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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]
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]
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Items 301–400 of 1,000
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“Vpx may be more important for allowing the infection of cell types such as macrophages that contain less SAMHD1 and support the Vpx function.(16,17) In vivo, cytokines such as IL-4 and GM-CSF that cause the maturation of myeloid cells may play a role in allowing Vpx to induce SAMHD1 degradation, analogous to what is s…”
Bernier, A., Cleret‐Buhot, A., Zhang, Y., Goulet, J.-P., Monteiro, P., Gosselin, A., DaFonseca, S., Wacleche, V. S., Jenabian, M.-A., Routy, J., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-160 · Cited by 53
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BackgroundGuardian of the Human Genome: Host Defense Mechanisms against LINE-1 Retrotransposition
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“…and SAMHD1 have been identified as restriction factors for human immunodeficiency virus type 1 (HIV-1) (Sheehy et al., 2002; Harris et al., 2003; Mangeat et al., 2003; Zhang et al., 2003; Burdick et al., 2010; Furtak et al., 2010; Wang et al., 2010; Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundGenome-wide CRISPR/Cas9-knockout in human induced Pluripotent Stem Cell (iPSC)-derived macrophages
Navarro‐Guerrero, E., Tay, C., Whalley, J. P., Cowley, S. A., Davies, B., Knight, J. C., & Ebner, D. V. (2021) · Scientific Reports · doi:10.1038/s41598-021-82137-z · Cited by 48
miRNA-1236 Inhibits HIV-1 Infection of Monocytes by Repressing Translation of Cellular Factor VprBP
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“However, SAMHD1 shows comparable expression in monocytes compared with MDDCs, suggesting that VprBP-facilitated HIV-1 infection in MDDCs is not attributed to the SAMHD1 degradation induced by CUL4–DDB1–DCAF1/VprBP E3 ubiquitin protein ligase complex.”
InfluentialThe mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP
Zhu, C. F., Wei, W., Peng, X., Dong, Y., Gong, Y., & Yu, X.-F. (2015) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s1399004714027527 · Cited by 47
“Recently, SAMHD1 has been reported to be a potent inhibitor of retroviruses such as HIV-1 (Laguette et al., 2011; Hrecka et al., 2011; Berger et al., 2011; Roesch & Schwartz, 2013; Descours et al., 2012; Baldauf et al., 2012), DNA viruses (Hollenbaugh et al., 2013; Kim et al., 2013) and endogenous…”
BackgroundAicardi–Goutieres syndrome: from patients to genes and beyond
Chahwan, C., & Chahwan, R. (2011) · Clinical Genetics · doi:10.1111/j.1399-0004.2011.01825.x · Cited by 48
Unmasking immune sensing of retroviruses: Interplay between innate sensors and host effectors
van Montfoort, N., Olagnier, D. P., & Hiscott, J. B. (2014) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2014.08.006 · Cited by 48
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“Recently studies using the SIV rhesus macaque model suggested that infected resting T cells can spontaneously release virions [47].”
BackgroundHIV-1 Vpr Protein Inhibits Telomerase Activity via the EDD-DDB1-VPRBP E3 Ligase Complex
Wang, X., Singh, S., Jung, H., Guo-jun, Y., Jun, S., Sastry, K. J., & Park, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.416735 · Cited by 48
“Similarly, Vpx fromHIV-2 targets SAMHD1 (SAM and HD domain-containing protein 1), a viral restriction factor, via E3 ligase (7, 8).”
BackgroundHuman cytomegalovirus overcomes SAMHD1 restriction in macrophages via pUL97
Businger, R., Deutschmann, J., Gruska, I., Milbradt, J., Wiebusch, L., Gramberg, T., & Schindler, M. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0557-8 · Cited by 45
Agudo, J., Ruzo, A., Kitur, K., Sachidanandam, R., Blander, J. M., & Brown, B. D. (2012) · Molecular Therapy · doi:10.1038/mt.2012.150 · Cited by 48
HIV relies on neddylation for ubiquitin ligase-mediated functions
Nekorchuk, M. D., Sharifi, H. J., Furuya, A. K. M., Jellinger, R. M., & de Noronha, C. M. C. (2013) · Retrovirology · doi:10.1186/1742-4690-10-138 · Cited by 47
“; licensee BioMed Cen Commons Attribution License (http://creativec reproduction in any medium, provided the or viruses (SIV) express Vpx to recruit SAMHD1 to the CRL4 complex and thereby trigger its ubiquitination and subsequent proteasomal degradation [2,3].”
