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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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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance
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“Germ-line mutations in SAMHD1 have been associated with Aicardi–Goutieres syndrome, a congenital autoimmune disease (23), and more recently SAMHD1 was shown to be an HIV-1 restriction factor operating in nondividing blood cells (24, 25).”
BackgroundDistinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B
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“The CRL4DCAF-Vpx complex targets SAMHD1, which is an antiviral deoxynucleoside triphosphohydrolase that blocks reverse transcription and is expressed in myeloid cells (Ahn et al., 2012; Hofmann et al., 2012; Hrecka et al., 2011).”
BackgroundLv, L., Wang, Q., Xu, Y., Tsao, L.-C., Nakagawa, T., Guo, H., Su, L., & Xiong, Y. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.05.007 · Cited by 100
“Vpx, a homolog of Vpr that is encoded by HIV-2 and most simian lentiviruses, also binds to VprBP and targets a host restriction factor, SAMHD1, for ubiquitylation by CRL4 and subsequent degradation by the proteasome (Hrecka et al., 2011; Laguette et al., 2011).”
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“For instance, the recent discovery of the restriction factor SAMHD1 has led to the insight that it hydrolyses deoxynucleotide triphosphates (dNTPs) to levels that are insufficient to support reverse transcription in monocytes, macrophages, dendritic and quiescent CD4+ T cells [17-21].”
BackgroundRestriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1
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“…factors directly interact with viral components (such as genome, capsid, and lipid envelope), the Sterile Alpha Motif- and HD-domain containing protein 1 (SAMHD1) (626 amino acids, 72.2 kDa, Figure 2H) exerts an indirect antiretroviral effect (Hrecka et al., 2011; Laguette et al., 2011).”
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“mRNA editing enzyme, catalytic polypeptide-like (APOBEC) 3G [1], tripartite motif (TRIM) 5α [2] and TrimCyp [3], SAM domain and HD domain-containing protein (SAMHD) 1 [4,5], and bone marrow stromal cell antigen (BST) 2/Tetherin [6,7].”
BackgroundClerc, I., Moussa, D. A., Vahlas, Z., Tardito, S., Oburoglu, L., Hope, T. J., Sitbon, M., Dardalhon, V., Mongellaz, C., & Taylor, N. N. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0084-1 · Cited by 108
Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction
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Are T cells the only HIV-1 reservoir?
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“Instead, they encode for vpx, which may be a critical difference: vpx degrades SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1), a key retroviral restriction factor in macrophages and DCs [125, 126].”
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Loss of transcriptional control over endogenous retroelements during reprogramming to pluripotencyPreprint
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“, APOBEC3A and SAMHD1) (Bogerd et al. 2006; Hrecka et al. 2011; Laguette et al. 2011) were transiently induced during reprogramming (Supplemental Fig.”
BackgroundCullin E3 Ligases and Their Rewiring by Viral Factors
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“This small viral protein was also known to hijack CRL4 [122,123] and was recently shown to drive the degradation of the host SAM domain and HD domain-containing protein 1 (SAMHD1), a nucleotide triphospho-hydrolase that restricts lentiviral reverse transcriptional activity in myeloid cells [63] (Figure 3e).”
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“Similarly, TRIM5α [11], tetherin [12] and SAMHD1 [13,14] are restriction factors that can inhibit the replication of exogenous retroviruses at different steps in the retroviral life cycle [15].”
HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages
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“Of note, we also validated our SILAC procedure with the observation that SAMHD1 levels were strongly decreased on delivery of HIV-2/SIVsmm Vpx protein as expected (57, 58).”
BackgroundMethodThe DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction
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A G1‐like state allows HIV‐1 to bypass SAMHD1 restriction in macrophages
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“Some lentiviruses have evolved counter-measures against SAMHD1; for example, the HIV-2/SIVsm lineage encodes the Vpx protein that degrades SAMHD1 and allows infection of otherwise SAMHD1-positive target cells (Kaushik et al , 2009; Hrecka et al , 2011; Laguette et al , 2011).”
SAMHD1 Functions and Human Diseases
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“HIV-2 and some SIVs circumvent host SAMHD1 restriction and rapidly replicate even in macrophages by inducing the proteasomal degradation of SAMHD1 through a viral accessory protein called viral protein X (Vpx) [81,82,100,101].”
