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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.
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“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]
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“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]
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“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]
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Single-cell RNA-seq analysis reveals dual sensing of HIV-1 in blood Axl+ dendritic cells
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“E-mail: yuxiaofang@jlu. edu.cn. 4 The abbreviations used are: SAMHD1, sterile -motif/histidine-aspartate domain-containing protein; TCEP, tris(2-carboxyethyl)phosphine; RMSD, root mean square deviation; P-SAMHD1C, purified SAMHD1C; DSAMHD1C, dialyzed SAMHD1C; Hs-SAMHD1, Homo sapiens SAMHD1. crossmark THE JOURNAL OF BI…”
BackgroundInfluentialMass spectrometry based proteomics profiling of human monocytes
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“HIV-2 and some SIV variants, including those derived from SIVsm, express the Vpx protein, which targets SAMHD1 for proteasome-mediated degradation, thus increasing viral replication in myeloid cells and in resting CD4+ T-cells [68,69].”
BackgroundVpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection
Cingöz, O., Arnow, N. D., Puig-Torrents, M., & Bannert, N. (2021) · Retrovirology · doi:10.1186/s12977-021-00548-2 · Cited by 15
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HIV-2 Vpx neutralizes host restriction factor SAMHD1 to promote viral pathogenesis
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HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65
Fink, D., Cai, J., Whelan, M. V. X., Monit, C., de Motes, C. M., Towers, G. J., & Sumner, R. P. (2022) · Retrovirology · doi:10.1186/s12977-021-00586-w · Cited by 14
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“Included among them was the nucleotide phosphohydrolase SAMHD1 (SAM domain and HD domaincontaining protein 1), which is a well-known HIV-1 restriction factor (24,25) and, accordingly, all three SAMHD1targeting sgRNAs were significantly enriched in HIVresistant MT4 cells (Supplementary Figure S1B).”
BackgroundHost–pathogen interaction in HIV infection
Chowdhury, A., & Silvestri, G. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.07.003 · Cited by 16
Musich, T., O’Connell, O., Gonzalez-Perez, M. P., Derdeyn, C. A., Peters, P. J., & Clapham, P. R. (2015) · Retrovirology · doi:10.1186/s12977-015-0141-0 · Cited by 15
“Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein.”
BackgroundOguariri, R. M., Dai, L., Adelsberger, J. W., Rupert, A. W., Stevens, R. A., Yang, J., Huang, D.-W., Lempicki, R. A., Zhou, M., Baseler, M., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.468975 · Cited by 14
“These include HLA-type (1–4), HIV co-re- ceptor expression (5), the cytidine deaminase APOBEC3G (6, 7), tetherin (BST-2) (8), SAMHD1 (9, 10), and an array of cytokines.”
BackgroundSwann, J., Murry, J. P., & Young, J. A. T. (2016) · Virology Journal · doi:10.1186/s12985-016-0491-9 · Cited by 14
“These proteins include SAMHD1, which blocks reverse transcription in myeloid cells and resting CD4+ T cells by hydrolyzing dNTPs and/or degrading viral RNA [40–43], and APOBEC3G, which deaminates cytidine to uridine resulting in hypermutation during DNA synthesis [44, 45].”
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“Vpx, which is expressed by HIV-2 and some SIVs, neutralizes the antiviral activity of the nucleotide hydrolase SAMHD1 [81,82].”
Intrinsic Immune Mechanisms Restricting Human Cytomegalovirus Replication
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Reply to SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity
Ryoo, J., Hwang, S.-Y., Choi, J., Oh, C., & Ahn, K. (2016) · Nature Medicine · doi:10.1038/nm.4164 · Cited by 14
Restricted Access to Myeloid Cells Explained
Planelles, V. (2011) · Viruses · doi:10.3390/v3091624 · Cited by 13
“the sterile alpha motif (SAM) and HD domain-containing protein-1 protein (SAMHD1) [29,30].”
