The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein
Open accessAbstract
Macrophages and dendritic cells have key roles in viral infections, providing virus reservoirs that frequently resist antiviral therapies and linking innate virus detection to antiviral adaptive immune responses. Human immunodeficiency virus 1 (HIV-1) fails to transduce dendritic cells and has a reduced ability to transduce macrophages, due to an as yet uncharacterized mechanism that inhibits infection by interfering with efficient synthesis of viral complementary DNA. In contrast, HIV-2 and related simian immunodeficiency viruses (SIVsm/mac) transduce myeloid cells efficiently owing to their virion-associated Vpx accessory proteins, which counteract the restrictive mechanism. Here we show that the inhibition of HIV-1 infection in macrophages involves the cellular SAM domain HD domain-containing protein 1 (SAMHD1). Vpx relieves the inhibition of lentivirus infection in macrophages by loading SAMHD1 onto the CRL4(DCAF1) E3 ubiquitin ligase, leading to highly efficient proteasome-dependent degradation of the protein. Mutations in SAMHD1 cause Aicardi-Goutières syndrome, a disease that produces a phenotype that mimics the effects of a congenital viral infection. Failure to dispose of endogenous nucleic acid debris in Aicardi-Goutières syndrome results in inappropriate triggering of innate immune responses via cytosolic nucleic acids sensors. Thus, our findings show that macrophages are defended from HIV-1 infection by a mechanism that prevents an unwanted interferon response triggered by self nucleic acids, and uncover an intricate relationship between innate immune mechanisms that control response to self and to retroviral pathogens.
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.
Integrity signals
Registry
Cites
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.
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?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“This approach was necessary because PU.1 is the master transcriptional regulator necessary for macrophage differentiation and silencing PU.1 prior to infection results in a change in the cellular phenotype that causes resistance to HIV infection72,73.”
From HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages (2024) · cites this paper as [73]
Experimental — accuracy not yet measuredIn the citing paper
“It was then determined that Vpx may facilitate the association of SAMHD1 with this complex to promote its proteasome-dependent degradation.”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [81]
In the citing paper
“Upon MS analysis, the cellular innate immune protein SAMHD1 was the most spectrally abundant association with the Vpx-E3 ubiquitin ligase complex.”
From Proteomic approaches to uncovering virus–host protein interactions during the progression of viral infection (2016) · cites this paper as [81]
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
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., & Trono, D. (1996) · Science · doi:10.1126/science.272.5259.263 · Cited by 4,903
Trex1 prevents cell-intrinsic initiation of autoimmunity
Stetson, D. B., Ko, J. S., Heidmann, T., & Medzhitov, R. (2008) · Cell · doi:10.1016/j.cell.2008.06.032 · Cited by 1,280
Dendritic Cells: Translating Innate to Adaptive Immunity
Steinman, R. M., & Hemmi, H. (2006) · Springer eBooks · doi:10.1007/3-540-32636-7_2 · Cited by 855
A quantitative assay for HIV DNA integration in vivo
Butler, S. L., Hansen, M. S., & Bushman, F. D. (2001) · Nature Medicine · doi:10.1038/87979 · Cited by 695
Rice, G., Bond, J., Asipu, A., Brunette, R. L., Manfield, I. W., Carr, I., Fuller, J. C., Jackson, R. M., Lamb, T., Briggs, T. A., et al. (2009) · Nature Genetics · doi:10.1038/ng.373 · Cited by 686
Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery
Angers, S., Li, T., Yi, X., MacCoss, M. J., Moon, R. T., & Zheng, N. (2006) · Nature · doi:10.1038/nature05175 · Cited by 674
The Challenge of Viral Reservoirs in HIV-1 Infection
Blankson, J. N., Persaud, D., & Siliciano, R. F. (2002) · Annual Review of Medicine · doi:10.1146/annurev.med.53.082901.104024 · Cited by 649 · cited 1×
“MDM were subjected to RNAi targeting DCAF1, SAMHD1 or non-targeting RNAi (NT1, NT2), and infected (1) or not (2) with SIV VLP loaded with SIVmac Vpx, 2 days later.”
MethodTrex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease
Yang, Y., Lindahl, T. L., & Barnes, D. E. (2007) · Cell · doi:10.1016/j.cell.2007.10.017 · Cited by 574
Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee‐Kirsch, M. A., & Lieberman, J. (2010) · Nature Immunology · doi:10.1038/ni.1941 · Cited by 522
A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells
Manel, N., Hogstad, B., Wang, Y., Levy, D. E., Unutmaz, D., & Littman, D. R. (2010) · Nature · doi:10.1038/nature09337 · Cited by 427
Flagged first, then by citations
Cited by
Sorted by citations
Items 201–300 of 1,000
Restricting HIV the SAMHD1 way: through nucleotide starvation
Ayinde, D., Casartelli, N., & Schwartz, O. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2862 · Cited by 73
The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis
Wacleche, V. S., Tremblay, C. L., Routy, J., & Ancuța, P. (2018) · Viruses · doi:10.3390/v10020065 · Cited by 82
“Several restriction factors including TRIM5α, APOBEC3G, BST-2 and SAMHD1 are expressed in DC [189,229,237,238].”