BackgroundMachida, S., Depierre, D., Chen, H., Thenin-Houssier, S., Petitjean, G., Doyen, C. M., Takaku, M., Cuvier, O., & Benkirane, M. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1913754117 · Cited by 45
“To evaluate the PF74-dependent inhibition of HIV DNA nuclear import, we infected differentiated THP-1 cells, which were incubated with viral protein X (Vpx) to overcome SAMHD1-mediated viral restriction (27 – 29), with HIV-1 in the presence or absence of PF74 (Fig.”
HIV-1 Trans Infection of CD4 + T Cells by Professional Antigen Presenting Cells
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CD4 + Memory Stem Cells Are Infected by HIV-1 in a Manner Regulated in Part by SAMHD1 Expression
Tabler, C. O., Lucera, M. B., Haqqani, A. A., McDonald, D. J., Migueles, S. A., Connors, M., & Tilton, J. C. (2014) · Journal of Virology · doi:10.1128/jvi.00324-14 · Cited by 50
HIV-1 Replication and APOBEC3 Antiviral Activity Are Not Regulated by P Bodies
Phalora, P. K., Sherer, N. M., Wolinsky, S. M., Swanson, C. M., & Malim, M. H. (2012) · Journal of Virology · doi:10.1128/jvi.00595-12 · Cited by 48
“The APOBEC3 proteins, along with Trim5 , tetherin, and most recently, SAMHD1, have been identified as host restriction factors that have the intrinsic ability to defend against invading exogenous viruses and endogenous retroelements (45, 58, 75, 90, 92).”
BackgroundRomani, B., Shaykh‐Baygloo, N., Hamidi-Fard, M., Aghasadeghi, M. R., & Allahbakhshi, E. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.689018 · Cited by 47
Small-Molecule Approaches to Targeted Protein Degradation
Faust, T. B., Donovan, K. A., Yue, H., Chamberlain, P. P., & Fischer, E. S. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-051420-114114 · Cited by 45
ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication
Radetskyy, R., Daher, A., & Gatignol, A. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.03.007 · Cited by 45
Schiffelers, L. D. J., Tesfamariam, Y. M., Jenster, L., Diehl, S., Binder, S. C., Normann, S., Mayr, J., Pritzl, S., Hagelauer, E., Kopp, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52110-1 · Cited by 49
“3 Vpr. Vpx-Vpr is packaged into lentivirus particles as Vpr binds to the structural protein Gag, and thus delivers Vpx into target cells, which mediates the Cullin-4a-mediated proteasomal degradation of SAMHD1 58,59 .”
Bocharov, G. A., Черешнев, В. А., Gainova, I., Bazhan, S. I., Bachmetyev, B. A., Argilaguet, J. M., Martínez, J. P., & Meyerhans, A. (2012) · Mathematical Modelling of Natural Phenomena · doi:10.1051/mmnp/20127507 · Cited by 48
“Multiple host factors can restrict HIV [121,147,179,180,224,225, 245,250]”
BackgroundInnate immune sensing of HIV infection
Silvin, A., & Manel, N. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.12.003 · Cited by 49
Marsili, G., Remoli, A. L., Sgarbanti, M., Perrotti, E., Fragale, A., & Battistini, A. (2012) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2012.06.001 · Cited by 52
“The recently characterized host restriction factor, SAMHD1, was identified as the factor targeted by Vpx of HIV-2 and some strains of SIV, that is able to inhibit HIV-1 infection in myeloid cells [130,131].”
BackgroundG 2 /M Cell Cycle Arrest Correlates with Primate Lentiviral Vpr Interaction with the SLX4 Complex
Berger, G., Lawrence, M., Hué, S., & Neil, S. J. D. (2014) · Journal of Virology · doi:10.1128/jvi.02307-14 · Cited by 47
“SIVrcm is a member of the same lineage as SIVsmm and HIV-2, in which the vpr gene was duplicated to generate vpx, with the former retaining cell cycle arrest activity and the latter targeting SAMHD1 (8, 10, 40).”
BackgroundNakagawa, T., Mondal, K., & Swanson, P. C. (2013) · BMC Molecular Biology · doi:10.1186/1471-2199-14-22 · Cited by 46
“by maintaining cellular dNTP levels below the threshold required for robust viral reverse transcriptase activity [61-66].”
BackgroundSchaller, T., Pollpeter, D., Apolonia, L., Goujon, C., & Malim, M. H. (2014) · Retrovirology · doi:10.1186/1742-4690-11-29 · Cited by 49
“[1-9].”