BackgroundMethodInfluentialApplication of CRISPR-Cas9 Gene Editing for HIV Host Factor Discovery and Validation
Cisneros, W. J., Cornish, D., & Hultquist, J. F. (2022) · Pathogens · doi:10.3390/pathogens11080891 · Cited by 16
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“in nondividing myeloid cells (3, 4) and resting CD4+ T cells (5, 6).”
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Host cell restriction factors of equine infectious anemia virus
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“, 1993), Vpx can be delivered via virion-packaging, allowing HIV-1 to counteract the SAMHD1 restriction in dendritic cells, resting CD4þ T cells and macrophages (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundCD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes
Kapitza, L., Ho, N., Kerzel, T., Frank, A. M., Thalheimer, F. B., Jamali, A., Schaser, T., Buchholz, C. J., & Hartmann, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1183698 · Cited by 13
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“HIV-2 Vpx is present within newly released virions [52,53], and determines the degradation of SAMHD1 upon entry [51,54].”
BackgroundHaag, S. M., Xie, S., Eidenschenk, C., Fortin, J., Callow, M. G., Costa, M., Lun, A. T. L., Cox, C., Wu, S. Z., Pradhan, R., et al. (2024) · Nature Genetics · doi:10.1038/s41588-024-01962-w · Cited by 13
“Macrophages express abundant amounts of the central restriction factor SAMHD1, which prevents lentiviral integration 12 .”
piRNA Defense Against Endogenous Retroviruses
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“These are the APOBEC3 family of proteins [3], BST-2 [4,5,6], TRIM5a [7,8,9] and SAMHD1 [10,11].”
BackgroundThe myeloid cytokine network in AIDS pathogenesis
Mir, K. D., Mavigner, M., & Silvestri, G. (2012) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2012.05.009 · Cited by 14
“Vpx promotes more efficient HIV-1 infection by mediating proteasome-dependent degradation of SAMHD1, which can be restored by treatment with a proteasome inhibitor [60,61].”
BackgroundInfluentialDual effect of the broad spectrum kinase inhibitor midostaurin in acute and latent HIV-1 infection
García-Vidal, E., Badía, R., Pujantell, M., Castellví, M., Felip, E., Clotet, B., Riveira‐Muñoz, E., Ballana, E., & Esté, J. A. (2019) · Antiviral Research · doi:10.1016/j.antiviral.2019.05.003 · Cited by 13
Hyeon, S., Lee, M. K., Kim, Y.-E., Lee, G. M., & Ahn, J. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00391 · Cited by 13
“…(HD) domain-containing protein 1 (SAMHD1) was initially identified as a restriction factor that inhibits HIV-1 infection and shown to be counteracted by the viral Vpx protein through proteasomal degradation (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011; Baldauf et al., 2012).”
BackgroundRabezanahary, H., Clain, J. A., Racine, G., Andreani, G., Benmadid-Laktout, G., Borde, C., Mammano, F., Mésplède, T., Ancuța, P., Zghidi‐Abouzid, O., et al. (2020) · Journal of Virology · doi:10.1128/jvi.01478-20 · Cited by 13
“Whereas HIV-1 expresses the Vpr protein, SIVmac expresses the Vpx protein, which has been shown to facilitate viral infectivity by counteracting SAMHD1 activity in myeloid cells in vitro (88, 89).”
BackgroundThe Human Antiviral Factor TRIM11 Is under the Regulation of HIV-1 Vpr
Yuan, T., Yao, W., Huang, F., Sun, B., & Yang, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104269 · Cited by 13
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“, 2003), and antiviral restriction factors such as SAMHD1 (Hrecka et al., 2011; Laguette et al., 2011).”
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The Evolution of Resistance to Simian Immunodeficiency Virus (SIV): A Review
Locatelli, S., McKean, K. A., Clee, P. R. S., & Gonder, M. K. (2014) · International Journal of Primatology · doi:10.1007/s10764-014-9763-7 · Cited by 13
“2008); and sterile α motif and HD domain 1 (SAMHD1), the most recently discovered restriction factor, highly expressed and functional in myeloid cells (Hrecka et al. 2011; Laguette et al. 2011).”