BackgroundCD32 expression is associated to T-cell activation and is not a marker of the HIV-1 reservoir
Badía, R., Ballana, E., Castellví, M., García-Vidal, E., Pujantell, M., Clotet, B., Prado, J. G., Puig, J., Martı́nez, M. Á., Riveira‐Muñoz, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05157-w · Cited by 79
Reverse Transcription of Retroviruses and LTR Retrotransposons
Hughes, S. H. (2015) · Microbiology Spectrum · doi:10.1128/microbiolspec.mdna3-0027-2014 · Cited by 83
“SAMHD1, which is found, in an active form, in some non-dividing cells, catalyzes the conversion of dNTPs to their corresponding nucleosides and free triphosphate, and it can reduce the levels of dNTPs to a point where the reverse transcription of retroviruses is blocked (157, 158, 159, 160, 161, 162).”
BackgroundInterferons: Reprogramming the Metabolic Network against Viral Infection
Raniga, K., & Liang, C. (2018) · Viruses · doi:10.3390/v10010036 · Cited by 74
“On the side of viruses, HIV-2 and SIV encode an accessory protein called Vpx that recognizes SAMHD1 and recruits it to the E3 ubiquitin ligase complex for ubiquitination and subsequent proteasomal degradation [113,114].”
BackgroundConserved Herpesvirus Protein Kinases Target SAMHD1 to Facilitate Virus Replication
Zhang, K., Lv, D., & Li, R. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.020 · Cited by 69
“Among the conserved lytic gene 60 products are the orthologous serine/threonine protein kinases, namely HSV-1/2 UL13, VZV 61 ORF47, HCMV UL97, HHV-6/7 U69, EBV BGLF4 and KSHV ORF36 (Gershburg and Pagano, 62 2008; Li et al., 2011).”
BackgroundMethodInfluentialKoharudin, L. M. I., Wu, Y. G., DeLucia, M., Mehrens, J., Gronenborn, A. M., & Ahn, J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.591958 · Cited by 72
TRIM21‐mediated proteasomal degradation of SAMHD1 regulates its antiviral activity
Li, Z., Huan, C., Wang, H., Liu, Y., Liu, X., Su, X., Yu, J., Zhao, Z., Yu, X., Zheng, B., et al. (2019) · EMBO Reports · doi:10.15252/embr.201847528 · Cited by 67
“SAMHD1 was initially discovered as HIV-1 restriction factor [1,2].”
Role of Dendritic Cells in Natural Immune Control of HIV-1 Infection
Martín‐Gayo, E., & Yu, X. G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01306 · Cited by 72
“While it is clear that SAMHD1 is a key factor limiting replication of HIV-1 in MDDCs (47) and inhibiting further spread of virions to T cells (48), recent studies demonstrated that MDDCs can actually support productive infection with HIV-1 to a certain degree, despite high levels of expression of this restriction fact…”
InfluentialRestrictive influence of SAMHD1 on Hepatitis B Virus life cycle
Sommer, A. F. R., Rivière, L., Qu, B., Schott, K., Rieß, M., Ni, Y., Shepard, C., Schnellbächer, E., Finkernagel, M., Himmelsbach, K., et al. (2016) · Scientific Reports · doi:10.1038/srep26616 · Cited by 69
Liu, Y., Fu, Y., Wang, Q., Li, M., Zhou, Z., Dabbagh, D., Fu, C., Zhang, H., Li, S., Zhang, T., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0372-2 · Cited by 64
Cellular defense against latent colonization foiled by human cytomegalovirus UL138 protein
Lee, S. H., Albright, E. R., Lee, J.-H., Jacobs, D., & Kalejta, R. F. (2015) · Science Advances · doi:10.1126/sciadv.1501164 · Cited by 65
Lentivirus Vpr and Vpx accessory proteins usurp the cullin4–DDB1 (DCAF1) E3 ubiquitin ligase
Romani, B., & Cohen, É. A. (2012) · Current Opinion in Virology · doi:10.1016/j.coviro.2012.09.010 · Cited by 63
Substrates and Inhibitors of SAMHD1
Hollenbaugh, J. A., Shelton, J. R., Tao, S., Amiralaei, S., Liu, P., Lu, X., Goetze, R. W., Zhou, L., Nettles, J. H., Schinazi, R. F., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169052 · Cited by 66
Wei, W., Guo, H., Han, X., Liu, X., Zhou, X., Zhang, W., & Yu, X.-F. (2012) · Cellular Microbiology · doi:10.1111/j.1462-5822.2012.01835.x · Cited by 69
“SIVmac Vpx targets SAMHD1 to DCAF1–DDB1–Cul4 E3 ubiquitin ligase complexes for polyubiquitination and proteasome-mediated degradation (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundInfluentialRomani, B., Shaykh‐Baygloo, N., Aghasadeghi, M. R., & Allahbakhshi, E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.641522 · Cited by 66
“Degradation of SAMHD1 and APOBEC proteins is beneficial for retroviruses (7, 9, 10).”
BackgroundKlockow, L. C., Sharifi, H. J., Wen, X., Flagg, M., Furuya, A. K. M., Nekorchuk, M. D., & de Noronha, C. M. C. (2013) · Virology · doi:10.1016/j.virol.2013.06.010 · Cited by 65
“Vpx enhances macrophage infection albeit more dramatically than HIV-1 Vpr (Sharova et al., 2008; Srivastava et al., 2008) by combating antiviral protein SAMHD1 through the CRL4DCAF1 complex.”