BackgroundAllouch, A., David, A., Amie, S. M., Lahouassa, H., Chartier, L., Margottin-Goguet, F., Barré‐Sinoussi, F., Kim, B., Sáez‐Cirión, A., & Pancino, G. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1306719110 · Cited by 106
“SIV and HIV-2 counteract SAMHD1 by the expression of Vpx, which targets SAMHD1 for proteosomal degradation, thus allowing these viruses to escape SAMHD1-mediated restriction in macrophages and dendritic cells (13, 14).”
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Distribution of Immune Cells in the Human Cervix and Implications for HIV Transmission
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“This is largely due to restriction by the cellular factor SAMHD1 in these cells [4,5].”
BackgroundType I Interferon Responses by HIV-1 Infection: Association with Disease Progression and Control
Soper, A., Kimura, I., Nagaoka, S., Konno, Y., Yamamoto, K., Koyanagi, Y., & Sato, K. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01823 · Cited by 102
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“The Vpx proteins were able to specifically trigger SAMHD1 degradation by the proteasomal pathway in these cells [315-317], and a similar observation was also made in resting CD4 T cells [301,302].”
MethodResultExpression profile of host restriction factors in HIV-1 elite controllers
Abdel-Mohsen, M., Raposo, R. A. S., Deng, X., Li, M., Liegler, T., Sinclair, E., Salama, M. S., Ghanem, H. E.-D. A., Hoh, R., Wong, J. K., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-106 · Cited by 96
“SAMHD1 SAM domain and HD domain 1 Inhibits HIV replication in myeloid cells, probably by regulating cellular dNTP supply [47]”
The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection
Taylor, H. E., Khatua, A. K., & Popik, W. (2013) · Journal of Virology · doi:10.1128/jvi.02828-13 · Cited by 101
“Although expression of restriction factor Samhd1 in macrophages (60, 61) was not significantly afTaylor et al.”
BackgroundIdentification of Cellular Proteins Interacting with the Retroviral Restriction Factor SAMHD1
Gelais, C. S., de Silva, S., Hach, J. C., White, T. E., Diaz‐Griffero, F., Yount, J. S., & Wu, L. J. (2014) · Journal of Virology · doi:10.1128/jvi.00155-14 · Cited by 99
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Cullin-RING E3 Ubiquitin Ligases: Bridges to Destruction
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“Vpx has recently been shown to degrade the restriction factor SAMHD1 (11, 14).”
BackgroundSAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction
Ballana, E., & Esté, J. A. (2015) · Trends in Microbiology · doi:10.1016/j.tim.2015.08.002 · Cited by 94
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“Hence, although myeloid cells are largely refractory to productive HIV-1 infection due to the presence of cellular restriction factors such as the recently identified SAMHD1 [19,20], the sialyllactose driven trans-infection process characterized here in mDCs seems to exploit a pre-existing cellulartrafficking machiner…”
BackgroundInfluentialSAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells
Bonifati, S., Daly, M. B., Gelais, C. S., Kim, S., Hollenbaugh, J. A., Shepard, C., Kennedy, E. M., Kim, D.-H., Schinazi, R. F., Kim, B., et al. (2016) · Virology · doi:10.1016/j.virol.2016.05.002 · Cited by 91
“SAMHD1 is a known restriction factor of HIV-1 infection in non-dividing cells such as primary monocytes, dendritic cells, macrophages and resting CD4 + T-cells, where SAMHD1 is highly expressed (Baldauf et al., 2012; Berger et al., 2012; Hrecka et al., 2011; Laguette et al., 2011).”
Greenwood, E. J. D., Matheson, N. J., Wals, K., van den Boomen, D. J. H., Antrobus, R., Williamson, J. C., & Lehner, P. J. (2016) · eLife · doi:10.7554/elife.18296 · Cited by 96
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“Two lentiviral lineages lack Vpx but use Vpr to degrade SAMHD1, whereas the HIV-1/SIVcpz lineage lacks SAMHD1 antagonism (Lim et al., 2012).”
BackgroundInfluentialHIV-1 Nef: a multifaceted modulator of T cell receptor signaling
Abraham, L., & Fackler, O. (2012) · Cell Communication and Signaling · doi:10.1186/1478-811x-10-39 · Cited by 99
“This Samhd1 dependent restriction might reflect the ability of this enzyme to reduce the pool of available dNTPs required for RT in resting but not activated T-lymphocytes, the latter of which display significantly higher dNTP levels.”
