Home LiteratureArticle Details
PMID: 18976920 Published · ppublish English Journal Article Review

Restriction of retroviral replication by APOBEC3G/F and TRIM5alpha.

Trends in microbiology ·Vol. 16 ·No. 12 ·2008-12-00 ·Pages 612-9

Huthoff H, Towers GJ

Abstract

Pathogenic viral infections have exerted selection pressure on their hosts to evolve cellular antiviral inhibitors referred to as restriction factors. Examples of such molecules are APOBEC3G, APOBEC3F and TRIM5alpha. APOBEC3G and APOBEC3F are cytidine deaminases that are able to strongly inhibit retroviral replication by at least two mechanisms. They are counteracted by the lentiviral Vif protein. TRIM5alpha binds to sensitive, incoming retroviruses via its C-terminal PRY/SPRY domain and rapidly recruits them to the proteasome before significant viral DNA synthesis can occur. Both of these proteins robustly block retroviral replication in a species-specific way. It remains an open but important question as to whether innate restriction factors such as these can be harnessed to inhibit HIV-1 replication in humans.

MeSH Terms
APOBEC-3G Deaminase Animals Antiviral Restriction Factors Carrier Proteins/metabolism,pharmacology Cytidine Deaminase/chemistry,metabolism,pharmacology Cytosine Deaminase/metabolism,pharmacology HIV-1/drug effects,physiology Humans Models, Molecular Retroviridae/drug effects,physiology Tripartite Motif Proteins Ubiquitin-Protein Ligases Virus Replication/drug effects
Chemicals
Antiviral Restriction Factors Carrier Proteins Tripartite Motif Proteins TRIM5 protein, human Ubiquitin-Protein Ligases APOBEC3F protein, human Cytosine Deaminase APOBEC-3G Deaminase APOBEC3G protein, human Cytidine Deaminase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Huthoff Hendrik
Department of Infectious Diseases, Guy's, King's and St Thomas' School of Medicine, London SE1 9RT, UK.
Towers Greg J
References (79)
79 references, click to expand
  1. Enzymatically active APOBEC3G is required for efficient inhibition of human immunodeficiency virus type 1.
    J Virol. 2007 Dec;81(24):13346-53 PMID: 17928335
  2. Evolution of a TRIM5-CypA splice isoform in old world monkeys.
    PLoS Pathog. 2008 Feb;4(2):e1000003 PMID: 18389077
  3. Retroviral restriction factors Fv1 and TRIM5alpha act independently and can compete for incoming virus before reverse transcription.
    J Virol. 2006 Mar;80(5):2100-5 PMID: 16474118
  4. Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species.
    Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3563-8 PMID: 18287034
  5. Rhesus monkey TRIM5alpha restricts HIV-1 production through rapid degradation of viral Gag polyproteins.
    Nat Med. 2007 May;13(5):631-5 PMID: 17435772
  6. Cyclophilin A renders human immunodeficiency virus type 1 sensitive to Old World monkey but not human TRIM5 alpha antiviral activity.
    J Virol. 2006 May;80(10):4683-90 PMID: 16641261
  7. Cytidine deamination induced HIV-1 drug resistance.
    Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5501-6 PMID: 18391217
  8. Dual inhibitory effects of APOBEC family proteins on retrotransposition of mammalian endogenous retroviruses.
    Nucleic Acids Res. 2006;34(5):1522-31 PMID: 16537839
  9. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.
    Nature. 2008 Jan 24;451(7177):425-30 PMID: 18200009
  10. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys.
    Nature. 2004 Feb 26;427(6977):848-53 PMID: 14985764
  11. Induction of APOBEC3G ubiquitination and degradation by an HIV-1 Vif-Cul5-SCF complex.
    Science. 2003 Nov 7;302(5647):1056-60 PMID: 14564014
  12. APOBEC3G restricts early HIV-1 replication in the cytoplasm of target cells.
    Virology. 2008 May 25;375(1):1-12 PMID: 18308358
  13. Resistance to superinfection by a vigorously replicating, uncloned stock of simian immunodeficiency virus (SIVmac251) stimulates replication of a live attenuated virus vaccine (SIVmacC8).
    J Gen Virol. 2008 Sep;89(Pt 9):2240-51 PMID: 18753233
  14. A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1.
    Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13324-8 PMID: 15326303
  15. Alpha interferon enhances TRIM5alpha-mediated antiviral activities in human and rhesus monkey cells.
    J Virol. 2007 Sep;81(18):10201-6 PMID: 17609277
  16. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity.
    Curr Biol. 2005 Jan 26;15(2):166-70 PMID: 15668174
  17. Mechanisms of protection induced by attenuated simian immunodeficiency virus. I. Protection cannot be transferred with immune serum.
    J Gen Virol. 1997 Aug;78 ( Pt 8):1919-22 PMID: 9266988
  18. Retroviral restriction factor TRIM5alpha is a trimer.
    J Virol. 2005 Nov;79(22):14446-50 PMID: 16254380
  19. Turning up the volume on mutational pressure: is more of a good thing always better? (A case study of HIV-1 Vif and APOBEC3).
