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PMID: 11119587 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The human immunodeficiency virus type 1 gag gene encodes an internal ribosome entry site.

Journal of virology ·Vol. 75 ·No. 1 ·2001-01-00 ·Pages 181-91

Buck CB, Shen X, Egan MA, Pierson TC, Walker CM, Siliciano RF

Abstract

Several retroviruses have recently been shown to promote translation of their gag gene products by internal ribosome entry. In this report, we show that mRNAs containing the human immunodeficiency virus type 1 (HIV-1) gag open reading frame (ORF) exhibit internal ribosome entry site (IRES) activity that can promote translational initiation of Pr55(gag). Remarkably, this IRES activity is driven by sequences within the gag ORF itself and is not dependent on the native gag 5'-untranslated region (UTR). This cap-independent mechanism for Pr55(gag) translation may help explain the high levels of translation of this protein in the face of major RNA structural barriers to scanning ribosomes found in the gag 5' UTR. The gag IRES activity described here also drives translation of a novel 40-kDa Gag isoform through translational initiation at an internal AUG codon found near the amino terminus of the Pr55(gag) capsid domain. Our findings suggest that this low-abundance Gag isoform may be important for wild-type replication of HIV-1 in cultured cells. The activities of the HIV-1 gag IRES may be an important feature of the HIV-1 life cycle and could serve as a novel target for antiretroviral therapeutic strategies.

MeSH Terms
5' Untranslated Regions Animals Blotting, Northern COS Cells Genes, gag HIV-1/genetics Open Reading Frames Protein Biosynthesis Ribosomes/physiology Virus Replication
Chemicals
5' Untranslated Regions
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Buck C B
Program in Cellular and Molecular Medicine, Cellular and Molecular Biology, Baltimore, Maryland 21205, USA.
Shen X
Egan M A
Pierson T C
Walker C M
Siliciano R F
References (90)
90 references, click to expand
  1. Selective translation initiation by ribosome jumping in adenovirus-infected and heat-shocked cells.
    Genes Dev. 1996 Jun 15;10(12):1557-67 PMID: 8666238
  2. The RU5 ('R') region from human leukaemia viruses (HTLV-1) contains an internal ribosome entry site (IRES)-like sequence.
    FEBS Lett. 1996 Sep 2;392(3):220-4 PMID: 8774848
  3. Targeting of HIV-1 antigens for rapid intracellular degradation enhances cytotoxic T lymphocyte (CTL) recognition and the induction of de novo CTL responses in vivo after immunization.
    J Exp Med. 1997 Mar 3;185(5):909-20 PMID: 9120397
  4. PDGF2/c-sis mRNA leader contains a differentiation-linked internal ribosomal entry site (D-IRES).
    J Biol Chem. 1997 Apr 4;272(14):9356-62 PMID: 9083072
  5. Inactivation of the human immunodeficiency virus type 1 inhibitory elements allows Rev-independent expression of Gag and Gag/protease and particle formation.
    J Virol. 1997 Jul;71(7):4892-903 PMID: 9188551
  6. Starting at the beginning, middle, and end: translation initiation in eukaryotes.
    Cell. 1997 Jun 13;89(6):831-8 PMID: 9200601
  7. Plant ribosome shunting in vitro.
    Nucleic Acids Res. 1997 Jul 15;25(14):2854-60 PMID: 9207035
  8. A viral sequence in the 3'-untranslated region mimics a 5' cap in facilitating translation of uncapped mRNA.
    EMBO J. 1997 Jul 1;16(13):4107-16 PMID: 9233819
  9. eIF4G: translation's mystery factor begins to yield its secrets.
    RNA. 1997 Oct;3(10):1085-104 PMID: 9326485
  10. Characterization of an internal ribosomal entry segment within the 5' leader of avian reticuloendotheliosis virus type A RNA and development of novel MLV-REV-based retroviral vectors.
