CoChat
Sign Up
Cited by 16HIV Research and TreatmentT-cell and B-cell ImmunologySARS-CoV-2 and COVID-19 Research

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions

Open access
Manoussaka, Maria S, Berry, Neil, Ferguson, Deborah, Stebbings, Richard, Robinson, Mark, Ham, Claire, Page, Mark, Li, Bo, Das, Atze T, Berkhout, Ben, Almond, Neil, Cranage, Martin P·2013·Retrovirology
DOI 10.1186/1742-4690-10-59PMC PMC3706341
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV. Results: Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239Δ nef (SIV-rtTAΔ nef), we show that under replication-permissive conditions SIV-rtTAΔ nef is fully viable. Twelve rhesus macaques were infected with a peak plasma vRNA on average two log 10 lower than in 6 macaques infected with unconditionally replication-competent SIVΔ nef. Consistent with the attenuated phenotype of the viruses the majority of animals displayed low or undetectable levels of viraemia by 42-84 days after infection. Next, comparison of circulating T cells before and after chronic infection with parental SIVΔ nef revealed a profound global polarisation toward CD28-CCR7- T-effector memory 2 (T EM2) cells within CD95+CD4+ and CD95+CD8+ populations. Critically, a similar effect was seen in the CD95+ CD4+ population and to somewhat lesser extent in the CD95+ CD8+ population of SIV-rtTAΔ nef chronically infected macaques that were maintained on doxycycline, but was not seen in animals from which doxycycline had been withdrawn. The proportions of gut-homing T-central memory (T CM) and T EM defined by the expression of α4β7 and CD95 and differential expression of CD28 were increased in CD4 and CD8 cells under replication competent conditions and gut-homing CD4 T CM were also significantly increased under non-permissive conditions. T EM2 polarisation was seen in the small intestines of animals under replication permissive conditions but the effect was less pronounced than in the circulation. Intracellular cytokine staining of circulating SIV-specific T cells for IL-2, IFN-γ, TNF-α and IL-17 showed that the extent of polyfunctionality in CD4 and CD8 T cells was associated with replication permissivity; however, signature patterns of cytokine combinations were not distinguishable between groups of macaques. Conclusion: Taken together our results show that the global T memory cell compartment is profoundly skewed towards a mature effector phenotype by attenuated SIV. Results with the replication-conditional mutant suggest that maintenance of this effect, that may be important in vaccine design, might require persistence of replicating virus.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/1742-4690-10-59

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Recent studies successfully applied V16 to control transgene expression in mice and non-human primates.

    “Recent studies successfully applied V16 to control transgene expression in mice [85, 86] and non-human primates [62, 87].”

    From Tet-On Systems For Doxycycline-inducible Gene Expression (2016) · cites this paper as [62]

    The Methods (Animals and viruses; page unavailable) identify rtTA-V16 in the doxycycline-dependent SIV used to infect rhesus macaques. The Results (Differential localisation of SIV-rtTAΔnef and SIVΔnef in tissues; page unavailable) report viral transcripts in sampled tissues of doxycycline-treated macaques but not in those from which doxycycline was withdrawn. This supports V16-associated control of viral expression in non-human primates, but the paper does not demonstrate control of a separate transgene; the mice portion is attributed to other citations. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 52

