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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]
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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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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
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Cell Cycle Regulation in Macrophages and Susceptibility to HIV-1
Ferreira, I. A. T. M., Porterfield, J. Z., Gupta, R. K., & Mlčochová, P. (2020) · Viruses · doi:10.3390/v12080839 · Cited by 27
Microglia: The Real Foe in HIV-1-Associated Neurocognitive Disorders?
Borrajo, A., Penedo, M. A., Baltanás, T. R., Pérez-Rodríguez, D., Alonso-Crespo, D., Fernández-Pereira, C., Olivares, J. M., & Agís‐Balboa, R. C. (2021) · Biomedicines · doi:10.3390/biomedicines9080925 · Cited by 27
The Interplay Among HIV, LINE-1, and the Interferon Signaling System
Zhao, X., Zhao, Y., Du, J., Gao, P., & Zhao, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.732775 · Cited by 28
“In addition, SAMHD1 is a potent HIV suppressor in non-dividing cells such as macrophages and dendritic cells (29, 30).”
BackgroundMolecular Mechanisms of HIV Immune Evasion of the Innate Immune Response in Myeloid Cells
Mashiba, M., & Collins, K. L. (2012) · Viruses · doi:10.3390/v5010001 · Cited by 27
“Based on these data, SAMHD1 is necessary and sufficient to inhibit infection of myeloid cells and quiescent CD4 + T cells by lentiviruses not expressing Vpx [38,39].”
BackgroundMethodInfluentialIdentification of the feline foamy virus Bet domain essential for APOBEC3 counteraction
Slavkovic‐Lukic, D., Hotz‐Wagenblatt, A., Lei-Rossmann, J., Räthe, A.-M., Muhle, M. E., Denner, J., Münk, C., & Löchelt, M. (2013) · Retrovirology · doi:10.1186/1742-4690-10-76 · Cited by 28
“Some viruses, for instance, have acquired special proteins that directly counteract restriction factors [1,2,8,12,15].”
InfluentialSIV Vpx Is Essential for Macrophage Infection but Not for Development of AIDS
Westmoreland, S. V., Converse, A. P., Hrecka, K., Hurley, M., Knight, H., Piatak, M., Lifson, J. D., Mansfield, K. G., Skowroński, J., & Desrosiers, R. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0084463 · Cited by 27
“Vpx loads the SAMHD1 protein onto the CRL4 E3 ubiquitin ligase so that SAMHD1 undergoes proteaosome degradation allowing the virus to replicate [14].”
BackgroundSelf-citationOdegard, J. M., Kelley-Clarke, B., Tareen, S. U., Campbell, D. J., Flynn, P. A., Nicolai, C. J., Slough, M. M., Vin, C. D., McGowan, P. J., Nelson, L. T., et al. (2015) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000067 · Cited by 26
The Role of Caveolin 1 in HIV Infection and Pathogenesis
Mergia, A. (2017) · Viruses · doi:10.3390/v9060129 · Cited by 29
“In nonhuman primate models, PAH is observed with the infection of chimeric SIV containing the HIV Nef (SHIV), while the control SIV shows no PAH, suggesting a role for Nef in PAH pathology [263].”
BackgroundInfluentialA viral kinase counteracts in vivo restriction of murine cytomegalovirus by SAMHD1
Deutschmann, J., Schneider, A. M., Gruska, I., Vetter, B., Thomas, D., Kießling, M., Wittmann, S., Herrmann, A., Schindler, M., Milbradt, J., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0529-z · Cited by 24
TRAF6 and TAK1 Contribute to SAMHD1-Mediated Negative Regulation of NF-κB Signaling
Espada, C. E., Gelais, C. S., Bonifati, S., Maksimova, V. V., Cahill, M. P., Kim, S. H., & Wu, L. J. (2020) · Journal of Virology · doi:10.1128/jvi.01970-20 · Cited by 25
“1 (HIV-1) infection in non-dividing cells of myeloid lineage (1, 2) and resting CD4+ T cells (3, 4).”