InfluentialThe Role of Human Dendritic Cells in HIV-1 Infection
Ahmed, Z., Kawamura, T., Shimada, S., & Piguet, V. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.490 · Cited by 68
“However, the most likely potent restriction in DCs and myeloid cells is the recently identified SAMHD1, blocking at the post-entry step (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundDual-regulated Lentiviral Vector for Gene Therapy of X-linked Chronic Granulomatosis
Chiriaco, M., Farinelli, G., Capo, V., Zonari, E., Scaramuzza, S., Matteo, G. D., Sergi, L. S., Migliavacca, M., Hernández, R. J., Bombelli, F., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.87 · Cited by 62
Tse, W. K. F., Sun, J., Zhang, H., Law, A. Y. S., Yeung, B. H. Y., Chow, S. C., Qiu, J., & Wong, C. K. C. (2013) · Journal of Proteomics · doi:10.1016/j.jprot.2013.05.026 · Cited by 62
“[55] Hrecka K, Hao C, Gierszewska M, et al.”
Host Factors and HIV-1 Replication: Clinical Evidence and Potential Therapeutic Approaches
Santa‐Marta, M., de Brito, P. M., Godinho‐Santos, A., & Gonçalves, J. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00343 · Cited by 62
“In cellular models using primary SIV, SAMHD1 restriction can also be overcome by transduction of cells with the Viral Protein R (Vpr) (289, 290).”
BackgroundPuigdomènech, I., Casartelli, N., Porrot, F., & Schwartz, O. (2012) · Journal of Virology · doi:10.1128/jvi.02514-12 · Cited by 70
“in various cell types, including myeloid cells (5, 7, 10, 11) and”
BackgroundEvolution of Foamy Viruses: The Most Ancient of All Retroviruses
Rethwilm, A., & Bodem, J. (2013) · Viruses · doi:10.3390/v5102349 · Cited by 67
“Weather the Sterile motif domain- and HD domain-containing protein 1 (SamHD1), which restricts HIV replication in myeloid cells by alteration of the nucleotide pool required for reverse transcription and which is counteracted by HIV-2 (and related viruses), Vpx protein [145] is also able to restrict FV replication and…”
BackgroundLow dNTP levels are necessary but may not be sufficient for lentiviral restriction by SAMHD1
Welbourn, S., & Strebel, K. (2015) · Virology · doi:10.1016/j.virol.2015.11.022 · Cited by 62
“…SAMHD1 is present in many actively dividing cell types, the restrictive effect has generally only been observed in differentiated/non-dividing cells (Baldauf et al., 2012; Berger et al., 2011; Descours et al., 2012; Hrecka et al., 2011; Laguette et al., 2011; St Gelais et al., 2012).”
InfluentialOgawa, Y., Kawamura, T., Matsuzawa, T., Aoki, R., Gee, P., Yamashita, A., Moriishi, K., Yamasaki, K., Koyanagi, Y., Blauvelt, A., et al. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2012.12.002 · Cited by 64
“In addition, APOBEC3G (A3G) and SAM domain and HD domain 1 (SAMHD1) has been recently shown to function as a potent postentry cellular restriction factor for HIV in DCs or LCs (Hrecka et al., 2011; Laguette et al., 2011; Ogawa et al., 2009; Pion et al., 2006).”
BackgroundBaldauf, H., Stegmann, L., Schwarz, S.-M., Ambiel, I., Trotard, M., Martin, M., Burggraf, M., Lenzi, G. M., Lejk, H., Pan, X., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1613635114 · Cited by 63
Schott, K., Fuchs, N. V., Derua, R., Mahboubi, B., Schnellbächer, E., Seifried, J., Tondera, C., Schmitz, H., Shepard, C., Brandariz-Núñez, A., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04671-1 · Cited by 62
Su, J., Rui, Y., Lou, M., Yin, L., Xiong, H., Zhou, Z., Shen, S., Chen, T., Zhang, Z., Zhao, N., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0585-4 · Cited by 62
Dendritic Cells, the Double Agent in the War Against HIV-1
Martín-Moreno, A., & Muñoz‐Fernández, M. Á. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02485 · Cited by 69
“and HD-domain containing protein 1 (SAMHD1) was first described in 2011 as the restriction factor that gives non-dividing myeloid cells certain resistance against HIV-1 infection (110, 111).”
BackgroundRudd, S. G., Tsesmetzis, N., Sanjiv, K., Paulin, C. B. J., Sandhow, L., Kutzner, J., Myrberg, I. H., Bunten, S. S., Axelsson, H., Zhang, S. M., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201910419 · Cited by 58
“As demonstrated previously (Hrecka et al, 2011; Laguette et al, 2011; Herold et al, 2017b), Vpx treatment efficiently depleted SAMHD1 protein (Fig 3C and E, Appendix Fig S10C) and, in line with our data in cancer cell lines, completely abolished the RNRi-mediated sensitisation to ara-C toxicity…”
Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity
Case, J. B., Li, Y., Elliott, R., Lu, X., Graepel, K. W., Sexton, N. R., Smith, E. C., Weiss, S. R., & Denison, M. R. (2017) · Journal of Virology · doi:10.1128/jvi.01531-17 · Cited by 60
Nonhuman Primate Models for HIV/AIDS Vaccine Development
Sui, Y., Gordon, S. N., Franchini, G., & Berzofsky, J. A. (2013) · Current Protocols in Immunology · doi:10.1002/0471142735.im1214s102 · Cited by 61
“Another recently identified host factor is SAMHD, whose activity was confined to differentiated uncycling cells like macrophages and mDC (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundMock, D. J., Hollenbaugh, J. A., Daddacha, W. B., Overstreet, M. G., Lazarski, C. A., Fowell, D. J., & Kim, B. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002635 · Cited by 61
“Several recent studies have shown that HIV-2 Vpx protein promotes the degradation of the SAMHD1, a host antiviral restriction factor [34–37].”