    Hum Gene Ther. 1997 Nov 1;8(16):1855-65 PMID: 9382952
  11. Cell cycle regulation of hepatitis C virus internal ribosomal entry site-directed translation.
    Gastroenterology. 2000 Jan;118(1):152-62 PMID: 10611164
  12. Characterization of an internal ribosomal entry segment in the 5' leader of murine leukemia virus env RNA.
    J Virol. 2000 Jan;74(2):846-50 PMID: 10623747
  13. Internal-ribosome-entry-site functional activity of the 3'-untranslated region of the mRNA for the beta subunit of mitochondrial H+-ATP synthase.
    Biochem J. 2000 Mar 15;346 Pt 3:849-55 PMID: 10698716
  14. An internal ribosome entry segment promotes translation of the simian immunodeficiency virus genomic RNA.
    J Biol Chem. 2000 Apr 21;275(16):11899-906 PMID: 10766817
  15. Identification and characterization of a novel cell cycle-regulated internal ribosome entry site.
    Mol Cell. 2000 Apr;5(4):597-605 PMID: 10882096
  16. A cell cycle-dependent internal ribosome entry site.
    Mol Cell. 2000 Apr;5(4):607-16 PMID: 10882097
  17. Capping of eucaryotic mRNAs.
    Cell. 1976 Dec;9(4 PT 2):645-53 PMID: 1017010
  18. mRNA cap binding proteins: essential factors for initiating translation.
    Cell. 1985 Feb;40(2):223-4 PMID: 3967293
  19. Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes.
    Cell. 1986 Jan 31;44(2):283-92 PMID: 3943125
  20. Monoclonal antibody to the amino-terminal L sequence of murine leukemia virus glycosylated gag polyproteins demonstrates their unusual orientation in the cell membrane.
    J Virol. 1986 Feb;57(2):413-21 PMID: 2418213
  21. Bifunctional messenger RNAs in eukaryotes.
    Cell. 1986 Nov 21;47(4):481-3 PMID: 3779834
  22. Methionine or not methionine at the beginning of a protein.
    Bioessays. 1985 Jul;3(1):27-31 PMID: 3024631
  23. Involvement of the 24-kDa cap-binding protein in regulation of protein synthesis in mitosis.
    J Biol Chem. 1987 Aug 15;262(23):11134-9 PMID: 3038908
  24. Human monoclonal antibody directed against gag gene products of the human immunodeficiency virus.
    J Immunol. 1988 Feb 1;140(3):941-3 PMID: 2828474
  25. A segment of the 5' nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation.
    J Virol. 1988 Aug;62(8):2636-43 PMID: 2839690
  26. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA.
    Nature. 1988 Jul 28;334(6180):320-5 PMID: 2839775
  27. Alternative translation of the proto-oncogene c-myc by an internal ribosome entry site.
    J Biol Chem. 1997 Dec 19;272(51):32061-6 PMID: 9405401
  28. Translation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia.
    Mol Cell Biol. 1998 Jun;18(6):3112-9 PMID: 9584152
  29. A small yeast RNA blocks hepatitis C virus internal ribosome entry site (HCV IRES)-mediated translation and inhibits replication of a chimeric poliovirus under translational control of the HCV IRES element.
    J Virol. 1998 Jul;72(7):5638-47 PMID: 9621022
  30. HIV-1 auxiliary proteins: making connections in a dying cell.
    Cell. 1998 May 29;93(5):685-92 PMID: 9630214
  31. Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites.
    RNA. 1998 Dec;4(12):1500-13 PMID: 9848649
  32. Structure and function of a small RNA that selectively inhibits internal ribosome entry site-mediated translation.
    Nucleic Acids Res. 1999 Jan 15;27(2):562-72 PMID: 9862981
  33. Cleavage of Poly(A)-binding protein by coxsackievirus 2A protease in vitro and in vivo: another mechanism for host protein synthesis shutoff?