BackgroundHost Restriction Factors Modulating HIV Latency and Replication in Macrophages
Pagani, I., Demela, P., Ghezzi, S., Vicenzi, E., Pizzato, M., & Poli, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063021 · Cited by 30
“In the case of HIV-2-restricted Vpx, midostaurin was identified as possessing both pro- and anti-viral effects in macrophages by, on the one hand, blocking the cell cycle in the G2/M phase, thereby preventing SAMHD1 phosphorylation and activation; on the other hand, in the absence of SAMHD1, midostaurin showed enhanci…”
BackgroundInfluentialKapoor-Vazirani, P., Rath, S. K., Liu, X., Shu, Z., Bowen, N. E., Chen, Y., Haji‐Seyed‐Javadi, R., Daddacha, W. B., Minten, E. V., Danelia, D., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34578-x · Cited by 29
“SAMHD1 (1-115) SAMHD1 (115-626) SAMHD1 (115-465) K354”
The role of O-GlcNAcylation in innate immunity and inflammation
Wang, Y., Fang, X., Wang, S., Wang, B., Chu, F., Tian, Z., Zhang, L., & Zhou, F. (2022) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjac065 · Cited by 26
“…HIV-1 ) , herpes simplex virus 1 ( HSV-1 ) , hepatitis B virus ( HBV ) , and vaccinia virus by regulating the levels of deoxynucleoside triphosphates ( dNTPs ) in non-cycling cells ( Hrecka et al., 2011 ; Laguette et al., 2011 ; Hollenbaugh et al., 2013 ; Kim et al., 2013 ; Sommer et al., 2016 ) .”
Role of Glycosphingolipids in Dendritic Cell-Mediated HIV-1 Trans-infection
Puryear, W. B., & Gummuluru, S. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-4433-6_5 · Cited by 26
“Recent studies have defined the molecular details of one such restriction mechanism that blocks HIV-1 infection of DCs at an early step in the viral life cycle (Hrecka et al. 2011; Laguette et al. 2011).”
BackgroundBehrendt, R., & Roers, A. (2013) · Clinical & Experimental Immunology · doi:10.1111/cei.12147 · Cited by 26
G3BP1 restricts HIV-1 replication in macrophages and T-cells by sequestering viral RNA
Jiménez, V. C., Martínez, F. O., Booiman, T., van Dort, K. A., van de Klundert, M. A. A., Gordon, S., Geijtenbeek, T. B. H., & Kootstra, N. A. (2015) · Virology · doi:10.1016/j.virol.2015.09.007 · Cited by 29
“, 2013) and SAMHD1 (Hrecka et al., 2011; Laguette et al., 2011; Lahouassaet al., 2012), or MCPIP1 in activated CD4þ T cells (Liu”
BackgroundMacaques as model hosts for studies of HIV-1 infection
Misra, A., Thippeshappa, R., & Kimata, J. T. (2013) · Frontiers in Microbiology · doi:10.3389/fmicb.2013.00176 · Cited by 27
Gavegnano, C., Kennedy, E. M., Kim, B., & Schinazi, R. F. (2012) · Molecular Biology International · doi:10.1155/2012/625983 · Cited by 26
“Recent reports have identified the sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1) protein, which is encoded by the SAMHD1 gene, as a cellular factor that regulates cell-specific restriction of HIV-1 replication in cells of the myeloid lineage [20, 30, 31].”
BackgroundSoliman, M., Srikrishna, G., & Balagopal, A. (2017) · Current HIV/AIDS Reports · doi:10.1007/s11904-017-0357-9 · Cited by 28
Roesch, F., OhAinle, M., & Emerman, M. (2018) · Retrovirology · doi:10.1186/s12977-018-0409-2 · Cited by 24
“One of the functions of Vpx is to promote degradation of the host antiviral protein SAMHD1 [10, 11].”
Zhang, Y., Ozono, S., Yao, W., Tobiume, M., Yamaoka, S., Kishigami, S., Fujita, H., & Tokunaga, K. (2019) · Scientific Reports · doi:10.1038/s41598-019-40003-z · Cited by 26
Liang, G., Zhao, L., Qiao, Y., Geng, W., Zhang, X., Liu, M., Dong, J., Ding, H., Sun, H., & Shang, H. (2019) · Nature Immunology · doi:10.1038/s41590-019-0385-2 · Cited by 24
“Studies have revealed that the restriction factor SAMHD1 is a central determinant of cellular restriction of HIV-1 reverse transcription in resting CD4 + T cells 15–17 .”
Antiviral factors and their counteraction by HIV-1: many uncovered and more to be discovered
Kmieć, D., & Kirchhoff, F. (2024) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjae005 · Cited by 31
“…the Benkirane and Skowronski laboratories showed that SAM domain and HD domain-containing protein 1 suppresses HIV-1 replication in some cell types by reducing the pool of available deoxynucle-oside triphosphates required for reverse transcription (Hrecka et al., 2011 ; Laguette et al., 2011 ).”
BackgroundLenzi, G. M., Domaoal, R. A., Kim, D., Schinazi, R. F., & Kim, B. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.691576 · Cited by 25
“Based on the findings that SAMHD1 mediates the dNTP depletion of macrophages, we reasoned that Vpx coding HIV2/SIV replicate under increased dNTP conditions even in nondividing cells by counteracting SAMHD1.”