BackgroundSAMHD1 and the innate immune response to cytosolic DNA during DNA replication
Coquel, F., Neumayer, C., Lin, Y., & Pasero, P. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.017 · Cited by 62
The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1
Knecht, K. M., Buzovetsky, O., Schneider, C., Thomas, D., Srikanth, V., Kaderali, L., Tofoleanu, F., Reiss, K. M., Ferreirós, N., Geißlinger, G., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805593115 · Cited by 59
“During viral infection, SAMHD1 depletes the cellular dNTPs needed for reverse transcription of the viral RNA genome (2-8).”
TRIM34 restricts HIV-1 and SIV capsids in a TRIM5α-dependent manner
OhAinle, M., Kim, K., Keceli, S. K., Felton, A., Campbell, E., Luban, J., & Emerman, M. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008507 · Cited by 58
“The SIV−VLPs were added to transfer Vpx to the cells in order to overcome restriction by SAMHD1 against lentiviral transduction [52, 53].”
MethodInnate and Adaptive Immunity in Long-Term Non-Progression in HIV Disease
Zaunders, J., & van Bockel, D. J. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00095 · Cited by 63
“At the peak of PHI, it is unlikely that activated cells have already reverted to resting cells.”
BackgroundInteractions between HIV-1 and the Cell-Autonomous Innate Immune System
Towers, G. J., & Noursadeghi, M. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.06.009 · Cited by 59
Early IFN type I response: Learning from microbial evasion strategies
Coccia, E. M., & Battistini, A. (2015) · Seminars in Immunology · doi:10.1016/j.smim.2015.03.005 · Cited by 59
“This SAMHD1mediated restriction is overcome by the viral protein Vpx [124, 125] that is a HIV-2 and SIV accessory protein absent in HIV-1.”
BackgroundHIV suppression by host restriction factors and viral immune evasion
Jia, X., Zhao, Q., & Xiong, Y. (2015) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2015.04.004 · Cited by 56
Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design
Mi, D., Li, Y., Gu, H., Li, Y., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115444 · Cited by 58
Pauls, E., Jiménez, E., Ruiz, A., Permanyer, M., Ballana, E., Costa, H., Nascimiento, R., Parkhouse, R. M. E., Peña, R., Riveira‐Muñoz, E., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1203226 · Cited by 63
SAMHD1’s protein expression profile in humans
Schmidt, S., Schenková, K., Adam, T., Erikson, E., Lehmann‐Koch, J., Sertel, S., Verhasselt, B., Fackler, O., Lasitschka, F., & Keppler, O. T. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.4hi0714-338rr · Cited by 63
“Besides the major protein band at 72 kDa, seen in all tissues and reported previously in cell lines [11, 12], additional, prominent, lower molecular weight bands were noted, particularly in a spleen lysate (Fig.”
BackgroundShen, C., Jia, Y., Tian, R., Ding, M., Zhang, C., & Wang, J. (2012) · The FASEB Journal · doi:10.1096/fj.12-209023 · Cited by 57
Bhattacharya, A., Wang, Z., White, T. E., Buffone, C., Nguyen, L. A., Shepard, C., Kim, B., Demeler, B., Diaz‐Griffero, F., & Ivanov, D. N. (2016) · Scientific Reports · doi:10.1038/srep31353 · Cited by 62
SAMHD1 Suppression of Antiviral Immune Responses
Chen, S., Bonifati, S., Qin, Z., Gelais, C. S., & Wu, L. J. (2018) · Trends in Microbiology · doi:10.1016/j.tim.2018.09.009 · Cited by 54
Phosphorylation of murine SAMHD1 regulates its antiretroviral activity
Wittmann, S., Behrendt, R., Eissmann, K., Volkmann, B., Thomas, D., Ebert, T. S., Cribier, A., Benkirane, M., Hornung, V., Bouzas, N. F., et al. (2015) · Retrovirology · doi:10.1186/s12977-015-0229-6 · Cited by 60
“been shown to directly bind to SAMHD1 [8, 9].”
Roles of HIV-1 capsid in viral replication and immune evasion
Sage, V. L., Mouland, A. J., & Valiente‐Echeverría, F. (2014) · Virus Research · doi:10.1016/j.virusres.2014.07.010 · Cited by 59
de Silva, S., Wang, F., Hake, T. S., Porcu, P., Wong, H. K., & Wu, L. J. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.311 · Cited by 58
“Non-dividing CD4+ T-cells, monocytes, macrophages and dendritic cells from healthy individuals express high levels of SAMHD1 protein and have significantly lower levels of intracellular dNTPs compared to activated CD4+ T-cells, while several leukemia/lymphoma CD4+ T-cell lines lack SAMHD1 protein expression and have i…”
BackgroundCoulon, P.-G. A., Richetta, C., Rouers, A., Blanchet, F. P., Urrutia, A., Guerbois, M., Piguet, V., Theodorou, I. D., Bet, A., Schwartz, O., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600286 · Cited by 62
Lee, E. J., Seo, J. H., Park, J., Vo, T. T. L., An, S., Bae, S., Le, H., Lee, H. S., Wee, H., Lee, D., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.19704 · Cited by 60
“…of the human innate immune system [8], SAMHD1 depletes the level of cellular dNTPs to an amount that is insufficient for reverse transcription to block early-stage retroviral replication in dendritic and other myeloid cells, and, in particular, has anti-viral activity against HIV-1 [9, 10].”