Reinhard, C., Bottinelli, D., Kim, B., & Luban, J. (2014) · Retrovirology · doi:10.1186/1742-4690-11-12 · Cited by 46
“Vpx targets SAMHD1 for degradation by recruiting the E3 ubiquitin ligase complex DCAF1-CUL4A [13,14].”
BackgroundCell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection
Fan, Y., Mok, C. K. P., Chan, M. C. W., Zhang, Y., Nal, B., Kien, F., Bruzzone, R., & Sanyal, S. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.776112 · Cited by 44
“Indeed, mislocalization and subsequent down-regulation of restriction factors is one of the recurring mechanisms viruses have adopted to overcome host defenses (72).”
BackgroundThe SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch
Mauney, C. H., Rogers, L. C., Harris, R. S., Daniel, L. W., Devarie‐Baez, N. O., Wu, H., Furdui, C. M., Poole, L. B., Perrino, F. W., & Hollis, T. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6888 · Cited by 49
“SAMHD1 has garnered significant attention for its antiviral properties in nondividing hematopoietic cells, where it acts as an interferon-inducible host restriction factor against viral infections, including HIV (3, 4, 18, 20, 21, 31, 33, 48, 54).”
BackgroundInfluentialImaging HIV-1 Genomic DNA from Entry through Productive Infection
Stultz, R. D., Cenker, J. J., & McDonald, D. J. (2017) · Journal of Virology · doi:10.1128/jvi.00034-17 · Cited by 48
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No evidence of human genome integration of SARS-CoV-2 found by long-read DNA sequencing
Smits, N., Rasmussen, J., Bodea, G. O., Amarilla, A. A., Gerdes, P., Sanchez-Luque, F. J., Ajjikuttira, P., Modhiran, N., Liang, B., Faivre, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109530 · Cited by 46
Defective HIV-1 genomes and their potential impact on HIV pathogenesis
Kuniholm, J., Coote, C., & Henderson, A. J. (2022) · Retrovirology · doi:10.1186/s12977-022-00601-8 · Cited by 46
MicroRNA-Mediated Restriction of HIV-1 in Resting CD4+ T Cells and Monocytes
Chiang, K., & Rice, A. P. (2012) · Viruses · doi:10.3390/v4091390 · Cited by 47
“discovered that Vpx counteracts the restriction factor SAMHD1, which appears to block viral replication at the reverse transcription step [77,78].”
BackgroundInhibition of CUL4A Neddylation Causes a Reversible Block to SAMHD1-Mediated Restriction of HIV-1
Hofmann, H., Norton, T. D., Schultz, M. L., Polsky, S. B., Sunseri, N., & Landau, N. R. (2013) · Journal of Virology · doi:10.1128/jvi.02002-13 · Cited by 46
“Vpx induces the degradation of SAMHD1 by interacting with the E3 ubiquitin ligase CRL4, a complex that consists of DDB1, RBX1, Cullin4A (CUL4A), and DCAF1.”
BackgroundArnold, L. H., Kunzelmann, S., Webb, M. R., & Taylor, I. A. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.03903-14 · Cited by 45
“In addition, SAMHD1 is an anti-HIV-1 restriction factor that blocks the infection of monocyte-derived dendritic cells (MDDCs) (8), monocyte-derived macrophages (MDMs) (9), and resting T cells (10) through its triphosphohydrolase activity (2).”