BackgroundSAMHD1 knockout mice: modeling retrovirus restriction in vivo
Wu, L. J. (2013) · Retrovirology · doi:10.1186/1742-4690-10-142 · Cited by 14
“The dNTP hydrolase SAMHD1 functions as a retroviral restriction factor in human non-cycling myeloid cells and resting CD4 T-cells [1-7].”
BackgroundResultLi, D., Schlaepfer, E., Audigé, A., Rochat, M.-A., Ivic, S., Knowlton, C., Kim, B., Keppler, O. T., & Speck, R. F. (2015) · Stem Cell Research · doi:10.1016/j.scr.2015.06.012 · Cited by 13
“SAMHD1 is expressed in cells of the myeloid lineage, such as dendritic cells (DCs), monocytes and macrophages, as well as CD4 T cells, although SAMHD1 expression was reported as missing in T cell lines (Hrecka et al., 2011; Laguette et al., 2011; Descours et al., 2012; Baldauf et al., 2012).”
BackgroundInfluentialHIV1‐viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies
Soares, R., Rocha, G., Meliço-Silvestre, A. A., & Gonçalves, T. (2016) · Reviews in Medical Virology · doi:10.1002/rmv.1889 · Cited by 14
“Indeed, Vpr and Vpx share several common features, including the assembly of an E3 Ub ligase complex composed of DCAF1 (DDB1-Cullin4-associated factor 1), previously known as Vpr-binding protein, (VprBP), DDB1 (damage-specific DNA binding protein 1), Cul4 (cullin4) and Rbx1 (ring box protein 1), also named as the CRL4…”
BackgroundInfluentialManipulation of immunometabolism by HIV—accessories to the crime?
Matheson, N. J., Greenwood, E. J. D., & Lehner, P. J. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.06.014 · Cited by 13
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Gélinas, J., Gill, D. R., & Hyde, S. C. (2018) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00051-17 · Cited by 14
“SAMHD1 is a restriction factor counteracted by Vpx (43, 44) and functions as a”
BackgroundRole of Protein–Lipid Interactions in Viral Entry
Nieto‐Garai, J. A., Contreras, F. ‐., Arboleya, A., & Lorizate, M. (2022) · Advanced Biology · doi:10.1002/adbi.202101264 · Cited by 14
Genome integrity and inflammation in the nervous system
Aditi, A., & McKinnon, P. J. (2022) · DNA repair · doi:10.1016/j.dnarep.2022.103406 · Cited by 13
Sulforaphane Reduces SAMHD1 Phosphorylation To Protect Macrophages from HIV-1 Infection
Sharifi, H. J., Paine, D. N., Fazzari, V. A., Tipple, A. F., Patterson, E., & de Noronha, C. M. C. (2022) · Journal of Virology · doi:10.1128/jvi.01187-22 · Cited by 12
“SIV/HIV-2 Vpx is an established antagonist of SAMHD1, triggering proteosome-dependent SAMHD1 degradation through the CRL4 ubiquitin ligase complex (6, 7, 30).”
BackgroundThe SAMHD1-MX2 axis restricts HIV-1 infection at postviral DNA synthesis
Guo, H., Yang, W., Li, H., Yang, J., Huang, Y., Tang, Y., Wang, S., Ni, F., Yang, W., Yu, X., et al. (2024) · mBio · doi:10.1128/mbio.01363-24 · Cited by 13
“The identification of Vpx’s host-binding proteins through mass spectrometry successfully identified SAMHD1 as the primary target for Vpx-mediated degradation (1, 5).”
BackgroundMcCown, C., Yu, C. H., & Ivanov, D. N. (2025) · Nature Communications · doi:10.1038/s41467-025-56208-y · Cited by 15
“The human HD-domain dNTPase, SAMHD1, impedes the ability of HIV-1 and related retroviruses to infect myeloid cells and resting T-lymphocytes and is speci fi cally targeted for degradation by the Vpx protein encoded by HIV-2 and SIV 7 – 9 .”