Megger, D. A., Philipp, J., Le‐Trilling, V. T. K., Sitek, B., & Trilling, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01139 · Cited by 56
SAMHD1 Modulates Early Steps during Human Cytomegalovirus Infection by Limiting NF-κB Activation
Kim, E. T., Roche, K. L., Kulej, K., Spruce, L. A., Seeholzer, S. H., Coen, D. M., Diaz‐Griffero, F., Murphy, E. A., & Weitzman, M. D. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.027 · Cited by 54
“The sterile alpha motif (SAM) and histidine-aspartate (HD) domain-containing protein (SAMHD1) can function as a restriction factor that inhibits HIV-1 infection in non-dividing myeloid cells (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundTissue dendritic cells as portals for HIV entry
Harman, A. N., Kim, M., Nasr, N., Sandgren, K. J., & Cameron, P. U. (2013) · Reviews in Medical Virology · doi:10.1002/rmv.1753 · Cited by 55
“Recent studies have demonstrated that SAMHD1 inhibits HIV-1 infection by restricting the intracellular pool of dNTPs required for HIV replication [136,137] and that Vpx promotes DC infection by targeting SAMHD1 for proteasomal degradation [138,139].”
BackgroundHIV controllers: A multifactorial phenotype of spontaneous viral suppression
Thèze, J., Chakrabarti, L. A., Vingert, B., Porichis, F., & Kaufmann, D. (2011) · Clinical Immunology · doi:10.1016/j.clim.2011.07.007 · Cited by 55
Evidence for IFNα-induced, SAMHD1-independent inhibitors of early HIV-1 infection
Goujon, C., Schaller, T., Galão, R. P., Amie, S. M., Kim, B., Olivieri, K. C., Neil, S. J. D., & Malim, M. H. (2013) · Retrovirology · doi:10.1186/1742-4690-10-23 · Cited by 58
“In particular, by taking advantage of the ability of Vpx to degrade SAMHD1 [7,8], dN addition to bypass its deoxynucleoside triphosphohydrolase activity, or selective SAMHD1 knock-down, our findings indicate that IFNα is often able to suppress HIV-1 infectivity independently of SAMHD1 activity.”
BackgroundInfluentialMlčochová, P., Caswell, S. J., Taylor, I. A., Towers, G. J., & Gupta, R. K. (2017) · The EMBO Journal · doi:10.15252/embj.201796880 · Cited by 55
“DNA damage-induced HIV-1 block is SAMHD1 dependent in macrophages We observed that lentiviruses encoding Vpx (HIV-2 and SIVsm), a SAMHD1 antagonist (Hrecka et al, 2011; Laguette et al, 2011), were insensitive to ETO in MDM suggesting that SAMHD1 might be responsible for the effect of ETO/CTH on…”
BackgroundHIV replication and latency in monocytes and macrophages
Veenhuis, R. T., Abreu, C. M., Shirk, E. N., Gama, L., & Clements, J. E. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101472 · Cited by 51
SAMHD1 Host Restriction Factor: A Link with Innate Immune Sensing of Retrovirus Infection
Sze, A., Olagnier, D. P., Lin, R., van Grevenynghe, J., & Hiscott, J. B. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.10.022 · Cited by 55
“For instance, SAMHD1 expression limits the synthesis of HIV-1 provirus of macrophages in vitro [40,45,46,48], yet this cell type can serve as a viral reservoir in vivo [118,119].”
BackgroundInfluentialBalasubramaniam, M., Pandhare, J., & Dash, C. (2019) · JoLS Journal of Life Sciences · doi:10.36069/jols/20190603 · Cited by 55
Cyclin L2 Is a Critical HIV Dependency Factor in Macrophages that Controls SAMHD1 Abundance
Kyei, G. B., Cheng, X., Ramani, R., & Ratner, L. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.11.009 · Cited by 56
“Recently, SAMHD1was identified as the critical restriction factor targeted by Vpx. Degradation of SAMHD1 by Vpx in macrophages, dendritic cells, and resting T cells allows for efficient infection by HIV-2/SIV (Laguette et al., 2011; Hrecka et al., 2011; Baldauf et al., 2012).”
InfluentialMelchjorsen, J. (2013) · Viruses · doi:10.3390/v5020470 · Cited by 59
“SAMHD1 has recently been identified as a HIV-1 restriction factor in cells of myeloid origin [260,261].”