  1. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB: Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994, 68 (9): 6103-6110. · DOI
  2. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD: Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994, 68 (7): 4650-4655. · DOI
  3. Kaur A, Alexander L, Staprans SI, Denekamp L, Hale CL, McClure HM, Feinberg MB, Desrosiers RC, Johnson RP: Emergence of cytotoxic T lymphocyte escape mutations in nonpathogenic simian immunodeficiency virus infection. Eur J Immunol. 2001, 31 (11): 3207-3217. 10.1002/1521-4141(200111)31:11<3207::AID-IMMU3207>3.0.CO;2-H. · DOI
  4. Soudeyns H, Paolucci S, Chappey C, Daucher MB, Graziosi C, Vaccarezza M, Cohen OJ, Fauci AS, Pantaleo G: Selective pressure exerted by immunodominant HIV-1-specific cytotoxic T lymphocyte responses during primary infection drives genetic variation restricted to the cognate epitope. Eur J Immunol. 1999, 29 (11): 3629-3635. 10.1002/(SICI)1521-4141(199911)29:11<3629::AID-IMMU3629>3.0.CO;2-O. · DOI
  5. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999, 283 (5403): 857-860. 10.1126/science.283.5403.857. · DOI
  6. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L: Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999, 189 (6): 991-998. 10.1084/jem.189.6.991. · DOI
  7. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD: HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996, 271 (5255): 1582-1586. 10.1126/science.271.5255.1582. · DOI
  8. Silvestri G, Feinberg MB: Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest. 2003, 112 (6): 821-824. · DOI
  9. De Milito A, Morch C, Sonnerborg A, Chiodi F: Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS. 2001, 15 (8): 957-964. 10.1097/00002030-200105250-00003. · DOI
  10. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT: CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004, 200 (6): 749-759. 10.1084/jem.20040874. · DOI
  11. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006, 12 (12): 1365-1371. · DOI · Paper page
  12. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC: Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science. 1992, 258 (5090): 1938-1941. 10.1126/science.1470917. · DOI
  13. Rud EW, Cranage M, Yon J, Quirk J, Ogilvie L, Cook N, Webster S, Dennis M, Clarke BE: Molecular and biological characterization of simian immunodeficiency virus macaque strain 32H proviral clones containing nef size variants. J Gen Virol. 1994, 75 (Pt 3): 529-543. · DOI
  14. Desrosiers RC, Wyand MS, Kodama T, Ringler DJ, Arthur LO, Sehgal PK, Letvin NL, King NW, Daniel MD: Vaccine protection against simian immunodeficiency virus infection. Proc Natl Acad Sci U S A. 1989, 86 (16): 6353-6357. 10.1073/pnas.86.16.6353. · DOI
  15. Nilsson C, Makitalo B, Thorstensson R, Norley S, Binninger-Schinzel D, Cranage M, Rud E, Biberfeld G, Putkonen P: Live attenuated simian immunodeficiency virus (SIV)mac in macaques can induce protection against mucosal infection with SIVsm. AIDS. 1998, 12 (17): 2261-2270. 10.1097/00002030-199817000-00006. · DOI
  16. Cranage MP, Whatmore AM, Sharpe SA, Cook N, Polyanskaya N, Leech S, Smith JD, Rud EW, Dennis MJ, Hall GA: Macaques infected with live attenuated SIVmac are protected against superinfection via the rectal mucosa. Virology. 1997, 229 (1): 143-154. 10.1006/viro.1996.8419. · DOI
  17. Almond N, Kent K, Cranage M, Rud E, Clarke B, Stott EJ: Protection by attenuated simian immunodeficiency virus in macaques against challenge with virus-infected cells. Lancet. 1995, 345 (8961): 1342-1344. 10.1016/S0140-6736(95)92540-6. · DOI
  18. Miller CJ, McChesney MB, Lu X, Dailey PJ, Chutkowski C, Lu D, Brosio P, Roberts B, Lu Y: Rhesus macaques previously infected with simian/human immunodeficiency virus are protected from vaginal challenge with pathogenic SIVmac239. J Virol. 1997, 71 (3): 1911-1921. · DOI
  19. Tenner-Racz K, Stahl Hennig C, Uberla K, Stoiber H, Ignatius R, Heeney J, Steinman RM, Racz P: Early protection against pathogenic virus infection at a mucosal challenge site after vaccination with attenuated simian immunodeficiency virus. Proc Natl Acad Sci USA. 2004, 101 (9): 3017-3022. 10.1073/pnas.0308677101. · DOI
  20. Whatmore AM, Cook N, Hall GA, Sharpe S, Rud EW, Cranage MP: Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence. J Virol. 1995, 69 (8): 5117-5123. · DOI
  21. Baba TW, Liska V, Khimani AH, Ray NB, Dailey PJ, Penninck D, Bronson R, Greene MF, McClure HM, Martin LN: Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques. Nat Med. 1999, 5 (2): 194-203. 10.1038/5557. · DOI
  22. Johnson RP, Lifson JD, Czajak SC, Cole KS, Manson KH, Glickman R, Yang J, Montefiori DC, Montelaro R, Wyand MS: Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation. J Virol. 1999, 73 (6): 4952-4961. · DOI
  23. Mori K, Yasutomi Y, Ohgimoto S, Nakasone T, Takamura S, Shioda T, Nagai Y: Quintuple deglycosylation mutant of simian immunodeficiency virus SIVmac239 in rhesus macaques: Robust primary replication, tightly contained chronic infection, and elicitation of potent immunity against the parental wild-type strain. J Virol. 2001, 75 (9): 4023-4028. 10.1128/JVI.75.9.4023-4028.2001. · DOI
  24. Das AT, Klaver B, Harwig A, Vink M, Ooms M, Centlivre M, Berkhout B: Construction of a doxycycline-dependent simian immunodeficiency virus reveals a nontranscriptional function of tat in viral replication. J Virol. 2007, 81 (20): 11159-11169. 10.1128/JVI.01354-07. · DOI
  25. Das AT, Klaver B, Centlivre M, Harwig A, Ooms M, Page M, Almond N, Yuan F, Piatak M, Lifson JD: Optimization of the doxycycline-dependent simian immunodeficiency virus through in vitro evolution. Retrovirology. 2008, 5: 44-10.1186/1742-4690-5-44. · DOI
  26. Pitcher CJ, Hagen SI, Walker JM, Lum R, Mitchell BL, Maino VC, Axthelm MK, Picker LJ: Development and homeostasis of T cell memory in rhesus macaque. J Immunol. 2002, 168 (1): 29-43. · DOI · Paper page
  27. Picker LJ, Reed-Inderbitzin EF, Hagen SI, Edgar JB, Hansen SG, Legasse A, Planer S, Piatak M, Lifson JD, Maino VC: IL-15 induces CD4 effector memory T cell production and tissue emigration in nonhuman primates. J Clin Invest. 2006, 116 (6): 1514-1524. 10.1172/JCI27564. · DOI