BackgroundInfluentialKohnken, R. A., Kodigepalli, K. M., Mishra, A., Porcu, P., & Wu, L. J. (2016) · Leukemia Research · doi:10.1016/j.leukres.2016.11.010 · Cited by 26
Huy, N. Đ., Gazy, N., & Venketaraman, V. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176148 · Cited by 28
Evolutionary conflicts and adverse effects of antiviral factors
Sauter, D., & Kirchhoff, F. (2021) · eLife · doi:10.7554/elife.65243 · Cited by 26
The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA
Dar, A. A., Sawada, K., Dybas, J. M., Moser, E. K., Lewis, E. L., Park, E., Fazelinia, H., Spruce, L. A., Ding, H., Seeholzer, S. H., et al. (2021) · PLoS Biology · doi:10.1371/journal.pbio.3001041 · Cited by 28
“DCAF1 modulates cellular responses against HIV in macrophages [64] and controls cell survival [65–67].”
BackgroundNeuropilin-1, a myeloid cell-specific protein, is an inhibitor of HIV-1 infectivity
Wang, S., Zhao, L., Zhang, X., Zhang, J., Shang, H., & Liang, G. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2114884119 · Cited by 25
IP6‐stabilised HIV capsids evade cGAS/STING‐mediated host immune sensing
Papa, G., Albecka, A., Mallery, D. L., Vaysburd, M., Renner, N., & James, L. C. (2023) · EMBO Reports · doi:10.15252/embr.202256275 · Cited by 26
A Mechanistic Overview of Dendritic Cell-Mediated HIV-1 Trans Infection: The Story So Far
Kijewski, S. D. G., & Gummuluru, S. (2015) · Future Virology · doi:10.2217/fvl.15.2 · Cited by 29
Cyclin-dependent kinases as therapeutic targets for HIV-1 infection
Rice, A. P. (2016) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2016.1254619 · Cited by 25
“quently identified to be a phosphohydrolase named SAMHD1 that cleaves dNTPs into deoxynucleotides and inorganic triphosphates [39,40].”
BackgroundShingai, M., Welbourn, S., Brenchley, J. M., Acharya, P., Miyagi, E., Plishka, R. J., Buckler-White, A. J., Kwong, P. D., Nishimura, Y., Strebel, K., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004928 · Cited by 26
“To ascertain whether a Vpx point mutant, specifically defective in recruiting DCAF1 and subsequently degrading SAMHD1[7,16 – 18], might possess similar properties, the X-Q76A Vpx mutant, carrying a 2-nucleotide substitution, was constructed (Fig 1A).”
PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation
Miyakawa, K., Matsunaga, S., Yokoyama, M., Nomaguchi, M., Kimura, Y., Nishi, M., Kimura, H., Sato, H., Hirano, H., Tamura, T., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09867-7 · Cited by 27
Johnson, J. S., Veaux, N. D., Rives, A. W., Lahaye, X., Lucas, S. Y., Pérot, B. P., Luka, M., Garcia-Paredes, V., Amon, L. M., Watters, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.054 · Cited by 30
“The major restriction factor in myeloid DCs is SAMHD1, an enzyme that exhibits phosphohydrolase activity and depletes the cellular pool of deoxyribonucleotide triphosphates (dNTPs) required for HIV reverse transcription (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundWidera, M., Hillebrand, F., Erkelenz, S., Vasudevan, A. A. J., Münk, C., & Schaal, H. (2014) · Retrovirology · doi:10.1186/preaccept-1252941606128392 · Cited by 25
The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway
Tang, H., Pang, X., Li, S., & Tang, L. (2024) · Biomolecules · doi:10.3390/biom14070738 · Cited by 25
“Once recruited, the neddylation–UPS pathway can potentiate the degradation of SAMHD1 and relieve its inhibition of SAMHD1 on the reverse transcription of HIV-2 [2,57,58].”
BackgroundProgress in Pseudotyping Lentiviral Vectors Towards Cell-Specific Gene Delivery In Vivo
Arduini, A., Katiyar, H., & Liang, C. (2025) · Viruses · doi:10.3390/v17060802 · Cited by 30
Yu, H., Usmani, S. M., Borch, A., Krämer, J., Stürzel, C. M., Khalid, M., Li, X., Krnavek, D., van der Ende, M. E., Osterhaus, A. D. M. E., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-27 · Cited by 25
“In contrast, HIV-1 and its direct simian counterpart (SIVcpz infecting chimpanzees) do not encode Vpx [15] and the HIV-1 Vpr protein does apparently not counteract SAMHD1-mediated restriction [3,4].”