    Retrovirology. 2008;5:26 PMID: 18339206
  20. APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo.
    Curr Biol. 2004 Aug 10;14(15):1385-91 PMID: 15296757
  21. Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication.
    J Virol. 2004 Jun;78(11):6073-6 PMID: 15141007
  22. Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.
    J Gen Virol. 2008 Jan;89(Pt 1):1-47 PMID: 18089727
  23. Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A.
    Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5247-52 PMID: 11929983
  24. Cyclophilin A is required for TRIM5{alpha}-mediated resistance to HIV-1 in Old World monkey cells.
    Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14849-53 PMID: 16203999
  25. The effect of Trim5 polymorphisms on the clinical course of HIV-1 infection.
    PLoS Pathog. 2008 Feb 8;4(2):e18 PMID: 18248091
  26. Human immunodeficiency virus type 1 DNA sequences genetically damaged by hypermutation are often abundant in patient peripheral blood mononuclear cells and may be generated during near-simultaneous infection and activation of CD4(+) T cells.
    J Virol. 2001 Sep;75(17):7973-86 PMID: 11483742
  27. Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification.
    PLoS Pathog. 2005 Sep;1(1):e6 PMID: 16201018
  28. Selective inhibition of Alu retrotransposition by APOBEC3G.
    Gene. 2007 Apr 1;390(1-2):199-205 PMID: 17079095
  29. Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G.
    Nature. 2008 Mar 6;452(7183):116-9 PMID: 18288108
  30. An active TRIM5 protein in rabbits indicates a common antiviral ancestor for mammalian TRIM5 proteins.
    J Virol. 2007 Nov;81(21):11713-21 PMID: 17728224
  31. TRIM family proteins: retroviral restriction and antiviral defence.
    Nat Rev Microbiol. 2005 Oct;3(10):799-808 PMID: 16175175
  32. G-->A hypermutation in protease and reverse transcriptase regions of human immunodeficiency virus type 1 residing in resting CD4+ T cells in vivo.
    J Virol. 2005 Feb;79(3):1975-80 PMID: 15650227
  33. High-molecular-mass APOBEC3G complexes restrict Alu retrotransposition.
    Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15588-93 PMID: 17030807
  34. Rhesus macaque TRIM5 alleles have divergent antiretroviral specificities.
    J Virol. 2008 Jul;82(14):7243-7 PMID: 18480454
  35. DNA deamination mediates innate immunity to retroviral infection.
    Cell. 2003 Jun 13;113(6):803-9 PMID: 12809610
  36. A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction.
    Curr Biol. 2005 Jan 11;15(1):73-8 PMID: 15649369
  37. Generation of simian-tropic HIV-1 by restriction factor evasion.
    Science. 2006 Oct 6;314(5796):95 PMID: 17023652
  38. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor.
    Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5514-9 PMID: 16540544
  39. Independent evolution of an antiviral TRIMCyp in rhesus macaques.
    Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3557-62 PMID: 18287035
  40. Ubiquitination of E3 ubiquitin ligase TRIM5 alpha and its potential role.
    FEBS J. 2008 Apr;275(7):1540-55 PMID: 18312418
  41. G-->A hypermutation of the human immunodeficiency virus type 1 genome: evidence for dCTP pool imbalance during reverse transcription.
    Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3092-6 PMID: 7512722
  42. Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses.
    J Virol. 2007 Sep;81(18):10055-63 PMID: 17609268
  43. AIDS research. Review of vaccine failure prompts a return to basics.
    Science. 2008 Apr 4;320(5872):30-1 PMID: 18388263
  44. APOBEC3F can inhibit the accumulation of HIV-1 reverse transcription products in the absence of hypermutation. Comparisons with APOBEC3G.
    J Biol Chem. 2007 Jan 26;282(4):2587-95 PMID: 17121840
  45. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain.
    Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2832-7 PMID: 15689398
  46. Inhibition of hepatitis B virus replication by APOBEC3G.
    Science. 2004 Mar 19;303(5665):1829 PMID: 15031497
  47. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells.
    Nature. 2005 May 5;435(7038):108-14 PMID: 15829920
  48. Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection.
    Proc Natl Acad Sci U S A. 2006 May 9;103(19):7454-9 PMID: 16648259
  49. Balancing selection and the evolution of functional polymorphism in Old World monkey TRIM5alpha.
    Proc Natl Acad Sci U S A. 2006 Dec 12;103(50):19134-9 PMID: 17142324
  50. Newly synthesized APOBEC3G is incorporated into HIV virions, inhibited by HIV RNA, and subsequently activated by RNase H.
    PLoS Pathog. 2007 Feb;3(2):e15 PMID: 17291161
  51. CD8+ lymphocytes do not mediate protection against acute superinfection 20 days after vaccination with a live attenuated simian immunodeficiency virus.
    J Virol. 2005 Oct;79(19):12264-72 PMID: 16160152