Prevention of SHIV transmission by topical IFN-β treatment
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Antiviral gene expression in psoriasis
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Albanese, M., Ruhle, A., Mittermaier, J., Mejías‐Pérez, E., Gapp, M., Linder, A., Schmacke, N. A., Hofmann, K., Hennrich, A. A., Levy, D. N., et al. (2021) · Nature Methods · doi:10.1038/s41592-021-01328-8 · Cited by 47
Early Vertebrate Evolution of the Host Restriction Factor Tetherin
Heusinger, E., Kluge, S. F., Kirchhoff, F., & Sauter, D. (2015) · Journal of Virology · doi:10.1128/jvi.02149-15 · Cited by 41
“TRIM5 induces the untimely uncoating of the incoming retroviral capsid (13), APOBEC3G is a deaminase introducing lethal hypermutations into the viral genome (14), SAMHD1 inhibits reverse transcription by depleting intracellular deoxynucleoside triphosphate (dNTP) pools (15, 16), and tetherin restricts the release of n…”
BackgroundTang, Y.-D., Lei, N., Zhu, C., Shen, N., Yang, F., Fu, X.-Q., Wang, Y., Fu, L.-H., Wang, J., Lin, Y., et al. (2014) · Journal of Virology · doi:10.1128/jvi.01379-14 · Cited by 43
“For example, the Vif protein of HIV-1 antagonizes APOBEC3G (45) by mediating APOBEC3G ubiquitination; the Vpu protein of this virus antagonizes the restriction factor Tetherin by altering its normal cellular localization (46), and the Vpx protein encoded by HIV-2 and related primate lentiviruses (such as SIVsm) degrad…”
BackgroundSulforaphane Inhibits HIV Infection of Macrophages through Nrf2
Furuya, A. K. M., Sharifi, H. J., Jellinger, R. M., Cristofano, P., Shi, B., & de Noronha, C. M. C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005581 · Cited by 43
Inhibition of HIV early replication by the p53 and its downstream gene p21
Shi, B., Sharifi, H. J., DiGrigoli, S., Kinnetz, M., Mellon, K., Hu, W., & de Noronha, C. M. C. (2018) · Virology Journal · doi:10.1186/s12985-018-0959-x · Cited by 43
“The Vpx protein from HIV-2 is able to degrade cellular restriction factor SAMHD1 [30], while p21 can inactivate SAMHD1 by phosphorylation [20].”
Enterovirus 71 antagonizes the inhibition of the host intrinsic antiviral factor A3G
Li, Z., Ning, S., Su, X., Liu, X., Wang, H., Liu, Y., Zheng, W., Zheng, B., Yu, X., & Zhang, W. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky840 · Cited by 43
Functional proteomic atlas of HIV infection in primary human CD4+ T cells
Naamati, A., Williamson, J. C., Greenwood, E. J. D., Marelli, S., Lehner, P. J., & Matheson, N. J. (2019) · eLife · doi:10.7554/elife.41431 · Cited by 44
Hsiao, F., Frouard, J., Gramatica, A., Xie, G., Telwatte, S., Lee, G. Q., Roychoudhury, P., Schwarzer, R., Luo, X., Yukl, S. A., et al. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008450 · Cited by 43
“As a complementary approach to determine whether SAMHD1 plays a role in infection restriction in the CD127+ Tm cells, we abrogated its activity with Vpx, an accessory protein from SIV and HIV-2 that degrades SAMHD1 [17, 18].”
HIV-1 mutates to evade IFITM1 restriction
Ding, S., Pan, Q., Liu, S., & Liang, C. (2014) · Virology · doi:10.1016/j.virol.2014.01.020 · Cited by 44
“…polypeptide-like 3G), TRIM5α (Tripartite motif-containing protein 5α), tetherin, SAMHD1 (SAM domain and HD domain-containing protein 1) and Schlafen 11 (Hrecka et al., 2011; Laguette et al., 2011; Li et al., 2012; Neil et al., 2008; Sadler and Williams, 2008; Stremlau et al., 2004).”
Tasker, C., Ding, J., Schmolke, M., Rivera, A., García‐Sastre, A., & Chang, T. L.-Y. (2014) · Viral Immunology · doi:10.1089/vim.2013.0120 · Cited by 42
“APOBEC3A can be induced by IFN-a and inhibits ethe early phase of HIV infection in cells of myeloid origins (2).”
InfluentialDong, J., Zhang, N., Ge, X., Zhou, L., Guo, X., & Yang, H. (2014) · Virology · doi:10.1016/j.virol.2014.07.036 · Cited by 44
“…a single strand positive RNA with approximately 15 kb in length, which encodes at least ten open reading frames (ORFs) comprising of ORF1a, ORF1b, ORF2a, ORF2b, ORFs3–7 and the newly discovered ORF5a (Conzelmann et al., 1993; Firth et al., 2011; Johnson et al., 2011; Snijder and Meulenberg, 1998).”
Jeong, G. U., Park, I.-H., Ahn, K., & Ahn, B.-Y. (2016) · Virology · doi:10.1016/j.virol.2016.05.001 · Cited by 43
“Sterile alpha motif (SAM) and histidine/aspartic acid (HD) domain-containing protein 1 (SAMHD1) is a recently discovered cellular restriction factor for HIV-1 (Laguette et al., 2011; Hrecka et al., 2011).”
BackgroundWang, X., Arceci, A., Bird, K. E., Mills, C. A., Choudhury, R., Kernan, J. L., Zhou, C., Bae-Jump, V. L., Bowers, A. A., & Emanuele, M. J. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00609-16 · Cited by 42
“Importantly, the amino acids in SamHD1 that mediate binding to VprBP and degradation have been mapped (55, 56).”