BackgroundHERV ‐K( HML ‐2), a seemingly silent subtenant – but still waters run deep
Hanke, K., Höhn, O., & Bannert, N. (2016) · Apmis · doi:10.1111/apm.12475 · Cited by 55
Interferons Induce Expression of SAMHD1 in Monocytes through Down-regulation of miR-181a and miR-30a
Rieß, M., Fuchs, N. V., Idica, A., Hamdorf, M., Flory, E., Pedersen, I. M., & König, R. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.752584 · Cited by 54
Potent Inhibition of HIV-1 Replication in Resting CD4 T Cells by Resveratrol and Pterostilbene
Chan, C. N., Trinité, B., & Levy, D. N. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00408-17 · Cited by 53
“counteract antiviral components that are most active in resting or post-mitotic cells such as the HIV-2/SIV 375 Vpx protein that counteracts cellular SAMHD1 degradation of dNTP (87, 88).”
BackgroundCRISPR-Cas Targeting of Host Genes as an Antiviral Strategy
Chen, S., Yu, X., & Guo, D. (2018) · Viruses · doi:10.3390/v10010040 · Cited by 54
“SAMHD1 is a dGTP-dependent deoxynucleoside triphosphohydrolase that reduces intracellular dNTPs below the levels required for HIV-1 reverse transcription, thereby blocking HIV-1 infection in resting CD4+ T-cells [114–117].”
BackgroundSAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity
Mauney, C. H., & Hollis, T. (2018) · Autoimmunity · doi:10.1080/08916934.2018.1454912 · Cited by 55
“of SAMHD1 to the CRL4 ubiquitin ligase complex where it is ubiquitinylated and marked for proteosomal degradation [69,146,147,153].”
BackgroundInfluentialChen, S., Wang, Y., Dang, J., Song, N., Chen, X., Wang, J., Huang, G. N., Brown, C. E., Yu, J., Weissman, I. L., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59326-9 · Cited by 60
“Macrophages are terminally differentiated with limited proliferative ability and are relatively impenetrable to lentiviral transduction 37 .”
Schwefel, D., Boucherit, V., Christodoulou, E., Walker, P. A., Stoye, J. P., Bishop, K. N., & Taylor, I. A. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.03.004 · Cited by 58
“More recently, SAMHD1 was shown to be a factor that restricts HIV-1 replication in non-dividing myeloid-lineage cells and resting T cells (Baldauf et al., 2012; Berger et al., 2011; Descours et al., 2012; Hrecka et al., 2011; Laguette et al., 2011).”
Interferon-Inducible CD169/Siglec1 Attenuates Anti-HIV-1 Effects of Alpha Interferon
Akiyama, H., Ramirez, N.-G. P., Gibson, G. A., Kline, C. E., Watkins, S. C., Ambrose, Z., & Gummuluru, S. (2017) · Journal of Virology · doi:10.1128/jvi.00972-17 · Cited by 55
“SAMHD1, whose expression can be induced by type I IFN in a cell-type-dependent manner (47, 48), can potently restrict replication of HIV-1 in macrophages (22, 24) and, therefore, may mask the effect of other ISGs on viral replication.”
BackgroundMethodType I interferonopathies—an expanding disease spectrum of immunodysregulation
Lee‐Kirsch, M. A., Wolf, C., Kretschmer, S., & Roers, A. (2015) · Seminars in Immunopathology · doi:10.1007/s00281-015-0500-x · Cited by 57
Design and potential of non-integrating lentiviral vectors
Shaw, A., & Cornetta, K. (2014) · Biomedicines · doi:10.3390/biomedicines2010014 · Cited by 60
“SAMHD1 restricts an early step in the viral life cycle and inhibiting this protein greatly improves the transduction of human and simian myeloid cells [107–110].”
BackgroundAutophagy in Mycobacterium tuberculosis and HIV infections
Espert, L., Beaumelle, B. D., & Vergne, I. (2015) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2015.00049 · Cited by 53
“This is due to a combination of several factors such as low expression of HIV-1 receptor (CD4) and coreceptor (CXCR5) on macrophages (Alexaki et al., 2008) and the expression in this cell type of SAMHD1 that is able to inhibit HIV-1 multiplication (Hrecka et al., 2011).”
BackgroundCuadrado, E., Jansen, M. H., Anink, J. J., Filippis, L. D., Vescovi, A. L., Watts, C. K. W., Aronica, E., Hol, E. M., & Kuijpers, T. W. (2013) · Brain · doi:10.1093/brain/aws321 · Cited by 52
“Recently, data have revealed that SAMHD1 might act as a restriction factor for HIV infection (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011), and that TREX1 (Yan et al., 2010) and RNASEH2A (Genovesio et al., 2011) also have a role in the metabolism of HIV.”
BackgroundAmie, S. M., Daly, M. B., Noble, E., Schinazi, R. F., Bambara, R. A., & Kim, B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.472159 · Cited by 55
Krupp, A., McCarthy, K. R., Ooms, M., Letko, M. C., Morgan, J. S., Simon, V. R., & Johnson, W. E. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003641 · Cited by 54
“Cellular restriction factors that target replication of primate lentiviruses include A3G [17], TRIM5 a [52], BST2/Tetherin [53,54,55] and SAMHD1 [56,57].”
