-title":"ACS Nano"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e00594-20","DOI":"10.1128\/JVI.00594-20","article-title":"SERINC5 Inhibits HIV-1 Infectivity by Altering the Conformation of gp120 on HIV-1 Particles","volume":"94","author":"Featherstone","year":"2020","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ramdas, P., and Chande, A. (2023). SERINC5 Mediates a Postintegration Block to HIV-1 Gene Expression in Macrophages. MBio, 14.","DOI":"10.1128\/mbio.00166-23"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Basmaciogullari, S., and Pizzato, M. (2014). The activity of Nef on HIV-1 infectivity. Front. Microbiol., 5.","DOI":"10.3389\/fmicb.2014.00232"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/0092-8674(91)90097-I","article-title":"Importance of the nef gene for maintenance of high virus loads and for development of AIDS","volume":"65","author":"Kestler","year":"1991","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1128\/jvi.67.8.4923-4931.1993","article-title":"Nef from primary isolates of human immunodeficiency virus type 1 suppresses surface CD4 expression in human and mouse T cells","volume":"67","author":"Anderson","year":"1993","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nm0396-338","article-title":"Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein","volume":"2","author":"Schwartz","year":"1996","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11422","DOI":"10.1128\/JVI.79.17.11422-11433.2005","article-title":"Human immunodeficiency virus Nef induces rapid internalization of the T-cell coreceptor CD8alphabeta","volume":"79","author":"Stove","year":"2005","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12977-021-00576-y","article-title":"Residues T(48) and A(49) in HIV-1 NL4-3 Nef are responsible for the counteraction of autophagy initiation, which prevents the ubiquitin-dependent degradation of Gag through autophagosomes","volume":"18","author":"Chen","year":"2021","journal-title":"Retrovirology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/15548627.2020.1725401","article-title":"HIV-1 Nef counteracts autophagy restriction by enhancing the association between BECN1 and its inhibitor BCL2 in a PRKN-dependent manner","volume":"17","author":"Shi","year":"2021","journal-title":"Autophagy"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15540","DOI":"10.1074\/jbc.RA120.014668","article-title":"Nef homodimers down-regulate SERINC5 by AP-2-mediated endocytosis to promote HIV-1 infectivity","volume":"295","author":"Staudt","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e01651-18","DOI":"10.1128\/JVI.01651-18","article-title":"Murine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome\/Lysosome Pathway to Counteract SERINC5 Antiretroviral Activity","volume":"93","author":"Li","year":"2019","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13197","DOI":"10.1073\/pnas.1612044113","article-title":"S2 from equine infectious anemia virus is an infectivity factor which counteracts the retroviral inhibitors SERINC5 and SERINC3","volume":"113","author":"Chande","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1038\/s41467-022-30609-9","article-title":"SARS-CoV-2 ORF7a potently inhibits the antiviral effect of the host factor SERINC5","volume":"13","author":"Timilsina","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhao, F., Xu, F., Liu, X., Hu, Y., Wei, L., Fan, Z., Wang, L., Huang, Y., Mei, S., and Guo, L. (2022). SERINC5 restricts influenza virus infectivity. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010907"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wang, H., Zhang, J., Yang, J., Bai, L., Zheng, B., Zheng, T., Wang, Y., Li, J., and Zhang, W. (2020). SERINC5 Inhibits the Secretion of Complete and Genome-Free Hepatitis B Virions Through Interfering With the Glycosylation of the HBV Envelope. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00697"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, W., Zhang, Z., Zhang, L., Li, H., Fan, S., Zhu, E., Fan, J., Li, Z., Chen, W., and Yi, L. (2020). Antiviral Role of Serine Incorporator 5 (SERINC5) Proteins in Classical Swine Fever Virus Infection. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.580233"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nature01593","article-title":"A role for Wnt signalling in self-renewal of haematopoietic stem cells","volume":"423","author":"Reya","year":"2003","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"85","DOI":"10.5501\/wjv.v5.i2.85","article-title":"Determination of 50% endpoint titer using a simple formula","volume":"5","author":"Ramakrishnan","year":"2016","journal-title":"World J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jviromet.2013.01.004","article-title":"Quantitation of HIV DNA integration: Effects of differential integration site distributions on Alu-PCR assays","volume":"189","author":"Brady","year":"2013","journal-title":"J. Virol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1242\/jeb.203.3.447","article-title":"Identification of a ubiquitous family of membrane proteins and their expression in mouse brain","volume":"203","author":"Grossman","year":"2000","journal-title":"J. Exp. