Using new gene delivery systems to advance HIV gene therapy

David S. Strayer, Harris Goldstein, Pierre Cordelier, Siddhartha Ghosh, Marlene S. Strayer, Massimo Pettoello-Mantovani, J. Roy Chowdhury

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Progress in gene therapy of human immunodeficiency virus (HIV) infection from laboratory to bedside, as for gene therapy in general, has been slow. Many transgenes, some very innovative, have been shown to inhibit HIV in cultured cells. But translation of such results to humans, or even to animal models of acquired immunodeficiency syndrome (AIDS), has been problematic. Among the reasons for this failure is ineffective gene delivery. Most gene delivery systems used for this purpose are limited by low production titers, fragility, poor transduction efficiency, waning transgene expression over time, requirements for ex vivo manipulation of target cells that constrain key aspects of these cells' utility on reimplantation, etc. These restrictions both prevent successful anti-HIV gene therapy and limit the scope of ideas as to how anti-HIV gene therapy may be used.Application of recombinant gene delivery vectors derived from simian virus-40 (rSV40s) may help to address many of these problems: They transduce all HIV-susceptible cell types (lymphocytes, monocytes, dendritic cells, neurons, microglia, etc.) and their progenitors (e.g., CD34+ cells) with >95% efficiency without selection, whether as cell lines or as primary cells, resting or dividing; Transgenes targeting almost every phase of the HIV-1 replicative cycle, from cell entry to virion morphogenesis have been delivered using these vectors. Individual transgenes vary in their abilities to inhibit HIV, but all do so. Strains of HIV-1 inhibited by rSV40 gene delivery include laboratory and clinical isolates, X4-, R5- and dual-tropic viruses, and neurotropic strains (including CD4-independent HIV-1). High transduction efficiency allows sequential transduction with multiple different rSV40s. Nearly all unselected cells treated with two different rSV40s are transduced by both. Combinations of transgenes provide far greater protection than any transgene individually. Vector deoxyribonucleic acids (DNAs) integrate rapidly into the cellular DNA, assuring permanent transduction. Transgene expression has not diminished with time. When severe combined immunodeficiency (SCID)-hu mice carrying implanted human tissues were transduced with a rSV40 vector in vivo, and then challenged with HIV in vivo, it provided the first demonstration that in vivo gene transfer with rSV40 vectors can inhibit HIV in vivo. These vectors are safe. Although this gene delivery system has limitations (transgenes must be smaller than 5 kb; some common nonvertebrate marker genes like green fluorescent protein are not expressed well), it has strong advantages for application to AIDS gene therapy. The development rSV40 vectors and their application to treating HIV infection may facilitate the translation of AIDS gene therapy from a laboratory curiosity to a therapeutic tool.

Original languageEnglish (US)
Pages (from-to)247-259
Number of pages13
JournalClinical and Applied Immunology Reviews
Volume3
Issue number4-5
DOIs
StatePublished - Jan 1 2003

Keywords

  • Gene therapy
  • SV40
  • Transduction
  • Vectors

ASJC Scopus subject areas

  • Microbiology
  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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