BackgroundSelect host restriction factors are associated with HIV persistence during antiretroviral therapy
Abdel‐Mohsen, M., Wang, C., Strain, M. C., Lada, S. M., Deng, X., Cockerham, L. R., Pilcher, C. D., Hecht, F. M., Liegler, T. J., Richman, D. D., et al. (2015) · AIDS · doi:10.1097/qad.0000000000000572 · Cited by 53
“In particular, the expression of eight host restriction factors correlated negatively with HLA-DR, CD38 coexpression on CD4þ T cells after Bonferroni correction: bromodomain containing 4 (BRD4) (P 0.0001, corrected P 0.004), tumor necrosis factor receptor superfamily member 10A (TNFRSF10A) (P 0.0001, corrected P 0.004…”
BackgroundInfluentialSensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages
Decalf, J., Desdouits, M., Rodrigues, V., Gobert, F.-X., Gentili, M., Marques-Ladeira, S., Chamontin, C., Mougel, M., de Alencar, B. C., & Benaroch, P. (2017) · Journal of Virology · doi:10.1128/jvi.00147-17 · Cited by 58
“In human myeloid cells, such as monocyte-derived dendritic cells (MDDC) (12) or monocyte-derived macrophages (MDM) (13), HIV-1 infection initially appears poorly detected, if at all, and does not trigger detectable secretion of type I interferon (IFN).”
BackgroundInfluentialIL-15 regulates susceptibility of CD4 + T cells to HIV infection
Manganaro, L., Hong, P. W.-P., Hernandez, M. M., Argyle, D., Mulder, L. C. F., Potla, U., Diaz‐Griffero, F., Lee, B., Fernández-Sesma, A., & Simon, V. R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1806695115 · Cited by 55
“To do that, we exploited an HIV GFP reporter virus modified to incorporate Vpx (HIV*GFP-Vpx) or a mutant form of Vpx (Q76A) that does not induce SAMHD1 degradation (6, 7, 10).”
MethodRuffin, N., Brezar, V., Ayinde, D., Lefebvre, C., Wiesch, J. S. Z., van Lunzen, J., Bockhorn, M., Schwartz, O., Hocini, H., Lelièvre, J., et al. (2015) · AIDS · doi:10.1097/qad.0000000000000594 · Cited by 55
“SAMHD1 restricts productive HIV-1 infection in dendritic cells, myeloid cells [4,5] and resting CD4þ T cells [6,7].”
BackgroundSAMHD1: a new insight into HIV-1 restriction in myeloid cells
Gelais, C. S., & Wu, L. J. (2011) · Retrovirology · doi:10.1186/1742-4690-8-55 · Cited by 55
“They demonstrated that Vpx relieves the inhibition of HIV-1 infection in monocyte-derived macrophages by mediating proteasomedependent degradation of SAMHD1 through the CUL4A/DCAF1 E3 ubiquitin ligase [10].”
InfluentialIFN-α Induces APOBEC3G, F, and A in Immature Dendritic Cells and Limits HIV-1 Spread to CD4+ T Cells
Mohanram, V., Sköld, A. E., Bächle, S. M., Pathak, S. K., & Spetz, A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1201184 · Cited by 53
The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation
Herrmann, A., Wittmann, S., Thomas, D., Shepard, C., Kim, B., Ferreirós, N., & Gramberg, T. (2018) · Mobile DNA · doi:10.1186/s13100-018-0116-5 · Cited by 59
“The reporter plasmid L1RP-luc and the L1 promoter activity assay have been described previously [2].”
SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA
Maharana, S., Kretschmer, S., Hunger, S., Yan, X., Kuster, D., Traikov, S., Zillinger, T., Gentzel, M., Elangovan, S., Dasgupta, P., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.08.031 · Cited by 53
Type I interferon in neurological disease—The devil from within
Hofer, M. J., & Campbell, I. L. (2013) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2013.03.006 · Cited by 50
“Interestingly, TREX1 [128], SAMHD1 [129–131] and RNaseH2 [132] have been implicated in”
Background90K, an interferon-stimulated gene product, reduces the infectivity of HIV-1
Lodermeyer, V., Suhr, K., Schrott, N., Kolbe, C., Stürzel, C. M., Krnavek, D., Münch, J., Dietz, C., Waldmann, T., Kirchhoff, F., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-111 · Cited by 50
“; licensee BioMed Ce Creative Commons Attribution License (http:/ distribution, and reproduction in any medium infected cell’s surface [2,3], and SAMHD1, that prevents reverse transcription in myeloid cells and resting CD4 T-cells [4-6].”
BackgroundPauls, E., Badía, R., Torres‐Torronteras, J., Ruiz, A., Permanyer, M., Riveira‐Muñoz, E., Clotet, B., Martí, R., Ballana, E., & Esté, J. A. (2014) · AIDS · doi:10.1097/qad.0000000000000399 · Cited by 52
“Notably, the viral accessory protein X (Vpx), encoded by some simian immunodeficiency virus (SIV) strains and the HIV-2, has acquired the capacity to drive SAMHD1 to the cellular proteasomal machinery, leading to its degradation, increasing the dNTP pool and eliminating the cellular restriction to lentiviral reverse t…”
BackgroundNuclear Envelope Protein SUN2 Promotes Cyclophilin-A-Dependent Steps of HIV Replication
Lahaye, X., Satoh, T., Gentili, M., Cerboni, S., Silvin, A., Conrad, C., Ahmed‐Belkacem, A., Rodriguez, E. C., Guichou, J., Dereuddre‐Bosquet, N., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.074 · Cited by 53
Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6
Livingston, C. M., Ramakrishnan, D., Strubin, M., Fletcher, S. P., & Beran, R. (2017) · Viruses · doi:10.3390/v9040069 · Cited by 49
“HIV Vpx also hijacks the DDB1–E3 ubiquitin ligase, but instead promotes the degradation of the antiviral factor SAMHD1 (SAM domain and HD domain-containing protein 1) [19].”
