{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:31:03Z","timestamp":1778873463425,"version":"3.51.4"},"reference-count":57,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T00:00:00Z","timestamp":1675728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PGT-162407"],"award-info":[{"award-number":["PGT-162407"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"College of Medicine Research Award","award":["PGT-162407"],"award-info":[{"award-number":["PGT-162407"]}]},{"name":"College of Medicine Graduate Research Award","award":["PGT-162407"],"award-info":[{"award-number":["PGT-162407"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The seven human APOBEC3 enzymes (APOBEC3A through H, excluding E) are host restriction factors. Most of the APOBEC3 enzymes can restrict HIV-1 replication with different efficiencies. The HIV-1 Vif protein combats APOBEC3-mediated restriction by inducing ubiquitination and degradation in the proteasome. APOBEC3F and APOBEC3G can hetero-oligomerize, which increases their restriction capacity and resistance to Vif. Here we determined if APOBEC3C, APOBEC3F, or APOBEC3G could hetero-oligomerize with APOBEC3H haplotype I. APOBEC3H haplotype I has a short half-life in cells due to ubiquitination and degradation by host proteins, but is also resistant to Vif. We hypothesized that hetero-oligomerization with APOBEC3H haplotype I may result in less Vif-mediated degradation of the interacting APOBEC3 and stabilize APOBEC3H haplotype I, resulting in more efficient HIV-1 restriction. Although we found that all three APOBEC3s could interact with APOBEC3H haplotype I, only APOBEC3F affected APOBEC3H haplotype I by surprisingly accelerating its proteasomal degradation. However, this increased APOBEC3F levels in cells and virions in the absence or presence of Vif and enabled APOBEC3F-mediated restriction of HIV-1 in the presence of Vif. Altogether, the data suggest that APOBEC3 enzymes can co-regulate each other at the protein level and that they cooperate to ensure HIV-1 inactivation rather than evolution.<\/jats:p>","DOI":"10.3390\/v15020463","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:57:16Z","timestamp":1675828636000},"page":"463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Stability of APOBEC3F in the Presence of the APOBEC3 Antagonist HIV-1 Vif Increases at the Expense of Co-Expressed APOBEC3H Haplotype I"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-4363","authenticated-orcid":false,"given":"Maria","family":"Yousefi","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun Kumar","family":"Annan Sudarsan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-8101","authenticated-orcid":false,"given":"Amit","family":"Gaba","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4673-8978","authenticated-orcid":false,"given":"Linda","family":"Chelico","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gaba, A., Flath, B., and Chelico, L. (2021). Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses. Viruses, 13.","DOI":"10.3390\/v13061084"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Uriu, K., Kosugi, Y., Ito, J., and Sato, K. (2021). The Battle between Retroviruses and APOBEC3 Genes: Its Past and Present. Viruses, 13.","DOI":"10.3390\/v13010124"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cheng, A., Moraes, S., Shaban, N., Fanunza, E., Bierle, C., Southern, P., Bresnahan, W., Rice, S., and Harris, R. (2021). APOBECs and Herpesviruses. Viruses, 13.","DOI":"10.3390\/v13030390"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1111\/jvh.12192","article-title":"The inhibition of hepatitis B virus by APOBEC cytidine deaminases","volume":"20","author":"Janahi","year":"2013","journal-title":"J. Viral Hepat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5960","DOI":"10.1038\/s41598-018-24448-2","article-title":"APOBEC3-mediated restriction of RNA virus replication","volume":"8","author":"Milewska","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Xu, W., Byun, H., and Dudley, J. (2020). The Role of APOBECs in Viral Replication. Microorganisms, 8.","DOI":"10.20944\/preprints202011.0013.v1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/s41564-017-0063-9","article-title":"Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G","volume":"3","author":"Pollpeter","year":"2017","journal-title":"Nat. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1006\/geno.2002.6718","article-title":"An Anthropoid-Specific Locus of Orphan C to U Rna-Editing Enzymes on Chromosome 22","volume":"79","author":"Jarmuz","year":"2002","journal-title":"Genomics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/molbev\/msi026","article-title":"Evolution of the AID\/APOBEC Family of Polynucleotide (Deoxy)cytidine Deaminases","volume":"22","author":"Conticello","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1093\/nar\/gkq174","article-title":"Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: Implications for HIV-1 restriction","volume":"38","author":"Refsland","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9474","DOI":"10.1128\/JVI.01089-09","article-title":"Defining APOBEC3 Expression Patterns in Human Tissues and Hematopoietic Cell Subsets","volume":"83","author":"Koning","year":"2009","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11220","DOI":"10.1128\/JVI.05238-11","article-title":"Human and Rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H Demonstrate