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Gene therapy progress and prospects: Novel gene therapy approaches for AIDS

Gene Therapy volume 12, pages 467–476 (2005)Cite this article

Abstract

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), kills millions worldwide every year. Vaccines against HIV still seem a distant promise. Pharmaceutical treatments exist, but these are not always effective, and there is increasing prevalence of viral strains with multidrug resistance. Highly active antiretroviral therapy (HAART) consists of inhibitors of viral enzymes (reverse transcriptase (RT) and protease). Gene therapy, first introduced as intracellular immunization, may offer hopes for new treatments to be used alone, or in conjunction with, conventional small molecule drugs. Gene therapy approaches against HIV-1, including suicide genes, RNA-based technology, dominant negative viral proteins, intracellular antibodies, intrakines, and peptides, are the subject of this review.

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References

  1. Blesch A . Lentiviral and MLV based retroviral vectors for ex vivo and in vivo gene transfer. Methods 2004; 33: 164–172.

    CAS  PubMed  Google Scholar 

  2. Muhlebach MD et al. Transduction efficiency of MLV but not of HIV-1 vectors is pseudotype dependent on human primary T lymphocytes. J Mol Med 2003; 81: 801–810.

    PubMed  Google Scholar 

  3. An DS et al. Efficient lentiviral vectors for short hairpin RNA delivery into human cells. Hum Gene Ther 2003; 14: 1207–1212.

    CAS  PubMed  Google Scholar 

  4. Mautino MR, Morgan RA . Gene therapy of HIV-1 infection using lentiviral vectors expressing anti-HIV-1 genes. AIDS Patient Care STDS 2002; 16: 11–26.

    PubMed  Google Scholar 

  5. Trono D . Lentiviral vectors: turning a deadly foe into a therapeutic agent. Gene Therapy 2000; 7: 20–23.

    CAS  PubMed  Google Scholar 

  6. Connolly JB . Lentiviruses in gene therapy clinical research. Gene Therapy 2002; 9: 1730–1734.

    CAS  PubMed  Google Scholar 

  7. Duprâe L et al. Lentiviral vector-mediated gene transfer in T cells from Wiskott–Aldrich syndrome patients leads to functional correction. Mol Ther: J Am Soci Gene Therapy 2004; 10: 903–915.

    Google Scholar 

  8. Kurre P et al. Efficient marking of murine long-term repopulating stem cells targeting unseparated marrow cells at low lentiviral vector particle concentration. Mol Ther: J Am Soci Gene Therapy 2004; 9: 914–922.

    CAS  Google Scholar 

  9. Miyoshi H . Subteam for Manipulation of Cell Fate, Gene delivery to hematopoietic stem cells using lentiviral vectors. Meth Mol Biol (Clifton, N.J.) 2004; 246: 429–438.

    CAS  Google Scholar 

  10. Stitz J et al. A novel lentivirus vector derived from apathogenic simian immunodeficiency virus. Virology 2001; 291: 191–197.

    CAS  PubMed  Google Scholar 

  11. Curran MA et al. Efficient transduction of pancreatic islets by feline immunodeficiency virus vectors1. Transplantation 2002; 74: 299–306.

    CAS  PubMed  Google Scholar 

  12. Poeschla EM . Non-primate lentiviral vectors. Curr Opin Mol Ther 2003; 5: 529–540.

    CAS  PubMed  Google Scholar 

  13. Saenz DT, Poeschla EM . FIV: from lentivirus to lentivector. J Gene Med 2004; 6 (Suppl 1): S95–S104.

    CAS  PubMed  Google Scholar 

  14. Luis Abad J et al. Novel interfering bifunctional molecules against the CCR5 coreceptor are efficient inhibitors of HIV-1 infection. Mol Ther 2003; 8: 475–484.

    PubMed  Google Scholar 

  15. Venkatesan S et al. Reduced cell surface expression of CCR5 in CCR5Delta 32 heterozygotes is mediated by gene dosage, rather than by receptor sequestration. J Biol Chem 2002; 277: 2287–2301.