The regulatory landscape of macrophage interferon signaling in inflammation
Siebeler, R., de Winther, M. P. J., & Hoeksema, M. A. (2023) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2023.04.022 · Cited by 95
Brain Microglial Cells Are Highly Susceptible to HIV-1 Infection and Spread
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The biased nucleotide composition of the HIV genome: a constant factor in a highly variable virus
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“SAMHD1 (sterile alpha factor and HD-domain 1) is another HIV-1 restriction factor that was recently identified [109,110].”
Breugel, P. C. V., Robert, E. I., Mueller, H., Decorsière, A., Zoulim, F., Hantz, O., & Strubin, M. (2012) · Hepatology · doi:10.1002/hep.25928 · Cited by 91
“Another and perhaps more attractive possibility, which also relies on a E3 ligase substrate receptor function, is that HBx acts indirectly to counteract a cellular restriction factor by triggering its ubiquitin-mediated degradation, as shown recently for the Vpx protein of human immunodeficiency virus (HIV).(40,41) Th…”
BackgroundThe highly polymorphic cyclophilin A-binding loop in HIV-1 capsid modulates viral resistance to MxB
Liu, Z., Pan, Q., Liang, Z., Qiao, W., Cen, S., & Liang, C. (2015) · Retrovirology · doi:10.1186/s12977-014-0129-1 · Cited by 93
“Examples of these restriction factors include APOBEC3G [1], Trim5α [2], tetherin [3,4], and SAMHD1 [5,6] (reviewed in [7]).”
HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137
Zhang, F., & Bieniasz, P. D. (2020) · eLife · doi:10.7554/elife.55806 · Cited by 75
“Recruitment of CRL4 by virion-associated Vpx and some SIV Vpr proteins can induce the degradation of the antiviral protein SAMHD1 shortly following viral entry (Hrecka et al., 2011; Laguette et al., 2011; Spragg and Emerman, 2013).”
BackgroundEradication of HIV-1 from the Macrophage Reservoir: An Uncertain Goal?
Abbas, W., Tariq, M., Iqbal, M., Kumar, A., & Herbein, G. (2015) · Viruses · doi:10.3390/v7041578 · Cited by 96
“SAMHD1 (sterile alpha motif domainand HD domain-containing protein 1) is a cellular restriction factor that restricts the replication of HIV-1 and Vpx deficient HIV-2 [135,136].”
BackgroundChemudupati, M., Kenney, A. D., Bonifati, S., Zani, A., McMichael, T. M., Wu, L. J., & Yount, J. S. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.09.012 · Cited by 92
“A study performed in rhesus macaques infected with two SIV strains showed that Vpx is required in vivo for the establishment of productive infection in memory CD4+ T lymphocytes, confirming the role of SAMHD1 in retroviral replication and virus-induced immunodeficiency in vivo [123].”
BackgroundInfluentialCUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases
Sharma, P. K., & Nag, A. (2014) · Open Biology · doi:10.1098/rsob.130217 · Cited by 88
“On the other hand, HIV-2 Vpx recruits CRL4 to target SAMHD1 (SAM domain and HD domain-containing protein 1) to facilitate HIV-2 invasion in macrophages and dendritic cells [124,129–131].”
BackgroundCyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain
Yan, J., Hao, C., DeLucia, M., Swanson, S. K., Florens, L. A., Washburn, M. P., Ahn, J., & Skowroński, J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.646588 · Cited by 92
“Another explanation is suggested by previous observations that SAMHD1 levels in leukocytes are naturally relatively high compared with those in fibroblasts (6, 7, 21).”
BackgroundMethodResultSelf-citationTherapies in Aicardi–Goutières syndrome
Crow, Y. J., Vanderver, A. L., Orcesi, S., Kuijpers, T. W., & Rice, G. (2013) · Clinical & Experimental Immunology · doi:10.1111/cei.12115 · Cited by 91
Intracellular nucleotide levels and the control of retroviral infections
Amie, S. M., Noble, E., & Kim, B. (2012) · Virology · doi:10.1016/j.virol.2012.11.010 · Cited by 92
“clear example of a metabolic bottleneck that HIV has to counteract during viral infection (19, 23, 35, 36, 50).”