  28. Grossman Z, Picker LJ: Pathogenic mechanisms in simian immunodeficiency virus infection. Curr Opin HIV AIDS. 2008, 3 (3): 380-386. 10.1097/COH.0b013e3282fbaae6. · DOI
  29. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA: Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998, 280 (5362): 427-431. 10.1126/science.280.5362.427. · DOI
  30. Cromwell MA, Veazey RS, Altman JD, Mansfield KG, Glickman R, Allen TM, Watkins DI, Lackner AA, Johnson RP: Induction of mucosal homing virus-specific CD8(+) T lymphocytes by attenuated simian immunodeficiency virus. J Virol. 2000, 74 (18): 8762-8766. 10.1128/JVI.74.18.8762-8766.2000. · DOI
  31. Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, Barclay GR, Smedley J, Pung R, Oliveira KM: Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog. 2010, 6 (8): e1001052-10.1371/journal.ppat.1001052. · DOI
  32. Gauduin MC, Yu Y, Barabasz A, Carville A, Piatak M, Lifson JD, Desrosiers RC, Johnson RP: Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection. J Exp Med. 2006, 203 (12): 2661-2672. 10.1084/jem.20060134. · DOI
  33. Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA: HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol. 2008, 9 (3): 301-309. 10.1038/ni1566. · DOI
  34. Kader M, Wang X, Piatak M, Lifson J, Roederer M, Veazey R, Mattapallil JJ: Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol. 2009, 2 (5): 439-449. 10.1038/mi.2009.90. · DOI
  35. Ansari AA, Reimann KA, Mayne AE, Takahashi Y, Stephenson ST, Wang R, Wang X, Li J, Price AA, Little DM: Blocking of alpha4beta7 gut-homing integrin during acute infection leads to decreased plasma and gastrointestinal tissue viral loads in simian immunodeficiency virus-infected rhesus macaques. J Immunol. 2011, 186 (2): 1044-1059. 10.4049/jimmunol.1003052. · DOI
  36. Wang X, Xu H, Gill AF, Pahar B, Kempf D, Rasmussen T, Lackner AA, Veazey RS: Monitoring alpha4beta7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol. 2009, 2 (6): 518-526. 10.1038/mi.2009.104. · DOI
  37. Schultheiss T, Schulte R, Sauermann U, Ibing W, Stahl-Hennig C: Strong mucosal immune responses in SIV infected macaques contribute to viral control and preserved CD4+ T-cell levels in blood and mucosal tissues. Retrovirology. 2011, 8: 24-10.1186/1742-4690-8-24. · DOI
  38. Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, Lederman MM, Benito JM, Goepfert PA, Connors M: HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood. 2006, 107 (12): 4781-4789. 10.1182/blood-2005-12-4818. · DOI
  39. Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, Ferrari MG, Zaffiri L, Tryniszewska E, Tsai WP, Vaccari M: Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 2008, 1 (4): 279-288. 10.1038/mi.2008.14. · DOI
  40. Nigam P, Kwa S, Velu V, Amara RR: Loss of IL-17-producing CD8 T cells during late chronic stage of pathogenic simian immunodeficiency virus infection. J Immunol. 2011, 186 (2): 745-753. 10.4049/jimmunol.1002807. · DOI
  41. Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, Whizin N, Oswald K, Shoemaker R, Swanson T: Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature. 2011, 473 (7348): 523-527. 10.1038/nature10003. · DOI
  42. Fukazawa Y, Park H, Cameron MJ, Lefebvre F, Lum R, Coombes N, Mahyari E, Hagen SI, Bae JY, Iii MD: Lymph node T cell responses predict the efficacy of live attenuated SIV vaccines. Nat Med. 2012, 18 (11): 1673-1681. 10.1038/nm.2934. · DOI
  43. Kleibeuker W, Zhou X, Centlivre M, Legrand N, Page M, Almond N, Berkhout B, Das AT: A sensitive cell-based assay to measure the doxycycline concentration in biological samples. Hum Gene Ther. 2009, 20 (5): 524-530. 10.1089/hum.2008.182. · DOI · Paper page
  44. Berry N, Stebbings R, Ferguson D, Ham C, Alden J, Brown S, Jenkins A, Lines J, Duffy L, Davis L: Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8). J Gen Virol. 2008, 89 (Pt 9): 2240-2251. · DOI
  45. Berry N, Herrera C, Cranage M: Detection, quantification, and characterisation of HIV/SIV. Methods Mol Biol. 2011, 665: 133-160. · DOI
  46. Canto-Nogues C, Jones S, Sangster R, Silvera P, Hull R, Cook R, Hall G, Walker B, Stott EJ, Hockley D: In situ hybridization and immunolabelling study of the early replication of simian immunodeficiency virus (SIVmacJ5) in vivo. J Gen Virol. 2001, 82 (Pt 9): 2225-2234. · DOI
  47. Clarke S, Berry N, Ham C, Alden J, Almond N, Ferguson D: Neuropathology of wild-type and nef-attenuated T cell tropic simian immunodeficiency virus (SIVmac32H) and macrophage tropic neurovirulent SIVmac17E-Fr in cynomolgus macaques. J Neurovirol. 2012, 18 (2): 100-112. 10.1007/s13365-012-0084-3. · DOI
  48. Kent KA, Gritz L, Stallard G, Cranage MP, Collignon C, Thiriart C, Corcoran T, Silvera P, Stott EJ: Production and of monoclonal antibodies to simian immunodeficiency virus envelope glycoproteins. AIDS. 1991, 5 (7): 829-836. 10.1097/00002030-199107000-00006. · DOI
  49. Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, Asher TE, Douek DC, Harari A, Pantaleo G: Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med. 2007, 204 (6): 1405-1416. 10.1084/jem.20062363. · DOI
  50. Petrovas C, Yamamoto T, Gerner MY, Boswell KL, Wloka K, Smith EC, Ambrozak DR, Sandler NG, Timmer KJ, Sun X: CD4 T follicular helper cell dynamics during SIV infection. J Clin Invest. 2012, 122 (9): 3281-3294. 10.1172/JCI63039. · DOI
  51. Kannanganat S, Ibegbu C, Chennareddi L, Robinson HL, Amara RR: Multiple-cytokine-producing antiviral CD4 T cells are functionally superior to single-cytokine-producing cells. J Virol. 2007, 81 (16): 8468-8476. 10.1128/JVI.00228-07. · DOI
  52. Genesca M, Rourke T, Li J, Bost K, Chohan B, McChesney MB, Miller CJ: Live attenuated lentivirus infection elicits polyfunctional simian immunodeficiency virus Gag-specific CD8+ T cells with reduced apoptotic susceptibility in rhesus macaques that control virus replication after challenge with pathogenic SIVmac239. J Immunol. 2007, 179 (7): 4732-4740. · DOI