BackgroundInfluentialHIV-1 Vpr counteracts HLTF-mediated restriction of HIV-1 infection in T cells
Yan, J., Shun, M.-C., Zhang, Y., Hao, C., & Skowroński, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818401116 · Cited by 44
“Viral particles were produced from HEK293 T cells as previously described (24, 75).”
MethodSelf-citationComplement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells
Posch, W., Steger, M., Knackmuss, U., Blatzer, M., Baldauf, H., Doppler, W., White, T. E., Hörtnagl, P., Diaz‐Griffero, F., Lass‐Flörl, C., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1005005 · Cited by 42
The HIV1 Protein Vpr Acts to Enhance Constitutive DCAF1-Dependent UNG2 Turnover
Wen, X., Klockow, L. C., Nekorchuk, M. D., Sharifi, H. J., & de Noronha, C. M. C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030939 · Cited by 45
“The same ubiquitin ligase complex is also recruited by the closely related HIV2- and SIVSM Vpx proteins to defeat an antiviral factor that blocks efficient reverse transcription in cells of the monocytic lineage [8,9,10,11].”
BackgrounddNTP pool modulation dynamics by SAMHD1 protein in monocyte-derived macrophages
Hollenbaugh, J. A., Tao, S., Lenzi, G. M., Ryu, S., Kim, D., Diaz‐Griffero, F., Schinazi, R. F., & Kim, B. (2014) · Retrovirology · doi:10.1186/preaccept-5624405321277583 · Cited by 41
CD169-Dependent Cell-Associated HIV-1 Transmission: A Driver of Virus Dissemination
Gummuluru, S., Ramirez, N.-G. P., & Akiyama, H. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu442 · Cited by 42
Seamon, K. J., Bumpus, N. N., & Stivers, J. T. (2016) · Biochemistry · doi:10.1021/acs.biochem.6b00986 · Cited by 42
Impairment of the type I interferon response by HIV-1: Potential targets for HIV eradication
Sandstrom, T. S., Ranganath, N., & Angel, J. B. (2017) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2017.04.004 · Cited by 43
Yan, J., Shun, M.-C., Hao, C., Zhang, Y., Qian, J., Hrecka, K., DeLucia, M., Monnie, C. M., Ahn, J., & Skowroński, J. (2018) · mBio · doi:10.1128/mbio.01732-18 · Cited by 47
Self-citationQuillay, H., Costa, H. E., Marlin, R., Duriez, M., Cannou, C., Chrétien, F., Fernandez, H., Lebreton, A., Ighil, J., Schwartz, O., et al. (2014) · Journal of Virology · doi:10.1128/jvi.01730-14 · Cited by 48
“HIV-1 infection is restricted by SAMHD1 in myeloid cells (28, 29) and in resting CD4 T lymphocytes (30, 31).”
BackgroundInfluentialDeficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner
Schumann, T., Ramon, S. C., Schubert, N., Mayo, M. A., Hega, M., Maser, K. I., Ada, S.-R., Sydow, L., Hajikazemi, M., Badstübner, M., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220829 · Cited by 41
“Through this activity, SAMHD1 limits the availability of dNTPs in resting cells, which hinders replication of pathogens like retroviruses that depend on cellular dNTP supply (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundIncreasing intracellular dNTP levels improves prime editing efficiency
Liu, P., Ponnienselvan, K., Nyalile, T., Oikemus, S., Joynt, A. T., Iyer, S., Kelly, K. L., Guo, D., Kyawe, P. P., Vanderleeden, E., et al. (2024) · Nature Biotechnology · doi:10.1038/s41587-024-02405-x · Cited by 45
“SAMHD1 inactivation increases intracellular dNTP levels, which promotes reverse transcription and successful viral infection in quiescent cells 32,36 .”
mi RNA s and HIV : unforeseen determinants of host‐pathogen interaction
Swaminathan, S., Murray, D. D., & Kelleher, A. D. (2013) · Immunological Reviews · doi:10.1111/imr.12077 · Cited by 40
“The SIV accessory protein, Vpx, inhibits the action of SAMHD1 by targeting it for degradation and can be used to increase HIV-1 infection of human macrophages (56, 117).”
BackgroundZhang, C., de Silva, S., Wang, J., & Wu, L. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037477 · Cited by 42
“Furthermore, Vpx of SIVmac251 and HIV-2 ROD from this clade have been demonstrated to degrade human SAMHD1 [3,4].”
