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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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In the citing paper
“This approach was necessary because PU.1 is the master transcriptional regulator necessary for macrophage differentiation and silencing PU.1 prior to infection results in a change in the cellular phenotype that causes resistance to HIV infection72,73.”
From HIV-1 Vpr combats the PU.1-driven antiviral response in primary human macrophages (2024) · cites this paper as [73]
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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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BackgroundCRL4-DCAF1 Ubiquitin Ligase Dependent Functions of HIV Viral Protein R and Viral Protein X
Dobransky, A., Root, M., Hafner, N., Marcum, M., & Sharifi, H. J. (2024) · Viruses · doi:10.3390/v16081313 · Cited by 10
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Jalloh, S., Hughes, I. A., Akiyama, H., Gojanovich, A. D., Quiñones-Molina, A. A., Yang, M., Henderson, A. J., Mostoslavsky, G., & Gummuluru, S. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003320 · Cited by 9
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Innate immune cells in chimeric antigen receptor therapy
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“53 To circumvent SAMHD1-mediated restriction, researchers have employed the accessory protein Vpx, which targets SAMHD1 for pro-teasomal degradation.”
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STRIPE3, encoding a human dNTPase SAMHD1 homolog, regulates chloroplast development in rice
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“SAMHD1 depletion leads to an increase in intermediates of reverse transcription (RT), especially late cDNA products, indicating that SAMHD1 inhibits the RT process (3, 7, 8).”
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Ananth, S., Ambiel, I., Schifferdecker, S., Müller, T. G., Wratil, P. R., Mejías‐Pérez, E., Kräusslich, H., Müller, B., Keppler, O. T., & Fackler, O. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113941 · Cited by 10
HIV and innate immunity – a genomics perspective
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“Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, Florens L, Washburn MP, Skowronski J: Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein.”
BackgroundInfluentialMCPIP1/regnase-I inhibits simian immunodeficiency virus and is not counteracted by Vpx
Li, H., & Wang, T. T. (2016) · Journal of General Virology · doi:10.1099/jgv.0.000482 · Cited by 10
“…et al., 2012; Descours et al., 2012), and its effect can be overcome by the HIV-2 or SIV-encoded accessory protein Vpx (Berger et al., 2011; Hrecka et al., 2011; Laguette et al., 2011), which targets SAMHD1 for cullin4ARING E3 ubiquitin ligase (CRL4)-dependent degradation (Ahn et al.,…”
BackgroundInfluentialPatra, K. K., Bhattacharya, A., & Bhattacharya, S. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00279 · Cited by 9
Forlani, G., & Accolla, R. S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01362 · Cited by 9
“SAMHD1 activity is prevented in HIV-2 and related SIVs by the viral proteins Vpx and Vpr (18, 19).”
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“Vpx is released from the virions into the cytoplasm, where it degrades SAMHD1.”
BackgroundHuman immunodeficiency virus-1 core: The Trojan horse in virus–host interaction
Wang, W., Li, Y., Zhang, Z., & Wei, W. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1002476 · Cited by 9
“, 2011), dGTPdependent deoxynucleotide triphosphohydrolase SAM domain, HD domain-containing protein 1 (SAMHD1) and BST-2/tetherin limit viral reproduction and spread through their unique manners (Neil et al., 2008; Hultquist and Harris, 2009; Goldstone et al., 2011; Hrecka et al., 2011; Laguette et al., 2011; Su et al…”
BackgroundMechanism of herpesvirus protein kinase UL13 in immune escape and viral replication
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Les IFITM, un obstacle commun à de nombreux virus
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“Par la suite, Trim5 (tripartite motif 5 protein), la tétherine/Bst2 (bone marrow stromal antigen 2), SAMHD1 (SAM domain and HD domain-containing protein 1) et Mx2 ont été identifiés comme autant de facteurs pouvant inhiber le VIH [2-9, 41, 42].”
BackgroundThe Innate Immune Response to HIV-1: To Sense or Not to Sense
Landau, N. R. (2014) · DNA and Cell Biology · doi:10.1089/dna.2014.2378 · Cited by 10
“The response required the addition of the lentiviral accessory protein Vpx to the cells as a means of overcoming the SAMHD1-mediated block to reverse transcription (Hrecka et al., 2011; Laguette et al., 2011).”