BackgroundResultInfluentialRyoo, J., Hwang, S.-Y., Choi, J., Oh, C., & Ahn, K. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.07.013 · Cited by 24
The Envelope Gene of Transmitted HIV-1 Resists a Late Interferon Gamma-Induced Block
Rihn, S. J., Foster, T. L., Busnadiego, I., Aziz, M. A., Hughes, J., Neil, S. J. D., & Wilson, S. J. (2017) · Journal of Virology · doi:10.1128/jvi.02254-16 · Cited by 26
“Over the last decade, much of the attention paid to the ability of type I IFNs to inhibit HIV-1 has focused on restriction factors, including TRIM5/TRIMCyp (20, 21), APOBEC3s (22), tetherin/BST2 (23), and SAMHD1 (24, 25).”
Elimination of rNMPs from mitochondrial DNA has no effect on its stability
Wanrooij, P. H., Tran, P., Thompson, L. J., Carvalho, G., Sharma, S., Kreisel, K., Navarrete, C., Feldberg, A., Watt, D. L., Nilsson, A. K., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1916851117 · Cited by 22
“By keeping dNTP levels low when they are not required for nDNA replication, SAMHD1 protects cells from viral infections (37, 38).”
BackgroundEpigenetic Landscape of HIV-1 Infection in Primary Human Macrophage
Lu, F. Y., Yi, Y., Vladimirova, O. V., Zankharia, U. S., Collman, R. G., & Lieberman, P. M. (2022) · Journal of Virology · doi:10.1128/jvi.00162-22 · Cited by 23
“To assess the relative abundance of integrated versus unintegrated HIV-1 genomes, MDMs were infected with YU2/VSVg using 50 ng p24 Gag antigen per 2 106 cells, EFV was added 4 days later, and total DNA was harvested 3 days later.”
MethodInfluentialAicardi–Goutières syndrome: clues from the RNase H2 knock-out mouse
Rabe, B. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1061-x · Cited by 24
Wang, Z., Bhattacharya, A., Villacorta, J., Diaz‐Griffero, F., & Ivanov, D. N. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.c116.751446 · Cited by 25
de Pablo-Maiso, L., Doménech, A., Echeverría, I., Gómez-Arrebola, C., de Andrés, D., Rosati, S., Gómez‐Lucía, E., & Reina, R. (2018) · Viruses · doi:10.3390/v10080435 · Cited by 25
“Recently, the human protein SAMHD1 has been identified to be causative for the post-entry restriction of HIV-1 in myeloid cells [183,184].”
BackgroundViral and cellular mechanisms of the innate immune sensing of HIV
Lahaye, X., & Manel, N. (2015) · Current Opinion in Virology · doi:10.1016/j.coviro.2015.01.013 · Cited by 26
Wang, F., Gelais, C. S., de Silva, S., Zhang, H., Geng, Y., Shepard, C., Kim, B., Yount, J. S., & Wu, L. J. (2015) · Virology · doi:10.1016/j.virol.2015.10.024 · Cited by 24
“, 2011) and functions as an HIV-1 restriction factor in non-dividing myeloid cells and resting CD4+ T cells (Baldauf et al., 2012; Hrecka et al., 2011; Laguette et al., 2011a).”
Recent Advances in Lentiviral Vaccines for HIV-1 Infection
Norton, T. D., & Miller, E. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00243 · Cited by 23
“HIV-2 and some SIV isolates encode the accessory protein Vpx that counteracts this block to infection by binding to SAMHD1 and recruiting an E3 ubiquitin ligase complex, CRL4, to mediate its proteasomal degradation (48, 49).”
SAMHD1 is active in cycling cells permissive to HIV-1 infection
Badía, R., Pujantell, M., Torres‐Torronteras, J., Menéndez‐Arias, L., Martí, R., Ruzo, A., Pauls, E., Clotet, B., Ballana, E., Esté, J. A., et al. (2017) · Antiviral Research · doi:10.1016/j.antiviral.2017.03.019 · Cited by 23
Snapin promotes HIV‐1 transmission from dendritic cells by dampening TLR8 signaling
Khatamzas, E., Hipp, M., Gaughan, D., Pichulik, T., Leslie, A. J., Fernandes, R. A., Muraro, D., Booth, S., Zausmer, K., Sun, M., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201695364 · Cited by 26
“Within the cytosol, HIV-1 encounters the deoxyribose nucleoside triphosphate hydrolase SAMHD1, which limits the efficiency of HIV reverse transcription and inhibits replication (Goldstone et al , 2011; Hrecka et al , 2011; Laguette et al , 2011).”