    CAS  PubMed  Google Scholar 

  16. Yang S, Sun Y, Zhang H . The multimerization of human immunodeficiency virus type I Vif protein: a requirement for Vif function in the viral life cycle. J Biol Chem 2001; 276: 4889–4893.

    CAS  PubMed  Google Scholar 

  17. Yang B et al. Potent suppression of viral infectivity by the peptides that inhibit multimerization of human immunodeficiency virus type 1 (HIV-1) Vif proteins. J Biol Chem 2003; 278: 6596–6602.

    CAS  PubMed  Google Scholar 

  18. Hrimech M et al. Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. EMBO J 2002; 21: 3918.

    CAS  PubMed  Google Scholar 

  19. Elder RT et al. HIV-1 VPR modulates cell cycle G2/M transition through an alternative cellular mechanism other than the classic mitotic checkpoints. Front Biosci: J Virtual Library 2002; 7: d349–d357.

    CAS  Google Scholar 

  20. Sawaya BE et al. Transdominant activity of human immunodeficiency virus type 1 Vpr with a mutation at residue R73. J Virol 2000; 74: 4877–4881.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yung E et al. Inhibition of HIV-1 virion production by a transdominant mutant of integrase interactor 1. Nat Med 2001; 7: 920–926.

    CAS  PubMed  Google Scholar 

  22. Cordelier P, Zern MA, Strayer DS . HIV-1 proprotein processing as a target for gene therapy. Gene Therapy 2003; 10: 467–477.

    CAS  PubMed  Google Scholar 

  23. Cordelier P et al. Inhibiting AIDS in the central nervous system: gene delivery to protect neurons from HIV. Molecular Ther: J Am Soci Gene Therapy 2003; 7: 801–810.

    CAS  Google Scholar 

  24. Goncalves J et al. Functional neutralization of HIV-1 Vif protein by intracellular immunization inhibits reverse transcription and viral replication. J Biol Chem 2002; 277: 32036–32045.

    CAS  PubMed  Google Scholar 

  25. Tewari D, Notkins AL, Zhou P . Inhibition of HIV-1 replication in primary human T cells transduced with an intracellular anti-HIV-1 p17 antibody gene. J Gene Med 2003; 5: 182–189.

    CAS  PubMed  Google Scholar 

  26. Herschhorn A, Admon A, Hizi A . Recombinant human antibodies against the reverse transcriptase of human immunodeficiency virus type-1. Biochim Biophys Acta 2003; 1648: 154–163.

    CAS  PubMed  Google Scholar 

  27. BouHamdan M et al. Inhibition of HIV-1 infection by down-regulation of the CXCR4 co-receptor using an intracellular single chain variable fragment against CXCR4. Gene Therapy 2001; 8: 408–418.

    CAS  PubMed  Google Scholar 

  28. Bai J et al. Inhibition of Tat-mediated transactivation and HIV-1 replication by human anti-hCyclinT1 intrabodies. J Biol Chem 2003; 278: 1433–1442.

    CAS  PubMed  Google Scholar 

  29. Reynolds L et al. Repression of the HIV-1 5′ LTR promoter and inhibition of HIV-1 replication by using engineered zinc-finger transcription factors. Proc Natl Acad Sci USA 2003; 100: 1615–1620.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Segal DJ et al. Attenuation of HIV-1 replication in primary human cells with a designed zinc finger transcription factor. J Biol Chem 2004; 279: 14509–14519.

    CAS  PubMed  Google Scholar 

  31. Takada N et al. RelA-associated inhibitor blocks transcription of human immunodeficiency virus type 1 by inhibiting NF-kappaB and Sp1 actions. J Virol 2002; 76: 8019–8030.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Michienzi A et al. RNA-mediated inhibition of HIV in a gene therapy setting. Ann NY Acad Sci 2003; 1002: 63–71.

    CAS  PubMed  Google Scholar 

  33. Puerta-Fernandez E, Barroso-DelJesus A, Berzal-Herranz A . Anchoring hairpin ribozymes to long target RNAs by loop-loop RNA interactions. Antisense Nucleic Acid Drug Dev 2002; 12: 1–9.