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Modulation of LINE-1 retrotransposition by a human SAMHD1 polymorphism
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“…restrcition; HIV-1 INTRODUCTION SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1 (Baldauf et al., 2012) (Berger et al., 2011; Descours et al., 2012; Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundMethodInfluentialAccess of HIV-2 to CD169-dependent dendritic cell-mediated trans infection pathway is attenuated
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“Though HIV-2 Vpx can overcome restriction by SAMHD1 (Hrecka et al., 2011; Laguette et al., 2011), LPS-matured DCs present a hostile cellular environment for HIV-2 replication (Pertel et al., 2011) that places additional roadblocks to establishment of productive infection.”
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Tactics used by HIV-1 to evade host innate, adaptive, and intrinsic immunities
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May I Help You with Your Coat? HIV-1 Capsid Uncoating and Reverse Transcription
Arribas, L., Menéndez‐Arias, L., & Betancor, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137167 · Cited by 10
“In myeloid cells and resting T cells infected with HIV-1, SAMHD1 depletion leads to an increase in late reverse transcription products, indicating that SAMHD1 inhibits reverse transcription through depletion of dNTPs [157,158].”
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“…factor sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), which was identi fi ed as an inhibitor of several lentiviruses, thereby promoting ubiquitin − mediated proteolysis of SAMHD1 to facilitate lentiviral evasion (Hrecka et al., 2011; Miyakawa et al., 2019).”
HIV Impairment of Immune Responses in Dendritic Cells
Ahmed, Z., Czubala, M. A., Blanchet, F. P., & Piguet, V. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-4433-6_8 · Cited by 10
Bolduan, S., Koppensteiner, H., Businger, R., Rebensburg, S. V., Kunze, C., Brack‐Werner, R., Draenert, R., & Schindler, M. (2017) · Journal of the International AIDS Society · doi:10.7448/ias.20.1.21865 · Cited by 8
“lower levels of HIV-1 RFs, more specifically SAMHD1 and p21 which are suppressors of HIV-1 reverse transcription and integration [14,15,17,36,37].”
BackgroundSingh, S. P., Raja, S., & Mahalingam, S. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-08-0438 · Cited by 8
“Recent reports suggest that Vpx promotes proteasomal degradation of host cell restriction factor SAMHD1, a triphos-phohydrolase, which is responsible for depleting the cytoplasmic dNTPs pool required for viral DNA synthesis in nondividing cells (Hrecka et al. , 2011; Laguette et al. , 2011).”
Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1
Estrella, L. V., López‐Serrat, M., Sánchez‐Sànchez, G., Vico, T., Lloberas, J., & Celada, A. (2020) · European Journal of Immunology · doi:10.1002/eji.201948491 · Cited by 8
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Simian Immunodeficiency Virus Interactions with Macaque Dendritic Cells
Teleshova, N., Derby, N. R., Martinelli, E., Pugach, P., Calenda, G., & Robbiani, M. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-4433-6_6 · Cited by 8
“Vpx is also important in the context of another barrier to HIV infection in myeloid cells, SAMHD1, which prevents HIV-1 infection in DCs by interfering with synthesis of viral cDNA (Hrecka et al. 2011; Laguette et al. 2011).”
BackgroundSAMHD1 prive le VIH des nucléotides essentiels à la synthèse d’ADN viral
Lahouassa, H., Dragin, L., Transy, C., & Margottin-Goguet, F. (2012) · médecine/sciences · doi:10.1051/medsci/20122811002 · Cited by 9
“(➜) [10], SAMHD1 [SAM domain and HD domain 1] a été découverte en 2011 comme une protéine cellulaire bloquant l’infection virale dans les macrophages et les cellules dendritiques [1, 2].”
BackgroundCalonge, E., Bermejo, M., Díez‐Fuertes, F., Mangeot, I., Gonzàlez, N., Coiras, M., Tormo, L. J., García‐Pérez, J., Dereuddre‐Bosquet, N., Grand, R. L., et al. (2017) · Journal of Virology · doi:10.1128/jvi.01379-16 · Cited by 8
“In this environment, SAMHD1 is inactivated through phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 in proliferating cells, which correlates with loss of its ability to restrict HIV-1 infection (32).”