BackgroundInfluentialEndogenous retroelements and autoimmune disease
Stetson, D. B. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.09.007 · Cited by 40
“Current Opinion in Immunology 2012, 24:692–697 two groups reported that SAMHD1 is an essential HIV restriction factor in human myeloid cells [32 ,33 ].”
BackgroundWang, X., Li, C., Zhou, L., Zhang, N., Wang, X., Ge, X., Guo, X., & Yang, H. (2014) · Virus Research · doi:10.1016/j.virusres.2014.07.025 · Cited by 41
Vpx is Critical for SIVmne infection of pigtail macaques
Belshan, M., Kimata, J. T., Brown, C. R., Cheng, X., McCulley, A., Larsen, A., Thippeshappa, R., Hodara, V. L., Giavedoni, L. D., Hirsch, V. M., et al. (2012) · Retrovirology · doi:10.1186/1742-4690-9-32 · Cited by 41
“Since recent studies demonstrated that SAMHD1 is a cellular restriction factor for HIVs and SIVs in myeloid cells, whose stability is regulated by DCAF1 and Vpx [22,23], we assessed the stability of FLAG-tagged SAMHD1 in the presence of wild type and mutant SIV Vpx proteins (Figure 8).”
BackgroundEpithelium-innate immune cell axis in mucosal responses to SIV
Shang, L., Duan, L., Perkey, K., Wietgrefe, S. W., Zupancic, M., Smith, A. J., Southern, P. J., Johnson, R. P., & Haase, A. T. (2016) · Mucosal Immunology · doi:10.1038/mi.2016.62 · Cited by 43
Reshaping of the Dendritic Cell Chromatin Landscape and Interferon Pathways during HIV Infection
Johnson, J. S., Lucas, S. Y., Amon, L. M., Skelton, S., Nazitto, R., Carbonetti, S., Sather, D. N., Littman, D. R., & Aderem, A. A. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.01.012 · Cited by 42
“This is largely due to DCs expressing high levels of the restriction factor, SAMHD1, a nucleotide phosphohydrolase that prevents reverse transcription of retroviruses (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundKueck, T., Cassella, E., Holler, J. M., Kim, B., & Bieniasz, P. D. (2018) · eLife · doi:10.7554/elife.38867 · Cited by 38
HIV Infection Stabilizes Macrophage-T Cell Interactions To Promote Cell-Cell HIV Spread
Lopez, P. G., Koh, W. H., Hnatiuk, R., & Murooka, T. T. (2019) · Journal of Virology · doi:10.1128/jvi.00805-19 · Cited by 47
“activated CD4 T cells due to high SAMHD1 expression (30, 31), their localization and”
BackgroundInfrequent HIV Infection of Circulating Monocytes during Antiretroviral Therapy
Massanella, M., Bakeman, W., Sithinamsuwan, P., Fletcher, J. L. K., Chomchey, N., Tipsuk, S., Chalermchai, T., Routy, J., Ananworanich, J., Valcour, V., et al. (2019) · Journal of Virology · doi:10.1128/jvi.01174-19 · Cited by 40
“(C D 3 co pi es e qu iv al en t) Median LOD for samples with >10,000 cells detected 18 [9-31] 9 [5-21] 45 [30-66] 4 [3-6] 23 [11-52]”
BackgroundThe Interplay between Viruses and Host DNA Sensors
Huérfano, S., Šroller, V., Bruštíková, K., Horníková, L., & Forstová, J. (2022) · Viruses · doi:10.3390/v14040666 · Cited by 41
Influence of Common Mucosal Co‐Factors on HIV Infection in the Female Genital Tract
Ferreira, V. H., Kafka, J. K., & Kaushic, C. (2014) · American Journal of Reproductive Immunology · doi:10.1111/aji.12221 · Cited by 43
Effects of Cellular Activation on Anti-HIV-1 Restriction Factor Expression Profile in Primary Cells
Raposo, R. A. S., Abdel‐Mohsen, M., Bilska, M., Montefiori, D. C., Nixon, D. F., & Pillai, S. K. (2013) · Journal of Virology · doi:10.1128/jvi.02128-13 · Cited by 43
“SAMHD1 was recently shown to inhibit HIV and SIV infection in quiescent CD4 T cells (4, 5) and myeloid cells (6, 7) by eliminating the intracellular pool of deoxynucleoside triphosphates (dNTPs) required for viral cDNA production during reverse transcription.”