Cited by

Sorted by citations

Metadata

Authors
Manoussaka, M. S., Berry, N., Ferguson, D., Stebbings, R., Robinson, M., Ham, C., Page, M., Li, B., Das, A. T., Berkhout, B., Almond, N., & Cranage, M. P.
Affiliations
  • St George's, University of London (GB)
  • National Institute for Biological Standards and Control (GB)
  • University of Amsterdam (NL)
Corresponding author
Cranage, Martin P
ORCID
Venue
Retrovirology
Publisher
Springer Science and Business Media LLC
Published
2013-06-05
Volume
10
Issue
1
Pages
59-59
ISSN
1742-4690 (ISSN-L)
DOI
10.1186/1742-4690-10-59
PMC
PMC3706341
OpenAlex
W2160719650
Cited by
16
References
1
Citations by year
2026: 1 · 2017: 1 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 1
FWCI
2.14
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Retrovirology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
  • International AIDS Vaccine Initiative
  • Aids Fonds (2005022)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
SIVmac239, CD28, CCR7, Fas, gut-homing T cells, alpha4beta7, CD4+ T cells, CD8+ T cells, T cell polyfunctionality, rhesus monkeys, HIV vaccine
MeSH terms
Animals, Anti-Infective Agents, Antibodies, Viral, Doxycycline, Immunologic Memory, Intestine, Small, Macaca mulatta, Phenotype, RNA, Viral, T-Lymphocytes, Vaccines, Attenuated, Viremia, Virus Replication, Superinfection, Simian Immunodeficiency Virus, Up-Regulation, Simian Acquired Immunodeficiency Syndrome, SAIDS Vaccines

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review