    CAS  PubMed  Google Scholar 

  34. Puerta-Fernandez E et al. HIV-1 TAR as anchoring site for optimized catalytic RNAs. Biol Chem 2003; 384: 343–350.

    CAS  PubMed  Google Scholar 

  35. Ramezani A et al. Development and testing of retroviral vectors expressing multimeric hammerhead ribozymes targeted against all major clades of HIV-1. Front Biosci 2002; 7: a29–a36.

    CAS  PubMed  Google Scholar 

  36. Jacque JM, Triques K, Stevenson M . Modulation of HIV-1 replication by RNA interference. Nature 2002; 418: 435–438.

    CAS  PubMed  Google Scholar 

  37. Paul CP et al. Localized expression of small RNA inhibitors in human cells. Mol Ther: J Am Soci Gene Therapy 2003; 7: 237–247.

    CAS  Google Scholar 

  38. Lee NS et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 2002; 20: 500–505.

    CAS  PubMed  Google Scholar 

  39. Coburn GA, Cullen BR . Potent and specific inhibition of human immunodeficiency virus type 1 replication by RNA interference. J Virol 2002; 76: 9225–9231.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Boden D et al. Human immunodeficiency virus type 1 escape from RNA interference. J Virol 2003; 77: 11531–11535.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Das AT et al. Human immunodeficiency virus type 1 escapes from RNA interference-mediated inhibition. J Virol 2004; 78: 2601–2605.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Chiu YL et al. Inhibition of human immunodeficiency virus type 1 replication by RNA interference directed against human transcription elongation factor P-TEFb (CDK9/CyclinT1). J Virol 2004; 78: 2517–2529.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cen S et al. Incorporation of lysyl-tRNA synthetase into human immunodeficiency virus type 1. J Virol 2001; 75: 5043–5048.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Guo F et al. Specific inhibition of the synthesis of human lysyl-tRNA synthetase results in decreases in tRNA(Lys) incorporation, tRNA(3)(Lys) annealing to viral RNA, and viral infectivity in human immunodeficiency virus type 1. J Virol 2003; 77: 9817–9822.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Anderson J et al. Potent suppression of HIV type 1 infection by a short hairpin anti-CXCR4 siRNA. AIDS Res Hum Retroviruses 2003; 19: 699–706.

    CAS  PubMed  Google Scholar 

  46. Park WS et al. Specific HIV-1 env gene silencing by small interfering RNAs in human peripheral blood mononuclear cells. Gene Therapy 2003; 10: 2046–2050.

    CAS  PubMed  Google Scholar 

  47. Lee MT et al. Inhibition of human immunodeficiency virus type 1 replication in primary macrophages by using Tat- or CCR5-specific small interfering RNAs expressed from a lentivirus vector. J Virol 2003; 77: 11964–11972.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Li MJ et al. Inhibition of HIV-1 infection by lentiviral vectors expressing Pol III-promoted anti-HIV RNAs. Mol Ther: J Am Soci Gene Therapy 2003; 8: 196–206.

    CAS  Google Scholar 

  49. Akkina R et al. siRNAs, ribozymes and RNA decoys in modeling stem cell-based gene therapy for HIV/AIDS. Anticancer Res 2003; 23: 1997–2005.

    CAS  PubMed  Google Scholar 

  50. Eckert DM, Kim PS . Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem 2001; 70: 777–810.

    CAS  PubMed  Google Scholar 

  51. Carr A . Toxicity of antiretroviral therapy and implications for drug development. Nature reviews. Drug Discov 2003; 2: 624–634.

    CAS  Google Scholar 

  52. Baldwin CE, Sanders RW, Berkhout B . Inhibiting HIV-1 entry with fusion inhibitors. Curr Med Chem 2003; 10: 1633–1642.

