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. 1994 May 24;91(11):5075–5079. doi: 10.1073/pnas.91.11.5075

Potent inhibition of human immunodeficiency virus type 1 replication by an intracellular anti-Rev single-chain antibody.

L Duan 1, O Bagasra 1, M A Laughlin 1, J W Oakes 1, R J Pomerantz 1
PMCID: PMC43934  PMID: 8197188

Abstract

Human immunodeficiency virus type 1 (HIV-1) has a complex life cycle, which has made it a difficult target for conventional therapeutic modalities. A single-chain antibody moiety, directed against the HIV-1 regulatory protein Rev, which rescues unspliced viral RNA from the nucleus of infected cells, has now been developed. This anti-Rev single-chain construct (SFv) consists of both light and heavy chain variable regions of anti-Rev monoclonal antibody, which, when expressed intracellularly within human cells, potently inhibits HIV-1 replication. This intracellular SFv molecule is demonstrated to specifically antagonize Rev function. Thus, intracellular SFv expression, against a retroviral regulatory protein, may be useful as a gene therapeutic approach to combat HIV-1 infections.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bagasra O., Wright S. D., Seshamma T., Oakes J. W., Pomerantz R. J. CD14 is involved in control of human immunodeficiency virus type 1 expression in latently infected cells by lipopolysaccharide. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6285–6289. doi: 10.1073/pnas.89.14.6285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Baltimore D. Gene therapy. Intracellular immunization. Nature. 1988 Sep 29;335(6189):395–396. doi: 10.1038/335395a0. [DOI] [PubMed] [Google Scholar]
  3. Biocca S., Neuberger M. S., Cattaneo A. Expression and targeting of intracellular antibodies in mammalian cells. EMBO J. 1990 Jan;9(1):101–108. doi: 10.1002/j.1460-2075.1990.tb08085.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Caruso M., Klatzmann D. Selective killing of CD4+ cells harboring a human immunodeficiency virus-inducible suicide gene prevents viral spread in an infected cell population. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):182–186. doi: 10.1073/pnas.89.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cochrane A. W., Perkins A., Rosen C. A. Identification of sequences important in the nucleolar localization of human immunodeficiency virus Rev: relevance of nucleolar localization to function. J Virol. 1990 Feb;64(2):881–885. doi: 10.1128/jvi.64.2.881-885.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cullen B. R. Mechanism of action of regulatory proteins encoded by complex retroviruses. Microbiol Rev. 1992 Sep;56(3):375–394. doi: 10.1128/mr.56.3.375-394.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fankhauser C., Izaurralde E., Adachi Y., Wingfield P., Laemmli U. K. Specific complex of human immunodeficiency virus type 1 rev and nucleolar B23 proteins: dissociation by the Rev response element. Mol Cell Biol. 1991 May;11(5):2567–2575. doi: 10.1128/mcb.11.5.2567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gibbs J. B. Ras C-terminal processing enzymes--new drug targets? Cell. 1991 Apr 5;65(1):1–4. doi: 10.1016/0092-8674(91)90352-y. [DOI] [PubMed] [Google Scholar]
  9. Lisziewicz J., Sun D., Klotman M., Agrawal S., Zamecnik P., Gallo R. Specific inhibition of human immunodeficiency virus type 1 replication by antisense oligonucleotides: an in vitro model for treatment. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11209–11213. doi: 10.1073/pnas.89.23.11209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Malim M. H., Böhnlein S., Hauber J., Cullen B. R. Functional dissection of the HIV-1 Rev trans-activator--derivation of a trans-dominant repressor of Rev function. Cell. 1989 Jul 14;58(1):205–214. doi: 10.1016/0092-8674(89)90416-9. [DOI] [PubMed] [Google Scholar]
  11. Malim M. H., Freimuth W. W., Liu J., Boyle T. J., Lyerly H. K., Cullen B. R., Nabel G. J. Stable expression of transdominant Rev protein in human T cells inhibits human immunodeficiency virus replication. J Exp Med. 1992 Oct 1;176(4):1197–1201. doi: 10.1084/jem.176.4.1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Malim M. H., Hauber J., Fenrick R., Cullen B. R. Immunodeficiency virus rev trans-activator modulates the expression of the viral regulatory genes. Nature. 1988 Sep 8;335(6186):181–183. doi: 10.1038/335181a0. [DOI] [PubMed] [Google Scholar]
  13. Marasco W. A., Haseltine W. A., Chen S. Y. Design, intracellular expression, and activity of a human anti-human immunodeficiency virus type 1 gp120 single-chain antibody. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7889–7893. doi: 10.1073/pnas.90.16.7889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ojwang J. O., Hampel A., Looney D. J., Wong-Staal F., Rappaport J. Inhibition of human immunodeficiency virus type 1 expression by a hairpin ribozyme. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10802–10806. doi: 10.1073/pnas.89.22.10802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pomerantz R. J., Seshamma T., Trono D. Efficient replication of human immunodeficiency virus type 1 requires a threshold level of Rev: potential implications for latency. J Virol. 1992 Mar;66(3):1809–1813. doi: 10.1128/jvi.66.3.1809-1813.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Pomerantz R. J., Trono D., Feinberg M. B., Baltimore D. Cells nonproductively infected with HIV-1 exhibit an aberrant pattern of viral RNA expression: a molecular model for latency. Cell. 1990 Jun 29;61(7):1271–1276. doi: 10.1016/0092-8674(90)90691-7. [DOI] [PubMed] [Google Scholar]
  17. Richman D. D., Guatelli J. C., Grimes J., Tsiatis A., Gingeras T. Detection of mutations associated with zidovudine resistance in human immunodeficiency virus by use of the polymerase chain reaction. J Infect Dis. 1991 Dec;164(6):1075–1081. doi: 10.1093/infdis/164.6.1075. [DOI] [PubMed] [Google Scholar]
  18. Sullenger B. A., Gallardo H. F., Ungers G. E., Gilboa E. Overexpression of TAR sequences renders cells resistant to human immunodeficiency virus replication. Cell. 1990 Nov 2;63(3):601–608. doi: 10.1016/0092-8674(90)90455-n. [DOI] [PubMed] [Google Scholar]
  19. Winter G., Milstein C. Man-made antibodies. Nature. 1991 Jan 24;349(6307):293–299. doi: 10.1038/349293a0. [DOI] [PubMed] [Google Scholar]

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