BackgroundDNA damage response signaling does not trigger redistribution of SAMHD1 to nuclear foci
Medeiros, A. C., Soares, C. S., Coelho, P. D. O., Vieira, N. A., Baqui, M. M. A., Teixeira, F. R., & Gomes, M. D. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.03.225 · Cited by 8
Role of Complement Receptors (CRs) on DCs in Anti-HIV-1 Immunity
Posch, W., Bermejo‐Jambrina, M., Lass‐Flörl, C., & Wilflingseder, D. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.572114 · Cited by 9
“SAMHD1 is a deoxynucleosidetriphosphate (dNTP) triphosphohydrolase that restricts the replication of HIV-1 in non-cycling monocytes, monocyte-derived macrophages (MDMs), DCs, and resting T-cells (17, 19, 20).”
BackgroundMechanism by which T7 bacteriophage protein Gp1.2 inhibits Escherichia coli dGTPase
Klemm, B. P., Singh, D., Smith, C., Hsu, A. L., Dillard, L. B., Krahn, J. M., London, R. E., Mueller, G. A., Borgnia, M. J., & Schaaper, R. M. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2123092119 · Cited by 11
“The enzyme is a hexameric homolog of the tetrameric human SAMHD1 (11), a dNTPase that was also implicated as a restriction factor against viruses such as HIV (6).”
BackgroundInfluentialInteractions Between HIV-1 and Innate Immunity in Dendritic Cells
Silvin, A., & Manel, N. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-4433-6_7 · Cited by 11
SAMHD1 does it again, now in resting T cells
Yan, N., & Lieberman, J. (2012) · Nature Medicine · doi:10.1038/nm.2980 · Cited by 8
A new activity for SAMHD1 in HIV restriction
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SAMHD1Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis
Li, W., Xin, B., Yan, J., Wu, Y. G., Hu, B., Liu, L., Wang, Y., Ahn, J., Skowroński, J., Zhang, Z., et al. (2015) · BioMed Research International · doi:10.1155/2015/739586 · Cited by 8
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The Early Bird Catches the Worm - Can Evolution Teach us Lessons in Fighting HIV?
Schaller, T., & Herold, N. (2016) · Current HIV Research · doi:10.2174/1570162x14999160224094914 · Cited by 8
Expression Profiles of Vpx/Vpr Proteins Are Co-related with the Primate Lentiviral Lineage
Sakai, Y., Miyake, A., Doi, N., Sasada, H., Miyazaki, Y., Adachi, A., & Nomaguchi, M. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.01211 · Cited by 9
SAMHD1 Posttranscriptionally Controls the Expression of Foxp3 and Helios in Human T Regulatory Cells
Kim, Y. C., Kim, K. K., Yoon, J., Scott, D. W., & Shevach, E. M. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800613 · Cited by 8
“We were unsuccessful in our attempts to knock down SAMHD1 in hTregs using short hairpin RNAs that have been reported to be useful in other cell types, including monocyte/macrophage cell lines (6, 7) and primary CD4 T cells (11).”
BackgroundMethodSliva, K., Martin, J. M., von Rhein, C., Herrmann, T., Weyrich, A., Toda, M., & Schnierle, B. S. (2019) · Journal of Virology · doi:10.1128/jvi.01097-19 · Cited by 8
Interaction of chikungunya virus glycoproteins with macrophage factors controls virion production
Yao, Z., Ramachandran, S., Huang, S., Kim, E. J., Jami‐Alahmadi, Y., Kaushal, P., Bouhaddou, M., Wohlschlegel, J. A., & Li, M. M. H. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00193-3 · Cited by 7
“…viral proteins, propel-ling viruses to evade or antagonize these blockades, such as the arms race between myeloid-cell-speci fi c SAMHD1 (SAM and HD domain containing deoxynucleoside triphosphate triphosphohy-drolase 1) and HIV-2 Vpx (Hrecka et al, 2011; Laguette et al, 2012; Daugherty et al, 2014).”