TRIM5 Acts as More Than a Retroviral Restriction Factor
de Silva, S., & Wu, L. J. (2011) · Viruses · doi:10.3390/v3071204 · Cited by 14
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InfluentialGao, S., Geng, C., Song, T., Lin, X., Liu, J., Cai, Z., & Cang, Y. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.761551 · Cited by 12
“Several viral proteins can hijack CRL4 to turn over host restriction factors to promote virus replication, including STAT1 targeted by SV5 virus V protein (12–14), SAMHD1 by simian HIV Vpr protein (15), and Smc5/6 by hepatitis B virus X protein (16).”
BackgroundInhibitory Effects of HIV-2 Vpx on Replication of HIV-1
Mahdi, M., Szojka, Z. I., Mótyán, J. A., & Tőzsér, J. (2018) · Journal of Virology · doi:10.1128/jvi.00554-18 · Cited by 13
“It is indeed fascinating that while Vpx had been used to facilitate the permissibility of myeloid cells to HIV-1 infection (36, 51), through the downregulation of SAMHD1, our findings suggest that in a pure intervirus context, Vpx is in fact detrimental to the infectivity of HIV-1.”
SAMHD1 Phosphorylation at T592 Regulates Cellular Localization and S-phase Progression
Batalis, S., Rogers, L. C., Hemphill, W. O., Mauney, C. H., Ornelles, D. A., & Hollis, T. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.724870 · Cited by 14
“Vpx relies on a nuclear E3 ubiquitin ligase to target SAMHD1 for proteasomal degradation; cytoplasmic SAMHD1 does not interact with the nuclear machinery and is protected from this degradation pathway (Brandariz-Nuñez et al., 2012; Hofmann et al., 2012; Wei et al., 2012; Schaller et al., 2014).”
BackgroundLi, Z., Yang, X., Zhao, Z., Liu, X., & Zhang, W. (2021) · Journal of Virology · doi:10.1128/jvi.01708-21 · Cited by 12
“Although host restrictive factors such as A3G, SAMHD1, and BST-2 exhibit potential antiviral activity, viruses evolve diverse strategies to evade this restriction (25, 42).”
BackgroundBowen, N. E., Oo, A., & Kim, B. (2022) · Viruses · doi:10.3390/v14081622 · Cited by 13
Kayesh, M. E. H., Kohara, M., & Tsukiyama–Kohara, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119624 · Cited by 14
Species tropism of HIV-1 modulated by viral accessory proteins
Nomaguchi, M., Doi, N., Matsumoto, Y., Sakai, Y., Fujiwara, S., & Adachi, A. (2012) · Frontiers in Microbiology · doi:10.3389/fmicb.2012.00267 · Cited by 12
“Very recently, SAMHD1 and APOBEC3A have been reported to be myeloid cell-specific restriction factors against HIV-1 counteracted by Vpx (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundCiftci, H. I., Fujino, H., Koga, R., Yamamoto, M., Kawamura, S., Tateishi, H., Iwatani, Y., Otsuka, M., & Fujita, M. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.04.038 · Cited by 12
“This process is induced by the formation of a Cul4-DDB1-DCAF1 E3 ligase complex and the proteasome-dependent degradation of a restriction factor [22– 24], identified as SAMHD1 in 2011 [25,26].”
BackgroundSensitivity to BST-2 restriction correlates with Orthobunyavirus host range
Varela, M., Piras, I. M., Mullan, C., Shí, X., Tilston‐Lunel, N. L., Pinto, R. M., Taggart, A., Welch, S. R., Neil, S. J. D., Kreher, F., et al. (2017) · Virology · doi:10.1016/j.virol.2017.06.017 · Cited by 12
“…mainly provided by studies on primate lentiviruses (Wain et al., 2007), suggests that viruses that have successfully established themselves in a given species are able to counteract, at least partially, the innate immune response of the host (Hrecka et al., 2011; Stremlau et al., 2004, 2006).”