BackgroundGorry, P. R., Francella, N., Lewin, S. R., & Collman, R. G. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.0713368 · Cited by 45
“ferred by SAMHD1 [36, 37].”
IFN-ε protects primary macrophages against HIV infection
Tasker, C., Subbian, S., Gao, P., Couret, J., Levine, C., Ghanny, S., Soteropoulos, P., Zhao, X., Landau, N. R., Lu, W., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.88255 · Cited by 42
Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells
Miller, C. M., Akiyama, H., Agosto, L. M., Emery, A., Ettinger, C. R., Swanstrom, R. I., Henderson, A. J., & Gummuluru, S. (2017) · Journal of Virology · doi:10.1128/jvi.00051-17 · Cited by 35
“HIV-1 replication in MDDCs is restricted at the reverse transcription (RT) step by SAMHD1, which controls the size of cytosolic deoxynucleoside triphosphate (dNTP) pools (51, 52).”
BackgroundSzaniawski, M. A., Spivak, A. M., Cox, J. E., Catrow, J. L., Hanley, T. M., Williams, E. S. C. P., Tremblay, M. J., Bosque, A., & Planelles, V. (2018) · mBio · doi:10.1128/mbio.00819-18 · Cited by 40
“control, VLP lacking Vpx [Vpx( )VLP] (8, 24).”
SUMOylation of SAMHD1 at Lysine 595 is required for HIV-1 restriction in non-cycling cells
Martinat, C., Cormier, A., Tobaly-Tapiero, J., Palmic, N., Casartelli, N., Mahboubi, B., Coggins, S. A., Buchrieser, J., Persaud, M., Diaz‐Griffero, F., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24802-5 · Cited by 44
Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages
Ruiz, A., Pauls, E., Badía, R., Torres‐Torronteras, J., Riveira‐Muñoz, E., Clotet, B., Martí, R., Ballana, E., & Esté, J. A. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1030558 · Cited by 40
“SAMHD1-induced restriction may be counteracted by viral protein X (Vpx) encoded by SIV or HIV subtype-2 (HIV-2), which triggers its degradation by the ubiquitin system.(6) Samhd1¡/¡ mice show increased intracellular levels of dNTP.”
BackgroundAlbershardt, T. C., Campbell, D. J., Parsons, A. J., Slough, M. M., ter Meulen, J., & Berglund, P. (2016) · Molecular Therapy - Oncolytics · doi:10.1038/mto.2016.10 · Cited by 38
Interplay between Intrinsic and Innate Immunity during HIV Infection
Bergantz, L., Subra, F., Deprez, E., Delelis, O., & Richetta, C. (2019) · Cells · doi:10.3390/cells8080922 · Cited by 42
“As a consequence, SAMHD1 inhibits HIV-1 replication in myeloid cells including moDCs and monocyte-derived macrophages [4,5].”
BackgroundExpression of HIV-1 Intron-Containing RNA in Microglia Induces Inflammatory Responses
Akiyama, H., Jalloh, S., Park, S., Lei, M., Mostoslavsky, G., & Gummuluru, S. (2020) · Journal of Virology · doi:10.1128/jvi.01386-20 · Cited by 39
“We report that while HIV-1 infection of MDMGs is attenuated, restriction to infection was alleviated upon SAM domain and HD domain-containing protein 1 (SAMHD1) degradation.”
MethodInfluentialThe Deubiquitinase USP29 Promotes SARS-CoV-2 Virulence by Preventing Proteasome Degradation of ORF9b
Gao, W., Wang, L., Ju, X., Zhao, S., Li, Z., Su, M., Xu, J., Wang, P., Ding, Q., Lv, G., et al. (2022) · mBio · doi:10.1128/mbio.01300-22 · Cited by 37
Advancing CAR-based immunotherapies in solid tumors: CAR- macrophages and neutrophils
Liang, Y., Xu, Q., & Gao, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1291619 · Cited by 39
“The virion-associated protein Vpx from HIV-2 or related simian immunode fi ciency viruses was found to induce SAMHD1 degradation, which increased the infection ef fi cacy of lentivirus to macrophages (71).”
BackgroundContribution of oligomerization to the anti-HIV-1 properties of SAMHD1
Brandariz-Núñez, A., Valle‐Casuso, J. C., White, T. E., Nguyen, L. A., Bhattacharya, A., Wang, Z., Demeler, B., Amie, S. M., Knowlton, C., Kim, B., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-131 · Cited by 41
“Mechanistic studies have suggested that Vpx induces the proteasomal degradation of SAMHD1 [20-22].”