Rabinowitz, J., Vila, I. K., Luchsinger, C., Bertelli, C., Schüssler, M., Taffoni, C., Cui, B., Dai, A. Z., Rashid, M. M., Cisneros, W. J., et al. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110430 · Cited by 8
SAMHD1 Joins the Red Queen's Court
Planelles, V. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.02.001 · Cited by 7
“Specifically, while SAMHD1 effectively restricts HIV-1 replication, Vpx from HIV-2 and related simian immunodeficiency viruses (SIVsmm/mac) counteract the restrictive mechanism by promoting proteasomedependent degradation of SAMHD1 (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundThe ISG15-Protease USP18 Is a Pleiotropic Enhancer of HIV-1 Replication
Lin, C., Kuffour, E. O., Li, T., Gertzen, C. G. W., Kaiser, J., Luedde, T., König, R., Gohlke, H., & Münk, C. (2024) · Viruses · doi:10.3390/v16040485 · Cited by 7
Interferon-Stimulated Genes that Target Retrovirus Translation
Jäger, N., Pöhlmann, S., Rodnina, M. V., & Ayyub, S. A. (2024) · Viruses · doi:10.3390/v16060933 · Cited by 9
“HIV and other viruses have evolved elaborate mechanisms to evade or counteract these factors, reflecting an evolutionary arms race between host cell restriction factors and their viral antagonists (termed resistance factors) [10,20–23].”
BackgroundHypoxia drives HIF2-dependent reversible macrophage cell cycle entry
Meng, B., Zhao, N., Mlčochová, P., Ferreira, I. A. T. M., Ortmann, B. M., Davis, T., Wit, N., Rehwinkel, J., Cook, S. J., Maxwell, P. H., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114471 · Cited by 8
SAMHD1 enhances HIV-1-induced apoptosis in monocytic cells via the mitochondrial pathway
Yang, H., Cheung, P. H., & Wu, L. J. (2025) · mBio · doi:10.1128/mbio.00425-25 · Cited by 7
Sakai, Y., Doi, N., Miyazaki, Y., Adachi, A., & Nomaguchi, M. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.01655 · Cited by 7
“Viral clones with/without SAMHD1-degrading activity (Laguette et al., 2012; Lim et al., 2012) are indicated by blue and red letters, respectively.”
BackgroundMethodInfluentialStrain-Specific Antagonism of the Human H1N1 Influenza A Virus against Equine Tetherin
Wang, M., Zhang, Z., & Wang, X. (2018) · Viruses · doi:10.3390/v10050264 · Cited by 7
“It is evident from several reports that host restriction factors, such as apolipoprotein B mRNA-editing enzyme catalytic subunit 3 proteins (APOBEC3) [3–5], tripartite motif protein 5a (TRIM5a) [6], SAM domain and HD domain-containing protein 1 (SAMHD1) [7,8], and tetherin [9] play important roles in blocking interspe…”
BackgroundCoggins, S. A., Holler, J. M., Kimata, J. T., Kim, D., Schinazi, R. F., & Kim, B. (2019) · Virology · doi:10.1016/j.virol.2019.08.010 · Cited by 7
“Many SIV strains from various primate species counteract the anti-viral activity of SAMHD1 by targeting the host protein for E3-ligase dependent proteasomal degradation (9,13,16,17,51).”
BackgroundInfluentialNucleotide Pool Imbalance and Antibody Gene Diversification
Azhar, A., Begum, N. A., & Husain, A. (2021) · Vaccines · doi:10.3390/vaccines9101050 · Cited by 7
Is the HTLV-1 Retrovirus Targeted by Host Restriction Factors?
Carcone, A., Journo, C., & Dutartre, H. (2022) · Viruses · doi:10.3390/v14081611 · Cited by 8
“This indicates that p30 might overcome a block in monocytes and dendritic cells, possibly by dampening antiviral ISG expression [31,32], and that this block would not be active in T cells.”