Generation of Powerful Human Tolerogenic Dendritic Cells by Lentiviral-Mediated IL-10 Gene Transfer
Comi, M., Amodio, G., Passeri, L., Fortunato, M., de Sio, F. R. S., Andolfi, G., Kajaste‐Rudnitski, A., Russo, F., Cesana, L., & Gregori, S. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01260 · Cited by 26
“One of the restriction factors mediating this resistance is SAMHD1 (19, 20), which depletes the cytoplasmic pool of deoxynucleoside triphosphates, affecting the reverse transcription process (21).”
BackgroundInfluentialRegulation of Viral Restriction by Post-Translational Modifications
Chamontin, C., Bossis, G., Nisole, S., Arhel, N. J., & Maarifi, G. (2021) · Viruses · doi:10.3390/v13112197 · Cited by 25
“Indeed, primate lentiviral lineages encode either the viral protein x (Vpx) or the viral protein R (Vpr), which in some strains, share the same ability to use the ubiquitin–proteasome system to induce SAMHD1 degradation (Figure 1) [10,36,163].”
BackgroundSiddiqui, M. A., & Yamashita, M. (2021) · mBio · doi:10.1128/mbio.02817-21 · Cited by 23
“Trex1, a cellular exonuclease, degrades aborted viral DNA (15, 31, 59), while SamHD1 may limit the amount of viral DNA to a minimum (94, 95).”
BackgroundMechanisms of HIV-1 cell-to-cell transfer to myeloid cells
Han, M., Woottum, M., Mascarau, R., Vahlas, Z., Vérollet, C., & Bénichou, S. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.4mr0322-737r · Cited by 24
Novel factors interfering with human immunodeficiency virus‐type 1 replication in vivo and in vitro
Vicenzi, E., & Poli, G. (2013) · Tissue Antigens · doi:10.1111/tan.12047 · Cited by 29
Myburgh, R., Cherpin, O., Schlaepfer, E., Rehrauer, H., Speck, R. F., Krause, K., & Salmon, P. (2014) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2014.58 · Cited by 26
Münk, C., Jensen, B. O., Zielonka, J., Häussinger, D., & Kamp, C. (2012) · Viruses · doi:10.3390/v4113132 · Cited by 25
“While in HIV-1 no protein evolved to inhibit SAMHD1, the related HIV-2 uses its Vpx protein to destroy this dNTPase [15–17].”
BackgroundCanine Hepacivirus NS3 Serine Protease Can Cleave the Human Adaptor Proteins MAVS and TRIF
Parera, M., Martrus, G., Franco, S., Clotet, B., & Martı́nez, M. Á. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042481 · Cited by 23
“Well-character- ized restriction factors are APOBEC3G [7], TRIM5-a proteins [8], tetherin (BST2) [9], and SAMHD1 [10,11], which inhibit human immunodeficiency virus (HIV) propagation at various steps in its replication cycle.”
BackgroundCavaleiro, R., Rego, R. T., Foxall, R. B., Soares, R. S., Baptista, A. P., Gómes, P., Valadas, E., Victorino, R. M. M., & Sousa, A. E. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit085 · Cited by 25
Metabolic pathways as regulators of HIV infection
Craveiro, M., Clerc, I., Sitbon, M., & Taylor, N. N. (2013) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0b013e32835fc53e · Cited by 25
Gelais, C. S., Kim, S., Maksimova, V. V., Buzovetsky, O., Knecht, K. M., Shepard, C., Kim, B., Xiong, Y., & Wu, L. J. (2018) · Journal of Virology · doi:10.1128/jvi.01787-17 · Cited by 25
“SIV, encode the Vpx protein, which targets SAMHD1 for proteasomal degradation (4, 5).”
BackgroundQin, Z., Bonifati, S., Gelais, C. S., Li, T.-W., Kim, S., Antonucci, J. M., Mahboubi, B., Yount, J. S., Xiong, Y., Kim, B., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010360 · Cited by 23
“The Vpx protein from HIV-2 and Vpx/Vpr of certain lineages of simian immunodeficiency viruses target SAMHD1 for degradation through the ubiquitin proteasome pathway (9, 10, 18).”
BackgroundToward a Macaque Model of HIV-1 Infection: Roadblocks, Progress, and Future Strategies
Thippeshappa, R., Kimata, J. T., & Kaushal, D. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00882 · Cited by 24
The SAM domain of mouse SAMHD1 is critical for its activation and regulation
Buzovetsky, O., Tang, C., Knecht, K. M., Antonucci, J. M., Wu, L. J., Ji, X., & Xiong, Y. (2018) · Nature Communications · doi:10.1038/s41467-017-02783-8 · Cited by 23
“The sterile alpha-motif (SAM) and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a dNTP phosphohydrolase that restricts viral replication by limiting the cellular dNTP pool 1-7 .”