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e01221-19","DOI":"10.1128\/JVI.01221-19","article-title":"Characterization of Endogenous SERINC5 Protein as Anti-HIV-1 Factor","volume":"93","author":"Passos","year":"2019","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e01554-19","DOI":"10.1128\/JVI.01554-19","article-title":"A Conserved Acidic-Cluster Motif in SERINC5 Confers Partial Resistance to Antagonism by HIV-1 Nef","volume":"94","author":"Stoneham","year":"2020","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e00137-17","DOI":"10.1128\/JVI.00137-17","article-title":"Identification of SERINC5-001 as the Predominant Spliced Isoform for HIV-1 Restriction","volume":"91","author":"Zhang","year":"2017","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1111\/j.1440-1681.2011.05599.x","article-title":"GAPDH: A common enzyme with uncommon functions","volume":"39","author":"Nicholls","year":"2012","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1152\/physiolgenomics.00025.2005","article-title":"GAPDH as a housekeeping gene: Analysis of GAPDH mRNA expression in a panel of 72 human tissues","volume":"21","author":"Barber","year":"2005","journal-title":"Physiol. Genom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1042\/BJ20081847","article-title":"Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum","volume":"417","author":"Michalak","year":"2009","journal-title":"Biochem. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1042\/bj3440281","article-title":"Calreticulin: One protein, one gene, many functions","volume":"344","author":"Michalak","year":"1999","journal-title":"Biochem. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-59745-157-4_4","article-title":"LC3 and Autophagy","volume":"445","author":"Tanida","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Koukourakis, M.I., Kalamida, D., Giatromanolaki, A., Zois, C.E., Sivridis, E., Pouliliou, S., Mitrakas, A., Gatter, K.C., and Harris, A.L. (2015). Autophagosome Proteins LC3A, LC3B and LC3C Have Distinct Subcellular Distribution Kinetics and Expression in Cancer Cell Lines. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137675"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Truman, C.T., Jarvelin, A., Davis, I., and Castello, A. (2020). HIV Rev-isited. Open Biol., 10.","DOI":"10.1098\/rsob.200320"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S1074-5521(97)90124-1","article-title":"Viral RNA export","volume":"4","author":"Hope","year":"1997","journal-title":"Chem. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1042\/bse0360115","article-title":"RNA export: Insights from viral models","volume":"36","author":"Harris","year":"2000","journal-title":"Essays Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e02515-16","DOI":"10.1128\/JVI.02515-16","article-title":"Characterizing HIV-1 Splicing by Using Next-Generation Sequencing","volume":"91","author":"Emery","year":"2017","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3527(09)74001-1","article-title":"Chapter 1. Regulation of HIV-1 alternative RNA splicing and its role in virus replication","volume":"74","author":"Stoltzfus","year":"2009","journal-title":"Adv. Virus Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1080\/15476286.2020.1814556","article-title":"Secondary structure of the SARS-CoV-2 5\u2032-UTR","volume":"18","author":"Miao","year":"2021","journal-title":"RNA Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5695","DOI":"10.1038\/s41467-021-25999-1","article-title":"In vivo structure and dynamics of the SARS-CoV-2 RNA genome","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.sjbs.2020.12.053","article-title":"Genome composition and genetic characterization of SARS-CoV-2","volume":"28","author":"Alshammari","year":"2021","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.cell.2020.04.011","article-title":"The Architecture of SARS-CoV-2 Transcriptome","volume":"181","author":"Kim","year":"2020","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Meseguer, S., Rubio, M.P., Lainez, B., Perez-Benavente, B., Perez-Moraga, R., Romera-Giner, S., Garcia-Garcia, F., Martinez-Macias, O., Cremades, A., and Iborra, F.J. (2023). SARS-CoV-2-encoded small RNAs are able to repress the host expression of SERINC5 to facilitate viral replication. Front. Microbiol., 14.","DOI":"10.3389\/fmicb.2023.1066493"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0079-6603(08)60742-4","article-title":"Actinomycin and nucleic acid function","volume":"3","author":"Reich","year":"1964","journal-title":"Prog. Nucleic Acid. Res. Mol. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e00753-18","DOI":"10.1128\/JVI.00753-18","article-title":"An N-Glycosylated Form of SERINC5 Is Specifically Incorporated into HIV-1 Virions","volume":"92","author":"Sharma","year":"2018","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4368","DOI":"10.1038\/s41467-023-39262-2","article-title":"Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry","volume":"14","author":"Leonhardt","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.chom.2011.05.004","article-title":"The TRIM family protein KAP1 inhibits HIV-1 integration","volume":"9","author":"Allouch","year":"2011","journal-title":"Cell Host Microbe"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1961\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:54:11Z","timestamp":1760129651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/9\/1961"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,20]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["v15091961"],"URL":"https:\/\/doi.org\/10.3390\/v15091961","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,20]]}}}