BackgroundInfluentialGreiner, D., Scott, T. M., Olson, G. S., Aderem, A. A., Roh‐Johnson, M., & Johnson, J. S. (2022) · Current Protocols · doi:10.1002/cpz1.514 · Cited by 7
“…triphosphohydrolase 1 (SAMHD1), is responsible for maintaining low levels of dNTPs in the cytosol (Goldstone et al., 2011; Lahouassa et al., 2012), which prevents retroviruses and many lentiviruses from reverse transcribing their genomes upon entry (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundZhao, S., Zheng, B., Wang, L., Cui, W., Jiang, C., Li, Z., Gao, W., & Zhang, W. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002478 · Cited by 8
“Because other host antiviral factors such as SAMHD1 and HLTF can be degraded by HIV accessory proteins through the UPS,([3,58-61]) we then examined the effect of USP3 on the expression of SAMHD1 and HLTFand found that it had no effect at either the protein or mRNAlevel [Figures 3Q–T].”
BackgroundHollenbaugh, J. A., Schader, S. M., Schinazi, R. F., & Kim, B. (2015) · Virology · doi:10.1016/j.virol.2015.08.006 · Cited by 7
“Vpx augments viral infectivity in non-dividing cells (Kappes et al., 1991) by the degradation of SAMDH1 (Hrecka et al., 2011; Laguette et al., 2011) and consequently increasing dNTP concentrations in primary human cells (Baldauf et al., 2012; Berger et al., 2011; Hrecka et al., 2011; Kim et al., 2012; Laguette et al.,…”
InfluentialCharacterization of the interactions between SIVrcm Vpx and red-capped mangabey SAMHD1
Li, J., Xu, F., Hu, S., Zhou, J., Mei, S., Zhao, X., Cen, S., Jin, Q., Liang, C., & Guo, F. (2015) · Biochemical Journal · doi:10.1042/bj20141331 · Cited by 7
The N-end rule and retroviral infection: no effect on integrase
Boso, G., Tasaki, T., Kwon, Y., & Somia, N. V. (2013) · Virology Journal · doi:10.1186/1743-422x-10-233 · Cited by 8
“…the years, a variety of studies have implicated the ubiquitin proteasome system in the viral life cycle, research on the role of this essential pathway in retroviral infection has mostly been focused on targeting of cellular restriction factors to the prote-asome by viral accessory proteins [9-11].”
Buchanan, E. L., Espinoza, D. A., McAlexander, M. A., Myers, S. L., Moyer, A. L., & Witwer, K. W. (2016) · Scientific Reports · doi:10.1038/srep22629 · Cited by 7
H11/HSPB8 Restricts HIV-2 Vpx to Restore the Anti-Viral Activity of SAMHD1
Kudoh, A., Miyakawa, K., Matsunaga, S., Matsushima, Y., Kosugi, I., Kimura, H., Hayakawa, S., Sawasaki, T., & Ryo, A. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00883 · Cited by 7
“Vpx degrades SAMHD1 in order to evade host intrinsic intracellular immunity and allow sustained HIV replication in myeloid cells (Goldstone et al., 2011; Hrecka et al., 2011; Laguette et al., 2011; Baldauf et al., 2012; Descours et al., 2012; Lahouassa et al., 2012).”
BackgroundResultInfluentialThe feasibility of incorporating Vpx into lentiviral gene therapy vectors
McAllery, S., Ahlenstiel, C., Suzuki, K., Symonds, G. P., Kelleher, A. D., & Turville, S. G. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2016.66 · Cited by 8
Incomplete Suppression of HIV-1 by SAMHD1 Permits Efficient Macrophage Infection
Plitnik, T., Sharkey, M. E., Mahboubi, B., Kim, B., & Stevenson, M. (2018) · Pathogens and Immunity · doi:10.20411/pai.v3i2.263 · Cited by 7
“Upon SAMHD1 degradation, intracellular dNTP levels rapidly increase to levels conducive to efficient reverse transcription [7, 22, 25, 26].”
BackgroundInfluentialAl-Shehabi, H., Fiebig, U., Kutzner, J., Denner, J., Schaller, T., Bannert, N., & Hofmann, H. (2019) · Journal of General Virology · doi:10.1099/jgv.0.001232 · Cited by 7
Oo, A., Kim, D., Schinazi, R. F., & Kim, B. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011466 · Cited by 7
“Indeed, Vpx elevates dNTP pool in macrophages (11) by targeting SAMHD1 for proteosomal degradation (12, 13).”