BackgroundEmerging Role of the Host Restriction Factor Tetherin in Viral Immune Sensing
Hotter, D., Sauter, D., & Kirchhoff, F. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.09.029 · Cited by 86
Martín‐Gayo, E., Buzón, M. J., Ouyang, Z., Hickman, T. L., Cronin, J., Pimenova, D., Walker, B. D., Lichterfeld, M. D., & Yu, X. G. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004930 · Cited by 86
“products [19–22] or enhancing their degradation [18,29], respectively.”
BackgroundZhou, D., Kang, K. H., & Spector, S. A. (2012) · The Journal of Infectious Diseases · doi:10.1093/infdis/jis187 · Cited by 92
“Additionally, recently the cellular SAM domain HD domain-containing protein 1 has been identified as an important HIV-1 restriction factor present in dendritic and myeloid cells that makes them less permissive to HIV-1 infection [24, 25].”
BackgroundSAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity
Antonucci, J. M., Gelais, C. S., de Silva, S., Yount, J. S., Tang, C., Ji, X., Shepard, C., Xiong, Y., Kim, B., & Wu, L. J. (2016) · Nature Medicine · doi:10.1038/nm.4163 · Cited by 86
SAMHD1 protects cancer cells from various nucleoside-based antimetabolites
Herold, N., Rudd, S. G., Sanjiv, K., Kutzner, J., Bladh, J., Paulin, C. B. J., Helleday, T., Henter, J., & Schaller, T. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1314407 · Cited by 86
“Sterile a motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) was identified in 2011 to restrict human immunodeficiency virus type 1 (HIV-1) in myeloid cells, a breakthrough in unravelling the, up to then, enigmatic reasons underlying the low permissivity of macrophages or dendritic cells to HIV-1 i…”
BackgroundHIV-1 and HIV-2 exhibit divergent interactions with HLTF and UNG2 DNA repair proteins
Hrecka, K., Hao, C., Shun, M.-C., Kaur, S., Swanson, S. K., Florens, L., Washburn, M. P., & Skowronski, J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1605023113 · Cited by 80
“Significantly, HIV-2/HIVsm viruses antagonize SAMHD1 dNTPase via their Vpx proteins (6, 7) whereas HIV-1/SIVcpz do not possess this ability.”
BackgroundMethodInfluentialSelf-citationGTP Is the Primary Activator of the Anti-HIV Restriction Factor SAMHD1
Amie, S. M., Bambara, R. A., & Kim, B. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.493619 · Cited by 85
“To overcome this restriction, some lentiviruses such as HIV-2 and several simian immunodeficiency viruses express the accessory protein Vpx to target SAMHD1 for proteasomal degradation (6, 7).”
BackgroundSensor Sensibility—HIV-1 and the Innate Immune Response
Yin, X., Langer, S., Zhang, Z., Herbert, K. M., Yoh, S. M., König, R., & Chanda, S. K. (2020) · Cells · doi:10.3390/cells9010254 · Cited by 91
“Another study reported that SAMHD1 is able to directly interact with the inhibitor-κB kinase ε (IKKε) and IRF7 to suppress the innate immune response by reducing IKKε-mediated IRF7 phosphorylation [72,74].”
BackgroundInfluentialN4BP1 restricts HIV-1 and its inactivation by MALT1 promotes viral reactivation
Yamasoba, D., Sato, K., Ichinose, T., Imamura, T., Koepke, L., Joas, S., Reith, E., Hotter, D., Misawa, N., Akaki, K., et al. (2019) · Nature Microbiology · doi:10.1038/s41564-019-0460-3 · Cited by 79
Andorko, J. I., Russell, R. M., Schnepp, B. C., Grubaugh, D., Mullen, K. F., Wakabayashi, A., Carrington, L. J., O’Malley, T. M., Kuri-Cervantes, L., Culp, T. D., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.06.036 · Cited by 90
Inhibition of Hepatitis B virus replication by SAMHD1
Chen, Z., Zhu, M., Pan, X., Zhu, Y., Yan, H., Jiang, T., Shen, Y., Dong, X., Zheng, N., Lu, J., et al. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.07.023 · Cited by 85
Innate Immune Recognition of HIV-1
Iwasaki, A. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.011 · Cited by 89
“Lentiviruses of the HIV-2 and SIV (simian immunodeficiency virus) sooty mangabey lineage express Vpx, which promotes ubiquitination and degradation of SAMHD1 through recruitment of multisubunit cullin 4A-ring E3 ubiquitin ligase CRL4 (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundPizzi, S., Sertic, S., Orcesi, S., Cereda, C., Bianchi, M., Jackson, A. P., Lazzaro, F., Plevani, P., & Muzi-Falconi, M. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu485 · Cited by 85
Fan, W., Mar, K. B., Sari, L., Gaszek, I. K., Cheng, Q., Evers, B. M., Shelton, J. M., Wight‐Carter, M., Siegwart, D. J., Lin, M. M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.04.047 · Cited by 81
The macrophage: a therapeutic target in HIV-1 infection
Kumar, A., & Herbein, G. (2014) · Molecular and Cellular Therapies · doi:10.1186/2052-8426-2-10 · Cited by 81
“Thus SAMHD1 reduces the dNTPs pool in macrophages to a certain level resulting in the inefficient reverse transcription of HIV-1 genomic RNA into proviral DNA [32].”