Subversion of Cell Cycle Regulatory Mechanisms by HIV
Rice, A. P., & Kimata, J. T. (2015) · Cell Host & Microbe · doi:10.1016/j.chom.2015.05.010 · Cited by 21
“Using mass spectrometry technology to identify cellular proteins that co-immunoprecipitated with wild-type but not with a mutant Vpx unable to associate with DCAF1, SAMHD1 was identified as this key restriction factor in non-dividing cells (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundThe missing link: allostery and catalysis in the anti-viral protein SAMHD1
Morris, E. R., & Taylor, I. A. (2019) · Biochemical Society Transactions · doi:10.1042/bst20180348 · Cited by 21
Davenne, T., Klintman, J., Sharma, S., Rigby, R. E., Blest, H. T. W., Cursi, C., Bridgeman, A., Dadonaite, B., Keersmaecker, K. D., Hillmen, P., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107640 · Cited by 23
An overview of intracellular interactions between immunodeficiency viruses and their hosts
Bieniasz, P. D. (2012) · AIDS · doi:10.1097/qad.0b013e328353bd04 · Cited by 22
“Gag Matrix NMT(N-myristoyl transferase) Lipid modification of Gag-N-terminus PI [4,5]P2 (phosphatidylinositol 4,5-bisphosphate) Plasma membrane resident phospholipid that drives Gag targeting to the plasma membrane Capsid TRIM5a (tripartite motif-5a) Antiviral protein that targets incoming capsids TRIMCyp (TRIM5-CypA…”
BackgroundTailored HIV-1 Vectors for Genetic Modification of Primary Human Dendritic Cells and Monocytes
Durand, S., Nguyen, X.-N., Turpin, J., Cordeil, S., Nazaret, N., Croze, S., Mahieux, R., Lachuer, J., Legras‐Lachuer, C., & Cimarelli, A. (2012) · Journal of Virology · doi:10.1128/jvi.01459-12 · Cited by 24
“A number of recent reports indicate that the cellular protein SAMHD1 specifies a major restriction during MDDC transduction by reducing the pool of intracellular nucleosides available for reverse transcription and indicate that Vpx relieves this restriction by degrading it (20, 21, 29, 37).”
BackgroundЧерешнев, В. А., Bocharov, G. A., Bazhan, S. I., Bachmetyev, B. A., Gainova, I., Likhoshvai, V. A., Argilaguet, J. M., Martínez, J. P., Rump, J. A., Mothe, B., et al. (2013) · International Reviews of Immunology · doi:10.3109/08830185.2013.779375 · Cited by 25
“[58] Hrecka K, Hao C, Gierszewska M, et al.”
BackgroundKobayashi, Y., Gélinas, C., & Dougherty, J. P. (2017) · Journal of General Virology · doi:10.1099/jgv.0.000716 · Cited by 22
“Advantage was taken of the finding that simian immunodeficiency virus (SIV)/HIV-2 encoded Vpx has the ability to overcome the restriction to infection posed by SAMHD1, which hydrolyses dNTPs needed for HIV-1 reverse transcription [18].”
BackgroundControl of HIV infection by IFN-α: implications for latency and a cure
Bourke, N. M., Napoletano, S., Bannan, C., Ahmed, S., Bergin, C. J., McKnight, Á., & Stevenson, N. J. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2652-4 · Cited by 22
“Another HIV protein, Vpx, present only in the HIV-2/ SIVsm/SIVmac group, has been shown to antagonise the restriction factor SAMHD1 [80].”
BackgroundInfluentialSERINC as a Restriction Factor to Inhibit Viral Infectivity and the Interaction with HIV
González-Enríquez, G. V., Escoto-Delgadillo, M., Vázquez-Valls, E., & Torres-Mendoza, B. M. (2017) · Journal of Immunology Research · doi:10.1155/2017/1548905 · Cited by 25
Current advances in HIV vaccine preclinical studies using Macaque models
Liang, B., Li, H., Li, L., Omange, R. W., Hai, Y., & Luo, M. (2019) · Vaccine · doi:10.1016/j.vaccine.2019.04.094 · Cited by 20
Simian immunodeficiency virus-Vpx for improving integrase defective lentiviral vector-based vaccines
Negri, D. R. M., Rossi, A., Blasi, M., Michelini, Z., Leone, P., Chiantore, M. V., Baroncelli, S., Perretta, G., Cimarelli, A., Klotman, M. E., et al. (2012) · Retrovirology · doi:10.1186/1742-4690-9-69 · Cited by 23
“In particular, Vpx prevented the SAMHD1-mediated decrease in dNTP concentration by inducing degradation of human and rhesus macaque SAMHD1, but had no effect on mouse SAMHD1.”