    CAS  PubMed  Google Scholar 

  53. Hildinger M et al. Membrane-anchored peptide inhibits human immunodeficiency virus entry. J Virol 2001; 75: 3038–3042.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Egelhofer M et al. Inhibition of human immunodeficiency virus type 1 entry in cells expressing gp41-derived peptides. J Virol 2004; 78: 568–575.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Baldwin CE et al. Emergence of a drug-dependent human immunodeficiency virus type 1 variant during therapy with the T20 fusion inhibitor. J Virol 2004; 78: 12428–12437.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mergia A et al. The efficiency of simian foamy virus vector type-1 (SFV-1) in nondividing cells and in human PBLs. Virology 2001; 280: 243–252.

    CAS  PubMed  Google Scholar 

  57. Garrus JE et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 2001; 107: 55–65.

    CAS  PubMed  Google Scholar 

  58. Perez OD, Nolan GP . Resistance is futile: assimilation of cellular machinery by HIV-1. Immunity 2001; 15: 687–690.

    CAS  PubMed  Google Scholar 

  59. Demirov DG et al. Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc Natl Acad Sci USA 2002; 99: 955–960.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Martin-Serrano J, Zang T, Bieniasz PD . Role of ESCRT-I in retroviral budding. J Virol 2003; 77: 4794–4804.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. von Schwedler UK et al. The protein network of HIV budding. Cell 2003; 114: 701–713.

    CAS  PubMed  Google Scholar 

  62. Strack B et al. AIP1/ALIX is a binding partner for HIV-1 p6 and EIAV p9 functioning in virus budding. Cell 2003; 114: 689–699.

    CAS  PubMed  Google Scholar 

  63. Ono A, Freed EO . Cell-type-dependent targeting of human immunodeficiency virus type 1 assembly to the plasma membrane and the multivesicular body. J Virol 2004; 78: 1552–1563.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Chakraborti S, Banerjea AC . Inhibition of HIV-1 gene expression by novel DNA enzymes targeted to cleave HIV-1 TAR RNA: potential effectiveness against all HIV-1 isolates. Mol Ther 2003; 7: 817–826.

    CAS  PubMed  Google Scholar 

  65. Joshi PJ, Fisher TS, Prasad VR . Anti-HIV inhibitors based on nucleic acids: emergence of aptamers as potent antivirals. Curr Drug Targets Infect Disord 2003; 3: 383–400.

    CAS  PubMed  Google Scholar 

  66. Xu X et al. Dominant effector genetics in mammalian cells. Nat Genet 2001; 27: 23–29.

    CAS  PubMed  Google Scholar 

  67. Wolkowicz R, Nolan GP . Retroviral technology—applications for expressed peptide libraries. Front Biosci 2003; 8: d603–d619.

    CAS  PubMed  Google Scholar 

  68. De Clercq E, Schols D . Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. Antivir Chem Chemother 2001; 12 (Suppl 1): 19–31.

    CAS  PubMed  Google Scholar 

  69. Ruff MR et al. Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors. Curr HIV Res 2003; 1: 51–67.

    CAS  PubMed  Google Scholar 

  70. Baraz L et al. Human immunodeficiency virus type 1 Vif binds the viral protease by interaction with its N-terminal region. J Gen Virol 2002; 83 (Part 9): 2225–2230.

    CAS  PubMed  Google Scholar 

  71. Hutoran M et al. Abrogation of Vif function by peptide derived from the N-terminal region of the human immunodeficiency virus type 1 (HIV-1) protease. Virology 2004; 5: 261–270.

    Google Scholar 

  72. Stremlau M et al. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 2004; 427: 848–853.

    CAS  PubMed  Google Scholar 

  73. Goff SP . HIV: replication trimmed back. Nature 2004; 427: 791–793.

    CAS  PubMed  Google Scholar 

  74. Sheehy AM, Gaddis NC, Malim MH . The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med 2003; 9: 1404–1407.

    CAS  PubMed  Google Scholar 

  75. Mangeat B et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 2003; 424: 99–103.

    CAS  PubMed  Google Scholar 

  76. Mariani R et al. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 2003; 114: 21–31.

    CAS  PubMed  Google Scholar 

  77. Stopak K et al. HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stability. Mol Cell 2003; 12: 591–601.

    CAS  PubMed  Google Scholar 

  78. Marin M et al. HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nat Med 2003; 9: 1398–1403.

    CAS  PubMed  Google Scholar 

  79. Liu B et al. Influence of primate lentiviral Vif and proteasome inhibitors on human immunodeficiency virus type 1 virion packaging of APOBEC3G. J Virol 2004; 78: 2072–2081.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Gabus C et al. The prion protein has DNA strand transfer properties similar to retroviral nucleocapsid protein. J Mol Biol 2001; 307: 1011–1021.