BackgroundJi, S., Lei, N., Ren, H., Wang, Y., & Wang, X. (2018) · Journal of Virology · doi:10.1128/jvi.00499-18 · Cited by 12
“The NL4-3 pseudotyped virus was inoculated at 24 h T he r el at iv e m R N A e xp re ss io n le ve l l T he r el at iv e m R N A e xp re ss io n le ve l T he r el at iv e m R N A e xp re ss io n le ve l T he r el at iv e m R N A e xp re ss io n le ve l T he r el at iv e m R N A e xp re ss io n le ve l 1 2 10 20 30 40…”
BackgroundInfluentialTargeting Cellular Cofactors in HIV Therapy
Dürr, R., Keppler, O. T., Christ, F., Crespan, E., Garbelli, A., Maga, G., & Dietrich, U. (2014) · Topics in medicinal chemistry · doi:10.1007/7355_2014_45 · Cited by 12
Inhibitory and Stimulatory Effects of IL-32 on HIV-1 Infection
Nasser, H., Takahashi, N., Eltalkhawy, Y. M., Reda, O., Lotfi, S., Nasu, K., Sakuragi, J.-I., & Suzu, S. (2022) · The Journal of Immunology · doi:10.4049/jimmunol.2200087 · Cited by 12
E3 Ubiquitin Ligases in Gammaherpesviruses and HIV: A Review of Virus Adaptation and Exploitation
Oswald, J., Constantine, M., Adegbuyi, A., Omorogbe, E., Dellomo, A. J., & Ehrlich, E. S. (2023) · Viruses · doi:10.3390/v15091935 · Cited by 11
“SAMHD1 is a restriction factor that inhibits HIV-1 infection of nondividing cells of myeloid lineage and resting CD4+ T cells [214–216].”
Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx
Cassiday, P. A., DePaula-Silva, A. B., Chumley, J., Ward, J. P., Barker, E., & Planelles, V. (2014) · Virology · doi:10.1016/j.virol.2014.11.024 · Cited by 10
“In 2011, SAMHD1 was identified as the cellular protein targeted by Vpx, in the context of CRL4DCAF1 (Hrecka et al., 2011; Laguette et al., 2011).”
Phage defense origin of animal immunity
Morehouse, B. R. (2023) · Current Opinion in Microbiology · doi:10.1016/j.mib.2023.102295 · Cited by 10
Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells
Tsai, M.-H., Caswell, S. J., Morris, E. R., Mann, M. C., Pennell, S., Kelly, G. P., Groom, H. C. T., Taylor, I. A., & Bishop, K. N. (2023) · Retrovirology · doi:10.1186/s12977-023-00620-z · Cited by 11
Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility
White, T. E., Brandariz-Núñez, A., Valle‐Casuso, J. C., Knowlton, C., Kim, B., Sawyer, S. L., & Diaz‐Griffero, F. (2014) · Virology · doi:10.1016/j.virol.2014.04.023 · Cited by 11
“As a control, we challenged cells expressing the SAMHD1-HD206AA variant, which does not block HIV-1 infection(Hrecka et al., 2011; Laguette et al., 2011), by using increasing amounts of EIAVGFP.”
BackgroundMethodInfluentialDistinct Requirements for HIV-1 Accessory Proteins during Cell Coculture and Cell-Free Infection
Zotova, A., Atemasova, A., Pichugin, A., Filatov, A., & Mazurov, D. (2019) · Viruses · doi:10.3390/v11050390 · Cited by 11
Tyrosine Kinase Inhibition: a New Perspective in the Fight against HIV
Rodríguez-Mora, S., Spivak, A. M., Szaniawski, M. A., López‐Huertas, M. R., Alcamı́, J., Planelles, V., & Coiras, M. (2019) · Current HIV/AIDS Reports · doi:10.1007/s11904-019-00462-5 · Cited by 11
Yap, M. W., Young, G. R., Varnaitė, R., Morand, S., & Stoye, J. P. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1008471 · Cited by 10
“Some of these, like TRIM5α [3], APOBEC3G [4], and SAMHD1 [5, 6], act at or before reverse transcription, while others, such as tetherin [7] and SERINC5 [8, 9], inhibit viral budding or fusion.”
BackgroundHIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages
Virgilio, M. C., Ramnani, B., Chen, T., Disbennett, W. M., Lubow, J., Welch, J. D., & Collins, K. L. (2024) · Nature Communications · doi:10.1038/s41467-024-49635-w · Cited by 14
“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 infection 72,73 .”
Volta, L. G., & Gill, S. I. (2025) · Blood Immunology & Cellular Therapy · doi:10.1016/j.bict.2025.100027 · Cited by 16
iPS cell–derived model to study the interaction between tissue macrophage and HIV-1
Eltalkhawy, Y. M., Takahashi, N., Ariumi, Y., Shimizu, J., Miyazaki, K., Senju, S., & Suzu, S. (2023) · Journal of Leukocyte Biology · doi:10.1093/jleuko/qiad024 · Cited by 9
A macrophage-cell model of HIV latency reveals the unusual importance of the bromodomain axis
Kisaka, J. K., Rauch, D. A., Griffith, M., & Kyei, G. B. (2024) · Virology Journal · doi:10.1186/s12985-024-02343-9 · Cited by 11
“Therefore, THP-1 cells provide a good model to study viral latency and reactivation in macrophages [63, 64].”
BackgroundRashid, F., Zaongo, S. D., Iqbal, H., Harypursat, V., Song, F., & Chen, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1390650 · Cited by 13
“…DNA, which is a synthesis step that consumes cellular dNTPs. SAMHD1 hydrolyzes all four dNTPs into inorganic triphosphate and deoxynucleotides, thereby controlling the pool of cytosolic dNTPs. Similarly, in myeloid cells, SAMHD1 inhibits proviral DNA formation and HIV-1 replication (17, 19, 107).”
BackgroundThe Seneca Valley virus 3C protease cleaves DCP1A to attenuate its antiviral effects
Yang, J., Li, Z., Ma, R., Xie, S., Wang, D., Quan, R., Wen, X., & Song, J. (2025) · Veterinary Research · doi:10.1186/s13567-025-01477-0 · Cited by 10
“Anti-ISG adaptations include inhibiting transcription [13], downregulating ISG protein expression [14], altering subcellular localization [15], and blocking ISG protein expression via direct interaction [16].”
Post-translational modifications inducing proteasomal degradation to counter HIV-1 infection
Proulx, J. M., Borgmann, K., & Park, I.-W. (2020) · Virus Research · doi:10.1016/j.virusres.2020.198142 · Cited by 11
Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx
Martin, M. M., Matkovic, R., Larrous, P., Morel, M., Lasserre, A., Vauthier, V., & Margottin-Goguet, F. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009609 · Cited by 14
“At the forefront, HIV-2/SIVsmm Vpx induces the degradation of SAMHD1, relieving a block at the reverse transcription step [31,32].”
BackgroundPoeschla, E. M. (2013) · Virology · doi:10.1016/j.virol.2013.03.010 · Cited by 12
“The primate lentiviral accessory protein Vpx, which is normally confined to the HIV-2/SIVsm/SIVrcm/SIVmac lineages, targets SAMHD1 for proteasomal degradation (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundWang, Y., Whittall, T., Neil, S. J. D., Britton, G., Mistry, M., Rerks‐Ngarm, S., Pitisuttithum, P., Kaewkungwal, J., Nitayaphan, S., Yu, X., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-01188-3 · Cited by 10
Martínez‐Picado, J., McLaren, P. J., Telenti, A., & Izquierdo‐Useros, N. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01593 · Cited by 9
“SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature (2011) 474:654–7. doi:10.1038/ nature10117 6.”
BackgroundInfluentialHost SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages
Mahboubi, B., Gavegnano, C., Kim, D., Schinazi, R. F., & Kim, B. (2018) · Retrovirology · doi:10.1186/s12977-018-0452-z · Cited by 10
Molecular dynamics investigation of a redox switch in the anti‐HIV protein SAMHD1
Patra, K. K., Bhattacharya, A., & Bhattacharya, S. (2019) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.25701 · Cited by 10
Bowen, N. E., Temple, J. E., Shepard, C., Oo, A., Arizaga, F., Kapoor-Vazirani, P., Persaud, M., Yu, C. H., Kim, D., Schinazi, R. F., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101170 · Cited by 10
“In addition, SAMHD1 dNTPase activity restricts HIV-1 infection in nondividing myeloid cells (10, 11).”