BackgroundHe, Y., Xu, M., Ouyang, J., Zhao, L., Ma, T., Zhang, X., Wang, R., Shang, H., & Liang, G. (2025) · Nature Communications · doi:10.1038/s41467-025-58218-2 · Cited by 6
The Involvement of Ubiquitination and SUMOylation in Retroviruses Infection and Latency
Liang, T., Li, G., Lu, Y., Hu, M., & Ma, X. (2023) · Viruses · doi:10.3390/v15040985 · Cited by 6
Phosphodiesterase 8a Supports HIV-1 Replication in Macrophages at the Level of Reverse Transcription
Booiman, T., Jiménez, V. C., van Dort, K. A., Wout, A. B. V. ’., & Kootstra, N. A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109673 · Cited by 6
The innate immune roles of host factors TRIM5α and Cyclophilin A on HIV-1 replication
Kuang, Y., Liu, H., & Zheng, Y. (2015) · Medical Microbiology and Immunology · doi:10.1007/s00430-015-0417-y · Cited by 6
“On the other hand, the host has evolved restriction factors, including APOBEC3G/F (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G/F) [1, 2], TRIM5α (tripartite motif protein 5α) [3], tetherin/BST-2/CD317 [4, 5], SAMHD1 (SAM domain and HD domain-containing protein 1) [6, 7] and Mx2 (myxovirus resi…”
BackgroundHIV-1 Trans Infection via TNTs Is Impeded by Targeting C5aR
Bertacchi, G., Posch, W., & Wilflingseder, D. (2022) · Biomolecules · doi:10.3390/biom12020313 · Cited by 6
“Biomolecules 2022, 12, 313. https://doi.org/10.3390/biom12020313 https://www.mdpi.com/journal/biomolecules Biomolecules 2022, 12, 313 2 of 17 Interestingly, complement-opsonized HIV-1 (HIV-C) efficiently infects DCs by evading SAMHD1 restriction due to phosphorylation of the T592 residue of the SAM domain, resulting i…”
BackgroundInfluentialHost Restrictive Factors Are the Emerging Storm Troopers Against Enterovirus: A Mini-Review
Huan, C., Qu, X., & Li, Z. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.910780 · Cited by 6
“Like A3G, SAMHD1, another anti-HIV-restrictive factor, has been extensively investigated (14, 58, 59).”
BackgroundTargeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies
Wang, T., Liu, P., & Yang, J. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.06.001 · Cited by 6
“Vpx could target the SAMHD1 C-terminal region and conjugate to the DNA damage-binding protein (DDB1) and comprising cullin4A (CUL4)-associated factors 1 (DCAF1), an E3 ligase substrate adaptor, and promote SAMHD1 degradation by the proteasome.(93,94) Depleting SAMHD1 significantly improved cytarabine sensitivity in he…”
BackgroundLabadie, K. P., Kreuser, S. A., Brempelis, K. J., Daniel, S. K., Jiang, X., Sullivan, K. M., Utria, A. F., Kenerson, H. L., Kim, T. S., Crane, C. A., et al. (2023) · Cancer Gene Therapy · doi:10.1038/s41417-023-00632-z · Cited by 6
The innate immune factor RPRD2/REAF and its role in the Lv2 restriction of HIV
Jackson-Jones, K. A., McKnight, Á., & Sloan, R. D. (2023) · mBio · doi:10.1128/mbio.02572-21 · Cited by 6
“Similarly, SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) blocks reverse transcription (13, 129) and was initially suggested by some to degrade viral RNA (130), although this was disproved by other studies (131).”
ResultHost ZCCHC3 blocks HIV-1 infection and production through a dual mechanism
Yi, B., Tanaka, Y., Cornish, D., Kosako, H., Butlertanaka, E. P., Sengupta, P., Lippincott‐Schwartz, J., Hultquist, J. F., Saito, A., & Yoshimura, S. H. (2024) · iScience · doi:10.1016/j.isci.2024.109107 · Cited by 6
“17,18 To counteract these restriction factors, HIV-1 encodes viral accessory proteins that relocalize and/or degrade these antiviral proteins.”