  52. Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G.
    Nucleic Acids Res. 2007;35(21):7096-108 PMID: 17942420
  53. Differential restriction of human immunodeficiency virus type 2 and simian immunodeficiency virus SIVmac by TRIM5alpha alleles.
    J Virol. 2005 Sep;79(18):11580-7 PMID: 16140735
  54. Visualization of a proteasome-independent intermediate during restriction of HIV-1 by rhesus TRIM5alpha.
    J Cell Biol. 2008 Feb 11;180(3):549-61 PMID: 18250195
  55. Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection.
    Proc Natl Acad Sci U S A. 2006 May 9;103(19):7465-70 PMID: 16648264
  56. Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism.
    Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11914-9 PMID: 12154227
  57. Antiretroviral potential of human tripartite motif-5 and related proteins.
    Virology. 2006 Sep 30;353(2):396-409 PMID: 16828831
  58. Trim-cyclophilin A fusion proteins can restrict human immunodeficiency virus type 1 infection at two distinct phases in the viral life cycle.
    J Virol. 2006 Apr;80(8):4061-7 PMID: 16571822
  59. APOBEC3G versus reverse transcriptase in the generation of HIV-1 drug-resistance mutations.
    AIDS. 2004 Sep 3;18(13):1861-3 PMID: 15316354
  60. The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities.
    Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10780-5 PMID: 15249687
  61. Generation of HIV-1 derivatives that productively infect macaque monkey lymphoid cells.
    Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16959-64 PMID: 17065315
  62. APOBEC-mediated viral restriction: not simply editing?
    Trends Biochem Sci. 2007 Mar;32(3):118-28 PMID: 17303427
  63. Isolation of an active Lv1 gene from cattle indicates that tripartite motif protein-mediated innate immunity to retroviral infection is widespread among mammals.
    J Virol. 2006 Aug;80(15):7332-8 PMID: 16840314
  64. The interferon response inhibits HIV particle production by induction of TRIM22.
    PLoS Pathog. 2008 Feb;4(2):e1000007 PMID: 18389079
  65. Vif is crucial for human immunodeficiency virus type 1 proviral DNA synthesis in infected cells.
    J Virol. 1993 Aug;67(8):4945-55 PMID: 8331734
  66. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins.
    EMBO J. 2004 Jun 16;23(12):2451-8 PMID: 15152192
  67. A novel fusion gene, TRIM5-Cyclophilin A in the pig-tailed macaque determines its susceptibility to HIV-1 infection.
    AIDS. 2007 Dec;21 Suppl 8:S19-26 PMID: 18172386
  68. Estimating the relative contribution of dNTP pool imbalance and APOBEC3G/3F editing to HIV evolution in vivo.
    J Comput Biol. 2007 Oct;14(8):1105-14 PMID: 17985990
  69. A conserved mechanism of retrovirus restriction in mammals.
    Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12295-9 PMID: 11027299
  70. TRIMCyp expression in Old World primates Macaca nemestrina and Macaca fascicularis.
    Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3569-74 PMID: 18287033
  71. Cytidine deamination of retroviral DNA by diverse APOBEC proteins.
    Curr Biol. 2004 Aug 10;14(15):1392-6 PMID: 15296758
  72. Comparative requirements for the restriction of retrovirus infection by TRIM5alpha and TRIMCyp.
    Virology. 2007 Dec 20;369(2):400-10 PMID: 17920096
  73. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.
    Nature. 2002 Aug 8;418(6898):646-50 PMID: 12167863
  74. The DNA deaminase activity of human APOBEC3G is required for Ty1, MusD, and human immunodeficiency virus type 1 restriction.
    J Virol. 2008 Mar;82(6):2652-60 PMID: 18184715
  75. The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif.
    Nat Med. 2003 Nov;9(11):1404-7 PMID: 14528300
  76. Highly attenuated vaccine strains of simian immunodeficiency virus protect against vaginal challenge: inverse relationship of degree of protection with level of attenuation.
    J Virol. 1999 Jun;73(6):4952-61 PMID: 10233957
  77. No effect of endogenous TRIM5alpha on HIV-1 production.
    Nat Med. 2008 Mar;14(3):235-6; author reply 236-8 PMID: 18323834
  78. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1.
    Nature. 2004 Jul 29;430(6999):569-73 PMID: 15243629
  79. TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.
    PLoS Pathog. 2008 Feb 8;4(2):e16 PMID: 18248090
Article Info
Journal
Trends in microbiology
Abbr.
Trends Microbiol
ISSN
0966-842X
DOI
10.1016/j.tim.2008.08.013
Published
2008-12-00
Epub
2008-00-29
Pages
612-9
Language
English
Region
England
NLM ID
9310916
PMCID
PMC3556578
Subset
IM
Grants
Wellcome Trust · 076608 · United Kingdom
Medical Research Council · G0801172 · United Kingdom
Medical Research Council · G0801172(87743) · United Kingdom
Medical Research Council · G9721629 · United Kingdom
External Links
PubMed source DOI: 10.1016/j.tim.2008.08.013 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2