BackgroundInfluentialMyeloid Cell Interaction with HIV: A Complex Relationship
Rodrigues, V., Ruffin, N., Jouve, M. J., & Benaroch, P. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01698 · Cited by 81
“This sensing step is macrophage specific as it does not occur in monocyte-derived dendritic cells (MDDCs) exposed to HIV-1 (Decalf et al., unpublished results).”
BackgroundInfluentialPromoter Methylation Regulates SAMHD1 Gene Expression in Human CD4+ T Cells
de Silva, S., Hoy, H., Hake, T. S., Wong, H. K., Porcu, P., & Wu, L. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.447201 · Cited by 81
“HEK 293T cells were chosen for cloning the SAMHD1 promoter because they express endogenous SAMHD1 protein (8, 22) and because they were not derived from a cancer cell line (28), whichwould avoid potential mutations of the SAMHD1 promoter.”
BackgroundOellerich, T., Schneider, C., Thomas, D., Knecht, K. M., Buzovetsky, O., Kaderali, L., Schliemann, C., Bohnenberger, H., Angenendt, L., Hartmann, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11413-4 · Cited by 80
Plasmacytoid Dendritic Cells in HIV Infection
O’Brien, M. P., Manches, O., & Bhardwaj, N. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-4433-6_3 · Cited by 85
“[PubMed: 21693759] Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Segeral E, Yatim A, Emiliani S, Schwartz O, Benkirane M. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature.”
BackgroundInfluentialDai, L., Lidie, K. B., Chen, Q., Adelsberger, J. W., Zheng, X. M., Huang, D.-W., Yang, J., Lempicki, R. A., Rehman, T. U., Dewar, R. L., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20120572 · Cited by 81
“More recently, SAMHD1, a restriction factor of myeloid cells, was found to limit HIV replication by depleting intracellular dNTPs, and it is largely opposed by Vpx (Hrecka et al., 2011; Laguette et al., 2011; Lahouassa et al., 2012).”
BackgroundCellular regulation of ribonucleotide reductase in eukaryotes
Guarino, E., Salguero, I., & Kearsey, S. E. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.03.030 · Cited by 82
“The ability of SAMHD1 to lower dNTP levels blocks IV-1 replication, and inactivation of SAMHD1 alleviates restricion of viral replication [95–97].”
BackgroundTartour, K., Nguyen, X.-N., Appourchaux, R., Assil, S., Barateau, V., Bloyet, L.-M., Burlaud Gaillard, J., Confort, M.-P., Escudero-Perez, B., Gruffat, H., et al. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006610 · Cited by 69
“This trick allows a very efficient transduction of myeloid cells by HIV-1 [88] [89] [90] thanks to the reported ability of Vpx to remove the restriction factor SAMHD1 [91, 92] .”
BackgroundSAMHD1 specifically restricts retroviruses through its RNase activity
Choi, J., Ryoo, J., Oh, C., Hwang, S.-Y., & Ahn, K. (2015) · Retrovirology · doi:10.1186/s12977-015-0174-4 · Cited by 89
“SAMHD1Q548A (dNTPase-positive) showed a similar infection ratio to SAMHD1mock despite having the ability to deplete the intracellular dNTP pool (Figure 1a), suggesting that SAMDH1 acts as an HIV-1 restriction factor via its RNase activity rather than via its dNTPase activity as previously described [10–13].”