BackgroundResultInfluentialWang, Z., Bhattacharya, A., White, T. E., Buffone, C., McCabe, A., Nguyen, L. A., Shepard, C., Pardo, S., Kim, B., Weintraub, S. T., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.090 · Cited by 23
“…2009) and that SAMHD1 restricts HIV-1 replication in non-cycling immune cells (Baldauf et al., 2012; Berger et al., 2011; Descours et al., 2012; Hrecka et al., 2011; Laguette et al., 2011) established the role of SAMHD1 as an innate immunity factor involved in interferon signaling and…”
Development of Lentiviral Vectors for HIV-1 Gene Therapy with Vif-Resistant APOBEC3G
Delviks-Frankenberry, K. A., Ackerman, D., Timberlake, N. D., Hamscher, M., Nikolaitchik, O. A., Hu, W.-S., Torbett, B. E., & Pathak, V. K. (2019) · Molecular Therapy Nucleic Acids · doi:10.1016/j.omtn.2019.10.024 · Cited by 21
Kobayashi, T., Takeuchi, J. S., Ren, F., Matsuda, K., Sato, K., Kimura, Y., Misawa, N., Yoshikawa, R., Nakano, Y., Yamada, E., et al. (2014) · Scientific Reports · doi:10.1038/srep05529 · Cited by 23
SAMHD1 Restricts HIV-1 Replication and Regulates Interferon Production in Mouse Myeloid Cells
Zhang, R., Bloch, N., Nguyen, L. A., Kim, B., & Landau, N. R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089558 · Cited by 22
“Because HIV-1 lacks the Vpx packaging motif it does not package Vpx [21,22].”
BackgroundInfluentialInnate immunity in the control of HIV/AIDS
Ploquin, M. J.-Y., Jacquelin, B., Jochems, S. P., Barré‐Sinoussi, F., & Müller-Trutwin, M. C. (2012) · AIDS · doi:10.1097/qad.0b013e328353e46b · Cited by 23
“specifically confined to differentiated uncycling cells like macrophages and mDC [37, 38].”
Harper, M. S., Barrett, B. S., Smith, D. S., Li, S. X., Sutter, K., Dittmer, U., Hasenkrug, K. J., & Santiago, M. L. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1202920 · Cited by 22
“HIV-1 in plasma (65), whereas restriction blocks because of another factor, SAMHD1, limit HIV-1 replication in myeloid cells (66, 67).”
BackgroundSzaniawski, M. A., Spivak, A. M., Bosque, A., & Planelles, V. (2018) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiy583 · Cited by 22
The ability of SAMHD1 to block HIV-1 but not SIV requires expression of MxB
Buffone, C., Kutzner, J., Opp, S., Martínez‐López, A., Selyutina, A., Coggins, S. A., Studdard, L. R., Ding, L., Kim, B., Spearman, P. W., et al. (2019) · Virology · doi:10.1016/j.virol.2019.03.018 · Cited by 21
“An important function of Vpx is its ability to recruit SAMHD1 for proteasomal degradation (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundMethodPharmacological Modulation of SAMHD1 Activity by CDK4/6 Inhibitors Improves Anticancer Therapy
Castellví, M., Felip, E., Ezeonwumelu, I. J., Badía, R., García-Vidal, E., Pujantell, M., Gutiérrez-Chamorro, L., Teruel, I., Martínez‐Cardús, A., Clotet, B., et al. (2020) · Cancers · doi:10.3390/cancers12030713 · Cited by 21
“SAMHD1 activity is counteracted by the HIV-2 accessory protein Vpx, a tool that has been extensively used to study SAMHD1 function [10,12].”
Daxx Inhibits HIV-1 Reverse Transcription and Uncoating in a SUMO-Dependent Manner
Maillet, S., Fernandez, J., Decourcelle, M., Koulali, K. E., Blanchet, F. P., Arhel, N. J., Maarifi, G., & Nisole, S. (2020) · Viruses · doi:10.3390/v12060636 · Cited by 23
“However, reverse transcription appears to be a hotspot for restriction, since it is targeted by several potent antiviral factors, including TRIM5α [8], APOBEC3G [4,9], and SAMHD1 [10,11].”