    J Virol. 1999 Jan;73(1):709-17 PMID: 9847377
  34. Cleavage of poly(A)-binding protein by enterovirus proteases concurrent with inhibition of translation in vitro.
    J Virol. 1999 Jan;73(1):718-27 PMID: 9847378
  35. Conserved features at the 5 end of Drosophila R2 retrotransposable elements: implications for transcription and translation.
    Insect Mol Biol. 1999 Feb;8(1):3-10 PMID: 9927169
  36. Identification of an internal ribosome entry segment in the 5' region of the mouse VL30 retrotransposon and its use in the development of retroviral vectors.
    J Virol. 1999 Oct;73(10):8393-402 PMID: 10482590
  37. Removal of cryptic poxvirus transcription termination signals from the human immunodeficiency virus type 1 envelope gene enhances expression and immunogenicity of a recombinant vaccinia virus.
    J Virol. 1990 May;64(5):2448-51 PMID: 2182912
  38. Cloning and functional analysis of multiply spliced mRNA species of human immunodeficiency virus type 1.
    J Virol. 1990 Jun;64(6):2519-29 PMID: 2335812
  39. The where, what and how of ribosomal frameshifting in retroviral protein synthesis.
    Trends Biochem Sci. 1990 May;15(5):186-90 PMID: 2193436
  40. A region of the 5' noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells: involvement with the role of L protease in translational control.
    J Virol. 1990 Nov;64(11):5389-95 PMID: 2170677
  41. Env and Vpu proteins of human immunodeficiency virus type 1 are produced from multiple bicistronic mRNAs.
    J Virol. 1990 Nov;64(11):5448-56 PMID: 2214021
  42. Direct evidence for translational regulation by leader RNA and Tat protein of human immunodeficiency virus type 1.
    Proc Natl Acad Sci U S A. 1990 Oct;87(19):7492-6 PMID: 2120701
  43. Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication.
    J Virol. 1991 Apr;65(4):1836-42 PMID: 2002544
  44. Expression of human immunodeficiency virus type 1 vif and vpr mRNAs is Rev-dependent and regulated by splicing.
    Virology. 1991 Aug;183(2):677-86 PMID: 1830183
  45. Internal initiation of translation mediated by the 5' leader of a cellular mRNA.
    Nature. 1991 Sep 5;353(6339):90-4 PMID: 1652694
  46. Mechanism of translation of monocistronic and multicistronic human immunodeficiency virus type 1 mRNAs.
    Mol Cell Biol. 1992 Jan;12(1):207-19 PMID: 1729599
  47. Internal ribosome entry site within hepatitis C virus RNA.
    J Virol. 1992 Mar;66(3):1476-83 PMID: 1310759
  48. Initiation of translation of human rhinovirus RNA: mapping the internal ribosome entry site.
    Virology. 1992 Jun;188(2):685-96 PMID: 1316679
  49. Translation of the rat LINE bicistronic RNAs in vitro involves ribosomal reinitiation instead of frameshifting.
    Mol Cell Biol. 1992 Sep;12(9):4242-8 PMID: 1380649
  50. Variable inhibition of cell-free translation by HIV-1 transcript leader sequences.
    Nucleic Acids Res. 1992 Aug 25;20(16):4291-7 PMID: 1354856
  51. Homeotic gene Antennapedia mRNA contains 5'-noncoding sequences that confer translational initiation by internal ribosome binding.
    Genes Dev. 1992 Sep;6(9):1643-53 PMID: 1355457
  52. Inhibition of HIV by an anti-HIV protease synthetic peptide blocks an early step of viral replication.
    Res Virol. 1992 Sep-Oct;143(5):311-9 PMID: 1480823
  53. Mutational analysis of the 5' non-coding region of human immunodeficiency virus type 1: effects of secondary structure on translation.