a Conserved Capacity To Restrict Vif-Deficient HIV-1","volume":"85","author":"Hultquist","year":"2011","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Wittkopp, C.J., Adolph, M.B., Wu, L.I., Chelico, L., and Emerman, M. (2016). A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses. PLOS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005865"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nsmb758","article-title":"Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome","volume":"11","author":"Yu","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1021\/acsinfecdis.7b00221","article-title":"Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates","volume":"4","author":"Adolph","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Adolph, M.B., Webb, J., and Chelico, L. (2013). Retroviral Restriction Factor APOBEC3G Delays the Initiation of DNA Synthesis by HIV-1 Reverse Transcriptase. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064196"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7096","DOI":"10.1093\/nar\/gkm750","article-title":"Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G","volume":"35","author":"Iwatani","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1111\/febs.15550","article-title":"Multifaceted HIV-1 Vif interactions with human E3 ubiquitin ligase and APOBEC3s","volume":"288","author":"Hu","year":"2020","journal-title":"FEBS J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhou, X., Evans, S.L., Han, X., Liu, Y., and Yu, X.F. (2012). Characterization of the Interaction of Full-Length Hiv-1 Vif Protein with Its Key Regulator Cbfbeta and Crl5 E3 Ubiquitin Ligase Components. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033495"},{"key":"ref_20","first-page":"371","article-title":"Vif Hijacks Cbf-Beta to Degrade Apobec3g and Promote Hiv-1 Infection","volume":"481","author":"Kim","year":"2011","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature10718","article-title":"T-Cell Differentiation Factor Cbf-Beta Regulates Hiv-1 Vif-Mediated Evasion of Host Restriction","volume":"481","author":"Zhang","year":"2011","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/nm.4156","article-title":"Defective proviruses rapidly accumulate during acute HIV-1 infection","volume":"22","author":"Bruner","year":"2016","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Holmes, M., Zhang, F., and Bieniasz, P.D. (2015). Single-Cell and Single-Cycle Analysis of HIV-1 Replication. PLOS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004961"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"02230-16","DOI":"10.1128\/JVI.02230-16","article-title":"Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G","volume":"91","author":"Ara","year":"2017","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e01498","DOI":"10.1016\/j.heliyon.2019.e01498","article-title":"Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance","volume":"5","author":"Mohammadzadeh","year":"2019","journal-title":"Heliyon"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3763","DOI":"10.1038\/s41598-018-21955-0","article-title":"Understanding the Structure, Multimerization, Subcellular Localization and mC Selectivity of a Genomic Mutator and Anti-HIV Factor APOBEC3H","volume":"8","author":"Ito","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/s41467-017-01309-6","article-title":"APOBEC3H structure reveals an unusual mechanism of interaction with duplex RNA","volume":"8","author":"Bohn","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.molcel.2017.12.010","article-title":"The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism","volume":"69","author":"Shaban","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10368","DOI":"10.1093\/nar\/gky676","article-title":"Structural basis of chimpanzee APOBEC3H dimerization stabilized by double-stranded RNA","volume":"46","author":"Matsuoka","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4891","DOI":"10.1016\/j.jmb.2018.11.006","article-title":"RNA-Mediated Dimerization of the Human Deoxycytidine Deaminase APOBEC3H Influences Enzyme Activity and Interaction with Nucleic Acids","volume":"430","author":"Feng","year":"2018","journal-title":"J. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1128\/JVI.01665-08","article-title":"Polymorphisms and Splice Variants Influence the Antiretroviral Activity of Human APOBEC3H","volume":"83","author":"Harari","year":"2009","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chesarino, N.M., and Emerman, M. (2020). Polymorphisms in Human APOBEC3H Differentially Regulate Ubiquitination and Antiviral Activity. Viruses, 12.","DOI":"10.1101\/2020.02.07.939439"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.chom.2008.07.005","article-title":"Antiretroelement Activity of APOBEC3H Was Lost Twice in Recent Human Evolution","volume":"4","author":"OhAinle","year":"2008","journal-title":"Cell Host Microbe"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8197","DOI":"10.1128\/JVI.00624-11","article-title":"Polymorphism in Human APOBEC3H Affects a Phenotype Dominant for Subcellular Localization and Antiviral Activity","volume":"85","author":"Li","year":"2011","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1128\/JVI.02049-10","article-title":"Analysis of Human APOBEC3H Haplotypes and Anti-Human Immunodeficiency Virus Type 1 Activity","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27188","DOI":"10.1074\/jbc.M115.666065","article-title":"Natural