BackgroundLenzi, G. M., Domaoal, R. A., Kim, D., Schinazi, R. F., & Kim, B. (2014) · Retrovirology · doi:10.1186/s12977-014-0111-y · Cited by 22
“Recent studies revealed that Vpx targets SAMHD1 for proteasomal degradation through the E3 ubiquitination pathway [15,16], and the cellular depletion of SAMHD1 leads to elevated dNTP concentrations and accelerated reverse transcription in macrophages, resting CD4 T cells, and DCs [17].”
BackgroundErratum: Efficient delivery of lentiviral vectors into resting human CD4 T cells
Geng, X., Doitsh, G., Yang, Z., Galloway, N. L. K., & Greene, W. C. (2016) · Gene Therapy · doi:10.1038/gt.2015.115 · Cited by 22
HIV-1 Myeloid Reservoirs — Contributors to Viral Persistence and Pathogenesis
Ferreira, E. A., Clements, J. E., & Veenhuis, R. T. (2024) · Current HIV/AIDS Reports · doi:10.1007/s11904-024-00692-2 · Cited by 21
“Vpx, encoded by HIV-2 and most SIV strains, is known to degrade SAMHD1 resulting in increased viral infection [127].”
Chronic HIV Transcription, Translation, and Persistent Inflammation
Kilroy, J. M., Leal, A. A., & Henderson, A. J. (2024) · Viruses · doi:10.3390/v16050751 · Cited by 22
“The ability of Vpr to alter cell function is, in part, due to its binding and co-opting of the host E3 ubiquitin ligase complex Cullin Ring Ligase 4/DDB1, Cul4 Associated Factor 1 complex, and the CRL4 DCAF E3 ubiquitin ligase complex [35,73].”
BackgroundBreaking Barriers to an AIDS Model with Macaque-Tropic HIV-1 Derivatives
Thippeshappa, R., Ruan, H., & Kimata, J. T. (2012) · Biology · doi:10.3390/biology1020134 · Cited by 20
“They showed that Vpx interacts with SAMHD1, resulting in its degradation via the proteasome [151,152].”
BackgroundTLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes
Hofmann, H., Vanwalscappel, B., Bloch, N., & Landau, N. R. (2016) · Retrovirology · doi:10.1186/s12977-016-0316-3 · Cited by 21
Mamede, J. I., Damond, F., de Bernardo, A., Matheron, S., Descamps, D., Battini, J., Sitbon, M., & Courgnaud, V. (2017) · Scientific Reports · doi:10.1038/srep45214 · Cited by 22
Rojas, M., Luz‐Crawford, P., Soto‐Rifo, R., Reyes-Cerpa, S., & Toro‐Ascuy, D. (2021) · Cells · doi:10.3390/cells10092378 · Cited by 22
“In macrophages and dendritic cells, USP18 can promote HIV-1 replication by enhancing reverse transcription through the downregulation of the expression of p21 (a cyclin-dependent kinase inhibitor), which correlates with the antiviral-inactive form of SAMHD1 [84].”
BackgroundInfluentialSertznig, H., Roesmann, F., Wilhelm, A., Heininger, D., Bleekmann, B., Elsner, C., Santiago, M. L., Schuhenn, J., Karakoese, Z., Benatzy, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.935800 · Cited by 22
Tada, T., Peng, J.-Y., Dcosta, B. M., & Landau, N. R. (2023) · JCI Insight · doi:10.1172/jci.insight.167306 · Cited by 20
Yang, S., Shan, T., Zhou, Y., Jiang, Y., Tong, W., Liu, F., Wen, F., Zhang, Q., & Tong, G. (2014) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2014.07.024 · Cited by 21
Large-Scale Arrayed Analysis of Protein Degradation Reveals Cellular Targets for HIV-1 Vpu
Jain, P., Boso, G., Langer, S., Soonthornvacharin, S., Jesus, P. D. D., Nguyen, Q., Olivieri, K. C., Portillo, A. J., Yoh, S. M., Pache, L., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.091 · Cited by 22
“The HIV-2 and simian immunodeficiency virus (SIV)-encoded Vpx protein causes degradation of SAMHD1 to facilitate reverse transcription in myeloid and resting T cells (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundIntertwined: SAMHD1 cellular functions, restriction, and viral evasion strategies
Majer, C., Schüssler, M., & König, R. (2019) · Medical Microbiology and Immunology · doi:10.1007/s00430-019-00593-x · Cited by 18
Morphine Withdrawal Enhances HIV Infection of Macrophages
Wang, X., Liu, J., Zhou, L., & Ho, W. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02601 · Cited by 20
“It is known that SAMHD1 can reduce the dNTPs pool in macrophages by hydrolyzing dNTPs into their precursors (nucleosides and triphosphates), resulting in inefficient HIV reverse transcription (38, 39).”
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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