    EMBO J. 1988 Sep;7(9):2831-7 PMID: 3181141
  54. Effect of mutations and deletions in a bicistronic mRNA on the synthesis of influenza B virus NB and NA glycoproteins.
    J Virol. 1989 Jan;63(1):28-35 PMID: 2908923
  55. Activation of double-stranded RNA-dependent kinase (dsl) by the TAR region of HIV-1 mRNA: a novel translational control mechanism.
    Cell. 1989 Jan 27;56(2):303-12 PMID: 2536299
  56. The scanning model for translation: an update.
    J Cell Biol. 1989 Feb;108(2):229-41 PMID: 2645293
  57. Cotranslational processing and protein turnover in eukaryotic cells.
    Biochemistry. 1988 Oct 18;27(21):7979-84 PMID: 3069123
  58. CUG initiation codon used for the synthesis of a cell surface antigen coded by the murine leukemia virus.
    J Mol Biol. 1989 Jan 20;205(2):363-72 PMID: 2538626
  59. Initiation of protein synthesis by internal entry of ribosomes into the 5' nontranslated region of encephalomyocarditis virus RNA in vivo.
    J Virol. 1989 Apr;63(4):1651-60 PMID: 2538648
  60. Circumstances and mechanisms of inhibition of translation by secondary structure in eucaryotic mRNAs.
    Mol Cell Biol. 1989 Nov;9(11):5134-42 PMID: 2601712
  61. Cleavage of HIV-1 gag polyprotein synthesized in vitro: sequential cleavage by the viral protease.
    AIDS Res Hum Retroviruses. 1989 Dec;5(6):577-91 PMID: 2692658
  62. Selection of the 5'-proximal translation initiation site is influenced by mRNA and eIF-2 concentrations.
    Eur J Biochem. 1990 Jan 26;187(2):361-71 PMID: 2298214
  63. Identification of the hepatitis A virus internal ribosome entry site: in vivo and in vitro analysis of bicistronic RNAs containing the HAV 5' noncoding region.
    Virology. 1993 Apr;193(2):842-52 PMID: 8384758
  64. The 5' and 3' untranslated regions of satellite tobacco necrosis virus RNA affect translational efficiency and dependence on a 5' cap structure.
    J Biol Chem. 1993 May 5;268(13):9504-10 PMID: 8486640
  65. Does HIV-1 Tat induce a change in viral initiation rights?
    Cell. 1993 May 7;73(3):417-20 PMID: 8490957
  66. The 3' untranslated region of satellite tobacco necrosis virus RNA stimulates translation in vitro.
    Mol Cell Biol. 1993 Jun;13(6):3340-9 PMID: 8497255
  67. A heptanucleotide sequence mediates ribosomal frameshifting in mammalian cells.
    J Virol. 1993 Sep;67(9):5579-84 PMID: 8350413
  68. Sequences in the rev-responsive element responsible for premature translational arrest in the human-immunodeficiency-virus-type-1 envelope.
    Eur J Biochem. 1993 Sep 1;216(2):459-67 PMID: 8375384
  69. A novel hepatitis B virus (HBV) genetic element with Rev response element-like properties that is essential for expression of HBV gene products.
    Mol Cell Biol. 1993 Dec;13(12):7476-86 PMID: 8246965
  70. Translation of the human LINE-1 element, L1Hs.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11533-7 PMID: 8265584
  71. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.
    Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4096-100 PMID: 8171040
  72. A small yeast RNA selectively inhibits internal initiation of translation programmed by poliovirus RNA: specific interaction with cellular proteins that bind to the viral 5'-untranslated region.
    J Virol. 1994 Nov;68(11):7200-11 PMID: 7933102
  73. Cap-dependent and cap-independent translation by internal initiation of mRNAs in cell extracts prepared from Saccharomyces cerevisiae.