BackgroundDiscrimination Between Self and Non-Self-Nucleic Acids by the Innate Immune System
Kawasaki, T., & Kawai, T. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.08.004 · Cited by 52
Ruffin, N., Gea‐Mallorquí, E., Brouiller, F., Jouve, M. J., Silvin, A., See, P., Dutertre, C., Ginhoux, F., & Benaroch, P. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1911007116 · Cited by 53
Efficient generation of isogenic primary human myeloid cells using CRISPR-Cas9 ribonucleoproteins
Hiatt, J. B., Cavero, D. A., McGregor, M., Zheng, W., Budzik, J. M., Roth, T. L., Haas, K. M., Wu, D., Rathore, U., Meyer‐Franke, A., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109105 · Cited by 51
“The identification of SAMHD1 as the key restriction factor in myeloid cells that prevents efficient lentiviral transduction (Hrecka et al., 2011; Laguette et al., 2011) led directly to improved approaches for studying innate immunity and has been leveraged to generate more effective DC vaccines…”
Rothenburger, T., McLaughlin, K.-M., Herold, T., Schneider, C., Oellerich, T., Rothweiler, F., Feber, A., Fenton, T. R., Wass, M. N., Keppler, O. T., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-1052-8 · Cited by 47
“Vpx is a protein encoded by HIV-2 and certain SIV strains that mediates proteasomal SAMHD1 degradation [Hrecka et al., 2011; Laguette et al., 2011; Baldauf et al., 2012].”
BackgroundMurrell, B., Vollbrecht, T., Guatelli, J., & Wertheim, J. O. (2016) · Journal of Virology · doi:10.1128/jvi.00972-16 · Cited by 52
With me or against me: Tumor suppressor and drug resistance activities of SAMHD1
Herold, N., Rudd, S. G., Sanjiv, K., Kutzner, J., Myrberg, I. H., Paulin, C. B. J., Olsen, T. K., Helleday, T., Henter, J., & Schaller, T. (2017) · Experimental Hematology · doi:10.1016/j.exphem.2017.05.001 · Cited by 49
From Entry to Egress: Strategic Exploitation of the Cellular Processes by HIV-1
Ramdas, P., Sahu, A. K., Mishra, T. K., Bhardwaj, V., & Chande, A. G. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.559792 · Cited by 50
Wang, H., Liu, Y., Huan, C., Yang, J., Li, Z., Zheng, B., Wang, Y., & Zhang, W. (2020) · Journal of Virology · doi:10.1128/jvi.01057-20 · Cited by 48
Targeting the DNA damage response and repair in cancer through nucleotide metabolism
Helleday, T., & Rudd, S. G. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13227 · Cited by 49
In vivo generation of CAR T cells in the presence of human myeloid cells
Ho, N., Agarwal, S., Milani, M., Cantore, A., Buchholz, C. J., & Thalheimer, F. B. (2022) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2022.06.004 · Cited by 48
“That we did not observe transduction of CD14+ cells despite vector particle binding is not surprising, since CD4-LV lacked the accessory viral protein Vpx, which is required to bypass antiviral restriction factors, such as SAMHD1 in myeloid cells, especially at low vector particle numbers, as is the case in vivo.(27)…”
ResultHIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup
Debaisieux, S., Lachambre, S., Gross, A., Mettling, C., Besteiro, S., Yezid, H., Henaff, D., Chopard, C., Mesnard, J.-M., & Beaumelle, B. D. (2015) · Nature Communications · doi:10.1038/ncomms7211 · Cited by 48
Metadata
- Authors
- Hrecka, K., Hao, C., Gierszewska, M., Swanson, S. K., Kesik-Brodacka, M., Srivastava, S., Florens, L., Washburn, M. P., & Skowronski, J.
- Affiliations
- Case Western Reserve University (US)
- Cold Spring Harbor Laboratory (US)
- Stowers Institute for Medical Research (US)
- Venue
- Nature
- Published
- 2011-06
- Volume
- 474
- Issue
- 7353
- Pages
- 658-661
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3179858
- OpenAlex
- W1964567249
- Cited by
- 1,200
- References
- 30
- Citations by year
- 2026: 30 · 2025: 51 · 2024: 54 · 2023: 47 · 2022: 62 · 2021: 58 · 2020: 66 · 2019: 82 · 2018: 88 · 2017: 87 · 2016: 91 · 2015: 101 · 2014: 125 · 2013: 125 · 2012: 109
- FWCI
- 48.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R21AI084694, R01AI077459)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- HIV-1, Vpx, SAMHD1, macrophages, dendritic cells, host restriction factors, proteasomal degradation, Aicardi-Goutières syndrome, innate immunity, interferon response, retroviral infection, HIV-2, simian immunodeficiency virus
- MeSH terms
- SAM Domain and HD Domain-Containing Protein 1, Carrier Proteins, Cells, Cultured, Humans, Macrophages, Nuclear Proteins, HIV-1, HIV Infections, Protein Serine-Threonine Kinases, Monomeric GTP-Binding Proteins, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Viral Regulatory and Accessory Proteins, HEK293 Cells
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