    CAS  PubMed  Google Scholar 

  81. Leblanc P, Baas D, Darlix JL . Analysis of the interactions between HIV-1 and the cellular prion protein in a human cell line. J Mol Biol 2004; 337: 1035–1051.

    CAS  PubMed  Google Scholar 

  82. Ganesh L et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Nature 2003; 426: 853–857.

    CAS  PubMed  Google Scholar 

  83. Greene WC . How resting T cells deMURR HIV infection. Nat Immunol 2004; 5: 18–19.

    CAS  PubMed  Google Scholar 

  84. Iordanskiy S et al. Heat shock protein 70 protects cells from cell cycle arrest and apoptosis induced by human immunodeficiency virus type 1 viral protein R. J Virol 2004; 78: 9697–9704.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Iordanskiy S et al. Heat–shock protein 70 exerts opposing effects on Vpr-dependent and Vpr-independent HIV-1 replication in macrophages. Blood 2004; 104: 1867–1872.

    CAS  PubMed  Google Scholar 

  86. DeVico AL, Gallo RC . Control of HIV-1 infection by soluble factors of the immune response. Nat Rev Microbiol 2004; 2: 401–413.

    CAS  PubMed  Google Scholar 

  87. Zhang L et al. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 2002; 298: 995–1000.

    CAS  PubMed  Google Scholar 

  88. Zhang L et al. Retraction of an interpretation. Science 2004; 303: 467.

    CAS  PubMed  Google Scholar 

  89. Chang TL et al. CAF-mediated human immunodeficiency virus (HIV) type 1 transcriptional inhibition is distinct from alpha-defensin-1 HIV inhibition. J Virol 2003; 77: 6777–6784.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Mackewicz CE, Craik CS, Levy JA . The CD8+ cell noncytotoxic anti-HIV response can be blocked by protease inhibitors. Proc Natl Acad Sci USA 2003; 100: 3433–3438.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rugeles MT et al. Ribonuclease is partly responsible for the HIV-1 inhibitory effect activated by HLA alloantigen recognition. AIDS 2003; 17: 481–486.

    CAS  PubMed  Google Scholar 

  92. Weiss RA . HIV and AIDS: looking ahead. Nat Med 2003; 9: 887–891.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Weiss RA . HIV and AIDS in relation to other pandemics. Among the viruses plaguing humans, HIV is a recent acquisition. Its outstanding success as an infection poses immense scientific challenges to human health and raises the question ‘What comes nest?’. EMBO Rep 2003; 4 (Spec No): S10–S14.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Global situation of the HIV/AIDS pandemic, end 2003. Part II: Estimating ARV global treatment needs (2003–2005). Wkly Epidemiol Rec 2003; 78: 426–430.

  95. UNAIDS report for 2003: most deaths and new infections ever; some good news. AIDS Treat News 2003; 396.

  96. Zarocostas J . WHO puts HIV/AIDS pandemic at top of its agenda. Lancet 2004; 363: 1615.

    PubMed  Google Scholar 

  97. Poluri A, Maanen MV, Sutton RE . Genetic therapy for HIV/AIDS. Expert Opin Biol Ther 2003; 3: 951–963.

    CAS  PubMed  Google Scholar 

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  1. Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA

    R Wolkowicz & G P Nolan

  2. Baxter Laboratory of Genetic Pharmacology, School of Medicine, Stanford University, Stanford, CA, USA

    R Wolkowicz & G P Nolan

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Wolkowicz, R., Nolan, G. Gene therapy progress and prospects: Novel gene therapy approaches for AIDS. Gene Ther 12, 467–476 (2005). https://doi.org/10.1038/sj.gt.3302488

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