BackgroundSpecific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses
Gao, W., Rui, Y., Li, G., Zhai, C., Su, J., Liu, H., Zheng, W., Zheng, B., Zhang, W., Yang, Y., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.740713 · Cited by 11
“Vpx proteins of HIV-2Rod and certain SIVs overcome the antiviral function of SAMHD1 in myeloid cells by inducing its polyubiquitination and degradation (19, 20).”
BackgroundReverse Transcription of Retroviruses and LTR Retrotransposons
Hughes, S. H. (2015) · ASM Press eBooks · doi:10.1128/9781555819217.ch46 · Cited by 11
Membrane Protein OTOF Is a Type I Interferon-Induced Entry Inhibitor of HIV-1 in Macrophages
Ding, H., Zhang, X., Zhu, Z., Wang, S., Xiong, Y., Shang, H., & Liang, G. (2022) · mBio · doi:10.1128/mbio.01738-22 · Cited by 14
Shi, H., Duan, J., Wang, J., Li, H., Wu, Z., Wang, S., Wu, X., & Lu, M. (2022) · Nutrients · doi:10.3390/nu14224935 · Cited by 10
“SAMHD1, a dNTP triphosphohydrolase (dNTPase), can hydrolyze intracellular dNTPs, thereby reducing viral reverse transcription and cDNA synthesis [43,44].”
BackgroundRestriction of Retroviral Infection of Macrophages
Sharkey, M. E. (2013) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-37765-5_4 · Cited by 11
Hou, J., Zhang, Q., Liu, Z., Wang, S., Li, D., Liu, C., Liu, Y., & Shao, Y. (2015) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2015.1082692 · Cited by 10
“Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, Yatim A, Emiliani S, Schwartz O, Benkirane M. SAMHD1 is the dendriticand myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 2011; 474:654-7; PMID:21613998; http://dx.doi.org/10.1038/ nature10117 33.”
BackgroundInfluentialThe TRIMCyp genotype in four species of macaques in China
Yu, C.-Q., Na, L., Lv, X.-L., Liu, J.-D., Liu, X.-M., Ji, F., Zheng, Y., Du, H.-L., Kong, X.-G., & Zhou, J.-H. (2012) · Immunogenetics · doi:10.1007/s00251-012-0670-9 · Cited by 11
“2008), and the recently reported SAM domain HD domain-containing protein 1 (SAMHD1) (Hrecka et al. 2011; Laguette et al. 2011).”
BackgroundVirological characterization of HIV-2 vpx gene mutants in various cell systems
Nomaguchi, M., Doi, N., & Adachi, A. (2014) · Microbes and Infection · doi:10.1016/j.micinf.2014.06.004 · Cited by 12
Lim, E. S., & Emerman, M. (2011) · Nature · doi:10.1038/474587a · Cited by 12
The SAMHD1 knockout mouse model: in vivo veritas?
Roesch, F., & Schwartz, O. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.190 · Cited by 10
“Finally, the dNTP hydrolase SAMHD1 acts to deplete the intracellular pool of nucleotides available for viral DNA synthesis by reverse transcriptase (RT) (Hrecka et al , 2011; Laguette et al , 2011; Lahouassa et al , 2012).”
Wang, W., Wang, J., Qu, M., Li, X., Zhang, J., Zhang, H., Wu, J., Yu, B., Wu, H., Kong, W., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0138190 · Cited by 11
“The recently identified SAMHD1 protein, which is also considered a restriction factor, suppresses the viral genome replication process [29–32].”
BackgroundGenetic variation in Trex1 affects HIV-1 disease progression
Booiman, T., Setiawan, L. C., & Kootstra, N. A. (2014) · AIDS · doi:10.1097/qad.0000000000000436 · Cited by 11
“0269-9370 Q 2014 Wolters Kluwer Hea described explaining how HIV-1 evades innate detection [3,4].”
Background
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
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