BackgroundThe G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells
Badía, R., Pujantell, M., Riveira‐Muñoz, E., Puig, T., Torres‐Torronteras, J., Martí, R., Clotet, B., Ampudia, R. M., Vives‐Pi, M., Esté, J. A., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005829 · Cited by 37
Roles of SAMHD1 in antiviral defense, autoimmunity and cancer
Li, M., Zhang, D., Zhu, M., Shen, Y., Wei, W., Ying, S., Körner, H., & Li, J. (2017) · Reviews in Medical Virology · doi:10.1002/rmv.1931 · Cited by 38
“containing protein 1 (SAMHD1) has been identified and is now the subject of intense research.(4,5) The SAMHD1 was originally discovered in human dendritic cells as the homologue of a mouse IFN‐γ–induced protein and named dendritic cell‐derived IFN‐γ–induced protein (DCIP).”
BackgroundUSP18 (UBP43) Abrogates p21-Mediated Inhibition of HIV-1
Kuffour, E. O., Schott, K., Vasudevan, A. A. J., Holler, J. M., Schulz, W. A., Lang, P. A., Lang, K. S., Kim, B., Häussinger, D., König, R., et al. (2018) · Journal of Virology · doi:10.1128/jvi.00592-18 · Cited by 35
HIV-1 Is a Poor Inducer of Innate Immune Responses
Cingöz, O., & Goff, S. P. (2019) · mBio · doi:10.1128/mbio.02834-18 · Cited by 38
“role of SAMHD1 in inhibiting reverse transcription (23, 24).”
BackgroundMlčochová, P., Winstone, H., Zuliani‐Alvarez, L., & Gupta, R. K. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.008 · Cited by 36
Porcine Deltacoronavirus nsp5 Cleaves DCP1A To Decrease Its Antiviral Activity
Zhu, X., Chen, J., Tian, L., Zhou, Y., Xu, S., Long, S., Wang, D., Fang, L., & Xiao, S. (2020) · Journal of Virology · doi:10.1128/jvi.02162-19 · Cited by 37
“antagonize their antiviral functions (39, 61).”
Humbert, J.-M., Frecha, C. A., Amirache, F., N′Guyen, T. H., Boni, S., Cosset, F., Verhoeyen, E., & Halary, F. A. (2012) · Journal of Virology · doi:10.1128/jvi.06283-11 · Cited by 38
“Vpx has been recently described as an interactant of the cellular host protein SAMHD1 identified as a major restriction factor of the transduction of myeloid cells by HIV-1based viruses (47, 54).”
BackgroundInfluentialSu, B., Biedma, M. E., Lederle, A., Peressin, M., Lambotin, M., Proust, A. M., Decoville, T., Schmidt, S., Laumond, G., & Moog, C. (2014) · Journal of Virology · doi:10.1128/jvi.03057-13 · Cited by 41
“SAMHD1 was identified as one of several cellular restriction factors, the expression of which prevents HIV-1 reverse transcription in myeloid DCs (3, 4).”
BackgroundSabbatucci, M., Covino, D. A., Purificato, C., Mallano, A., Federico, M., Lu, J. N., Rinaldi, A. O., Pellegrini, M. A., Bona, R., Michelini, Z., et al. (2015) · Retrovirology · doi:10.1186/s12977-014-0132-6 · Cited by 38
“Since it has been shown that SIV-Vpx induces proteasomal degradation of SAMHD1 [30,31], we utilized an HIV-1 based lentiviral vector (LV) containing SIV-Vpx and expressing GFP (LV/Vpx) to knock-down SAMHD1 and then compare LV/Vpx infected MDM treated with”
Kodigepalli, K. M., Bonifati, S., Tirumuru, N., & Wu, L. J. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1480218 · Cited by 36
“SAMHD1 inhibits infections of retroviruses and certain DNA viruses by reducing the dNTP levels in the host cells required for viral genome replication [19,21,22].”
BackgroundStillman, B. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1312901110 · Cited by 40
Li, D., Lopez, A., Sandoval, C., Doyle, R. N., & Fregoso, O. I. (2020) · mBio · doi:10.1128/mbio.00940-20 · Cited by 41
“This is analogous to the degradation of SAMHD1 by lentiviral Vpx/Vpr (5, 81, 82) and could help to explain why Vpr from HIV-2, which encodes both Vpr and the paralogous Vpx protein, does not attenuate host repair machinery, or recruit host DDR proteins (6, 36, 37, 40, 41, 83), as efficiently as HIV-1 Vpr.”
Method
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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