Single-stranded nucleic acids promote SAMHD1 complex formation
Tüngler, V., Staroske, W., Kind, B., Dobrick, M., Kretschmer, S., Schmidt, F., Krug, C., Lorenz, M., Chara, O., Schwille, P., et al. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-0995-3 · Cited by 79
Aicardi–Goutières syndrome: a model disease for systemic autoimmunity
Lee‐Kirsch, M. A., Wolf, C., & Günther, C. (2013) · Clinical & Experimental Immunology · doi:10.1111/cei.12160 · Cited by 76
Hiding in Plain Sight: How HIV Evades Innate Immune Responses
Manel, N., & Littman, D. R. (2011) · Cell · doi:10.1016/j.cell.2011.09.010 · Cited by 85
Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins
Seissler, T., Marquet, R., & Paillart, J. (2017) · Viruses · doi:10.3390/v9110322 · Cited by 82
“Vpx (and Vpr of certain Simian Immunodefi iency Virus (SIV) strains) counteracts SAMHD1 by inducing its proteaso al degradation [67,83,84].”
BackgroundInfluentialHIV-1 replicates and persists in vaginal epithelial dendritic cells
Peña‐Cruz, V., Agosto, L. M., Akiyama, H., Olson, A., Moreau, Y., Larrieux, J.-R., Henderson, A. J., Gummuluru, S., & Sagar, M. (2018) · Journal of Clinical Investigation · doi:10.1172/jci98943 · Cited by 81
Impaired dNTPase Activity of SAMHD1 by Phosphomimetic Mutation of Thr-592
Tang, C., Ji, X., Wu, L. J., & Xiong, Y. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.677435 · Cited by 80
Innate Immune Sensing of HIV-1 by Dendritic Cells
Luban, J. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.10.002 · Cited by 79
“SAMHD1 knockdown permitted HIV-1 reverse transcription to proceed in myeloid cells in the absence of Vpx (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundRegulation of cGAS and STING signaling during inflammation and infection
Chauvin, S. D., Stinson, W. A., Platt, D. J., Poddar, S., & Miner, J. J. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104866 · Cited by 77
MCPIP1 restricts HIV infection and is rapidly degraded in activated CD4+ T cells
Liu, S., Qiu, C., Miao, R., Zhou, J., Lee, A., Liu, B., Lester, S. N., Fu, W., Zhu, L., Zhang, L., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1316208110 · Cited by 76
“Goldstone DC, et al. (2011) HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.”
BackgroundInfluentialLINE‐1 retrotransposons in healthy and diseased human brain
Suarez, N. A., Macia, Á., & Muotri, A. R. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22567 · Cited by 80
“SAMHD1 is a known inhibitor against certain retroviruses, including HIV and simian immunodeficiency virus (SIV) (Hrecka et al. 2011; Laguette et al. 2011).”
Vpr Overcomes Macrophage-Specific Restriction of HIV-1 Env Expression and Virion Production
Mashiba, M., Collins, D. R., Terry, V. H., & Collins, K. L. (2014) · Cell Host & Microbe · doi:10.1016/j.chom.2014.10.014 · Cited by 71
“Previously identified Vpr-dependent phenotypes observed in permissive cell-line systems depend on an interaction with the Cul4A-DDB1-DCAF1 ubiquitin ligase (Ahn et al., 2010; Belzile et al., 2007; Hrecka et al., 2011; Le Rouzic et al., 2007; Wen et al., 2007), which activates the SLX4-endonuclease complex.”
How Samhd1 changes our view of viral restriction
Laguette, N., & Benkirane, M. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.11.002 · Cited by 81
“SAMHD1 was recovered in biochemical purification of Vpx and its associated cofactors and was identified as the restriction factor operating in myeloid cells [6,7].”
BackgroundInfluentialPertel, T., Reinhard, C., & Luban, J. (2011) · Retrovirology · doi:10.1186/1742-4690-8-49 · Cited by 75
“Vpx was recently shown to bind to SAMHD1 and promote the degradation of this myeloid cell protein [69,70].”
BackgroundViral Determinants of HIV-1 Macrophage Tropism
Duncan, C. J. A., & Sattentau, Q. J. (2011) · Viruses · doi:10.3390/v3112255 · Cited by 79
“Recent studies have identified a host SAM-domain HD-domain containing protein 1 (SAMHD1) as a target for Vpx-mediated proteosomal degradation, which overcomes a post-entry block to reverse transcription in myeloid cells [158,159].”
BackgroundInfluential
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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