    Mol Cell Biol. 1994 Nov;14(11):7322-30 PMID: 7935446
  74. Alternative translation of human fibroblast growth factor 2 mRNA occurs by internal entry of ribosomes.
    Mol Cell Biol. 1995 Jan;15(1):35-44 PMID: 7799942
  75. Major histocompatibility class I molecules can present cryptic translation products to T-cells.
    J Biol Chem. 1995 Jan 20;270(3):1088-91 PMID: 7836364
  76. An internal ribosomal entry mechanism promotes translation of murine leukemia virus gag polyprotein precursors.
    J Virol. 1995 Apr;69(4):2214-22 PMID: 7884868
  77. Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs.
    Science. 1995 Apr 21;268(5209):415-7 PMID: 7536344
  78. An epitope-selective, transporter associated with antigen presentation (TAP)-1/2-independent pathway and a more general TAP-1/2-dependent antigen-processing pathway allow recognition of the HIV-1 envelope glycoprotein by CD8+ CTL.
    J Immunol. 1995 Jun 1;154(11):6140-56 PMID: 7538543
  79. Efficiency of reinitiation of translation on human immunodeficiency virus type 1 mRNAs is determined by the length of the upstream open reading frame and by intercistronic distance.
    J Virol. 1995 Jul;69(7):4086-94 PMID: 7769666
  80. Role of the hepatitis B virus posttranscriptional regulatory element in export of intronless transcripts.
    Mol Cell Biol. 1995 Jul;15(7):3864-9 PMID: 7791793
  81. Alternative translation initiation of the Moloney murine leukemia virus mRNA controlled by internal ribosome entry involving the p57/PTB splicing factor.
    J Biol Chem. 1995 Sep 1;270(35):20376-83 PMID: 7657611
  82. An internal ribosomal entry signal in the rat VL30 region of the Harvey murine sarcoma virus leader and its use in dicistronic retroviral vectors.
    J Virol. 1995 Oct;69(10):6400-7 PMID: 7666541
  83. Cap-independent translation and internal initiation of translation in eukaryotic cellular mRNA molecules.
    Curr Top Microbiol Immunol. 1995;203:155-77 PMID: 7555089
  84. Internal initiation of translation directed by the 5'-untranslated region of the mRNA for eIF4G, a factor involved in the picornavirus-induced switch from cap-dependent to internal initiation.
    J Biol Chem. 1996 Jan 12;271(2):623-6 PMID: 8557663
  85. The human immunodeficiency virus type 1 5' packaging signal structure affects translation but does not function as an internal ribosome entry site structure.
    J Virol. 1996 Feb;70(2):944-51 PMID: 8551634
  86. The human foamy virus pol gene is expressed as a Pro-Pol polyprotein and not as a Gag-Pol fusion protein.
    J Virol. 1996 Feb;70(2):1033-40 PMID: 8551561
  87. The human insulin-like growth factor II leader 1 contains an internal ribosomal entry site.
    Biochim Biophys Acta. 1995 Dec 27;1264(3):403-8 PMID: 8547330
  88. Internal initiation of translation in eukaryotes: the picornavirus paradigm and beyond.
    RNA. 1995 Dec;1(10):985-1000 PMID: 8595564
  89. Sequences within a small yeast RNA required for inhibition of internal initiation of translation: interaction with La and other cellular proteins influences its inhibitory activity.
    J Virol. 1996 Mar;70(3):1624-32 PMID: 8627683
  90. Stable MLV-VL30 dicistronic retroviral vectors with a VL30 or MoMLV sequence promoting both packaging of genomic RNA and expression of the 3' cistron.
    Hum Gene Ther. 1996 Mar 20;7(5):603-12 PMID: 8845385
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.75.1.181-191.2001
Published
2001-01-00
Pages
181-91
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC113911
Subset
IM
Grants
NIAID NIH HHS · AI28108 · United States
NIAID NIH HHS · AI37924 · United States
External Links
PubMed source DOI: 10.1128/JVI.75.1.181-191.2001 PMC Full Text View journal details
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