BackgroundHelp or Hinder: Protein Host Factors That Impact HIV-1 Replication
Moezpoor, M. R., & Stevenson, M. (2024) · Viruses · doi:10.3390/v16081281 · Cited by 7
HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1
Miguel, J. (2013) · InTech eBooks · doi:10.5772/53201 · Cited by 5
“Paradoxically, recent data have disclosed a cellular protein (SAMHD1) that inhibits HIV-1 replication in immature monocytes-derived dendritic cells, in dendritic cells derived from PMA-differentiated THP-1 monocytic cell line [69] and in macrophages [70].”
BackgroundMcCulley, A., & Ratner, L. (2012) · Virology · doi:10.1016/j.virol.2012.02.002 · Cited by 6
“Absence of a Vpx band in pESdelX lane is due tomutations in vpx at the initiating and first internal methionine, plus a frameshift that introduces a termination codon at position 70 (Hu et al., 1989).”
BackgroundKrebs, K. C., Tian, M., Asmal, M., Ling, B., Nelson, K. N., Henry, K., Gibson, R. M., Li, Y., Han, W., Shattock, R. J., et al. (2016) · AIDS Research and Therapy · doi:10.1186/s12981-016-0125-8 · Cited by 6
Introduction of H2C2‐type zinc‐binding residues into HIV‐2 Vpr increases its expression level
Koga, R., Yamamoto, M., Ciftci, H. I., Otsuka, M., & Fujita, M. (2017) · FEBS Open Bio · doi:10.1002/2211-5463.12358 · Cited by 6
Sharma, S., Jafari, M., Bangar, A., William, K. A., Guatelli, J., & Lewinski, M. K. (2019) · Journal of Virology · doi:10.1128/jvi.02315-18 · Cited by 6
Risk association of BST2 gene variants with disease progression in HIV-1 infected Indian cohort
Gupte, D. S., Patil, A., Kumar, C. S., Pandey, S. S., Achrekar, S. K., Paranjape, R., & Jagtap, D. D. (2019) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2019.104139 · Cited by 6
HIV suppressors against LINE-1: one functions as two
Du, J., & Zhao, K. (2021) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2021.1893640 · Cited by 6
Wang, C., Zhang, K., Meng, L., Zhang, X., Song, Y., Zhang, Y., Gai, Y., Zhang, Y., Yu, B., Wu, J., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012767 · Cited by 7
Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes
Pacheco, B., Menéndez‐Arias, L., & Sodroski, J. (2016) · Scientific Reports · doi:10.1038/srep37489 · Cited by 6
Sharma, M., & Panda, N. K. (2020) · Preprints.org · doi:10.20944/preprints202006.0206.v1 · Cited by 5
“Interestingly, SAMHD1 (other potential ISG downregulated in our dataset) was initially identified as an interferon-g-induced gene, and an anti-HIV-1 restriction factor (Hrecka et al., 2011; Laguette et al., 2011).”
BackgroundVictoria, S., Leyens, J., Meckes, L. M., Syrigos, G. V., Turk, G., & Schindler, M. (2025) · Journal of Virology · doi:10.1128/jvi.00182-25 · Cited by 6
“For a robust readout, macrophages were pre-treated for 2 h with SIV VPX-VLPs (41, 42).”
The Confluence of HIV‐1 and HIV‐2: Implications for Disease Progression and Insights for Therapy
Magomere, E. O., Olwal, C. O., Tetteh, B. E., Appeaning, M., Ndung’u, T., Kyei, G. B., & Quashie, P. K. (2025) · International Journal of Microbiology · doi:10.1155/ijm/3145677 · Cited by 5
“While the degradation of SAMHD1 and suppression of the proin fl ammatory immune response by HIV-2 Vpx and SIV Vpx promoted their ability to infect noncycling immune cells such as macrophages [65, 66], the presence of Vpx dampened the infectivity of HIV-1 in vitro [67].”
Rodríguez-Mora, S., Sánchez-Menéndez, C., Bautista, G., Mateos, E., Moreno‐Serna, L., Megı́as, D., Cantón, J., García‐Gutiérrez, V., Murciano-Antón, M. A., Cervero, M., et al. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116512 · Cited by 5
Sharma, M., Nag, M., & Prete, G. Q. D. (2024) · Viruses · doi:10.3390/v16101618 · Cited by 5
“As noted above, SIV genomes encode the Vpx accessory protein, which counteracts the SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) restriction factor and is required for SIV pathogenesis in macaques [65–67].”
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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