Polymorphisms and Oligomerization of Human APOBEC3H Contribute to Single-stranded DNA Scanning Ability","volume":"290","author":"Feng","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.virol.2018.11.004","article-title":"Polymorphisms of the cytidine deaminase APOBEC3F have different HIV-1 restriction efficiencies","volume":"527","author":"Mohammadzadeh","year":"2018","journal-title":"Virology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1128\/JVI.00676-12","article-title":"APOBEC3G Restricts HIV-1 to a Greater Extent than APOBEC3F and APOBEC3DE in Human Primary CD4 + T Cells and Macrophages","volume":"87","author":"Chaipan","year":"2013","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1093\/nar\/gkx066","article-title":"Cytidine deaminase efficiency of the lentiviral viral restriction factor APOBEC3C correlates with dimerization","volume":"45","author":"Adolph","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"30812","DOI":"10.1074\/jbc.M112.393181","article-title":"Biochemical Analysis of Hypermutation by the Deoxycytidine Deaminase APOBEC3A","volume":"287","author":"Love","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"167306","DOI":"10.1016\/j.jmb.2021.167306","article-title":"Divergence in Dimerization and Activity of Primate APOBEC3C","volume":"433","author":"Gaba","year":"2021","journal-title":"J. Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/s41467-020-14377-y","article-title":"Understanding the structural basis of HIV-1 restriction by the full length double-domain APOBEC3G","volume":"11","author":"Yang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7438","DOI":"10.1093\/nar\/gkt527","article-title":"Binding of RNA by APOBEC3G controls deamination-independent restriction of retroviruses","volume":"41","author":"Savoie","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ara, A., Love, R.P., and Chelico, L. (2014). Different Mutagenic Potential of HIV-1 Restriction Factors APOBEC3G and APOBEC3F Is Determined by Distinct Single-Stranded DNA Scanning Mechanisms. PLOS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004024"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/msb.2011.75","article-title":"Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega","volume":"7","author":"Sievers","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/bioinformatics\/16.4.400","article-title":"Detecting hypermutations in viral sequences with an emphasis on G \u2192 A hypermutation","volume":"16","author":"Rose","year":"2000","journal-title":"Bioinformatics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1128\/JVI.01509-09","article-title":"A Single Amino Acid Difference in Human APOBEC3H Variants Determines HIV-1 Vif Sensitivity","volume":"84","author":"Zhen","year":"2010","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1128\/JVI.01344-09","article-title":"The Range of Human APOBEC3H Sensitivity to Lentiviral Vif Proteins","volume":"84","author":"Li","year":"2010","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.cub.2004.06.050","article-title":"APOBEC3F Properties and Hypermutation Preferences Indicate Activity against HIV-1 In Vivo","volume":"14","author":"Liddament","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7848","DOI":"10.1093\/nar\/gkw653","article-title":"APOBEC3 proteins can copackage and comutate HIV-1 genomes","volume":"44","author":"Desimmie","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"McDonnell, M.M., Karvonen, S.C., Gaba, A., Flath, B., Chelico, L., and Emerman, M. (2021). Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms. PLOS Pathog., 17.","DOI":"10.1101\/2021.04.06.438583"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12918","DOI":"10.1038\/ncomms12918","article-title":"The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis","volume":"7","author":"Starrett","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1016\/j.jmb.2016.05.022","article-title":"APOBEC3DE Antagonizes Hepatitis B Virus Restriction Factors APOBEC3F and APOBEC3G","volume":"428","author":"Bouzidi","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/s41586-022-04972-y","article-title":"Mechanisms of APOBEC3 mutagenesis in human cancer cells","volume":"607","author":"Petljak","year":"2022","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"200188","DOI":"10.1098\/rsob.200188","article-title":"The interesting relationship between APOBEC3 deoxycytidine deaminases and cancer: A long road ahead","volume":"10","author":"Flath","year":"2020","journal-title":"Open Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1158\/2159-8290.CD-15-0344","article-title":"APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity","volume":"5","author":"Swanton","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1038\/s41588-022-01196-8","article-title":"Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer","volume":"54","author":"Petljak","year":"2022","journal-title":"Nat. Genet."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/463\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:26:30Z","timestamp":1760120790000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/463"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,7]]},"references-count":57,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["v15020463"],"URL":"https:\/\/doi.org\/10.3390\/v15020463","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,7]]}}}