Antiviral potency of drug-gene therapy combinations against human immunodeficiency virus type 1.
Gene therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infection using intracellular immunization strategies is currently being tested in clinical trials. With the continuing development of potent antiretroviral drugs (e.g., reverse transcriptase [RT] and protease [PR] inhibitors), it is likely that HIV-1 gene therapy will be applied to humans concurrently receiving such antiretroviral medication. In this study, we assessed the in vitro antiviral efficacy of two gene therapy strategies (trans-dominant RevM10, Gag antisense RNA) in combination with clinically relevant RT (AZT, ddC) or PR (indinavir) inhibitors. Retrovirally transduced, human T cell lines expressing antiviral gene constructs were inoculated with high doses of HIV-1HXB3 in the presence or absence of inhibitors. The combination of RevM10 or Gag antisense RNA with antiviral drugs inhibited HIV-1 replication 10-fold more effectively than the single antiviral drug regimen alone. More importantly, we also addressed whether gene therapy strategies are effective against drug-resistant HIV-1 isolates. Both the RevM10 and Gag antisense RNA strategies showed antiviral efficacy against several RT inhibitor-resistant HIV-1 isolates equivalent to their inhibition of HIV-1HXB3 replication. In summary, our data demonstrate the greater than additive antiviral efficacy of gene therapy strategies and RT or PR inhibitors, and that gene therapy approaches are effective against drug-resistant HIV-1 viral isolates.
Junker
U
U
Progenesys Program, Systemix Inc., Palo Alto, California 94304, USA. ujunker@stem.com
Baker
J
J
Kalfoglou
C S
CS
Veres
G
G
Kaneshima
H
H
Böhnlein
E
E
D000163:Acquired Immunodeficiency Syndrome / Q000628:therapy*; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002460:Cell Line; D003131:Combined Modality Therapy; D004274:DNA, Recombinant; D004305:Dose-Response Relationship, Drug; D015683:Gene Products, gag / Q000235:genetics / Q000502:physiology; D015694:Gene Products, rev / Q000235:genetics / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D016679:Genome, Viral; D016655:HIV Core Protein p24 / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D016372:RNA, Antisense / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology; D016047:Zalcitabine / Q000008:administration & dosage / Q000627:therapeutic use; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use; D054321:rev Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D004274:DNA, Recombinant; D015683:Gene Products, gag; D015694:Gene Products, rev; D016655:HIV Core Protein p24; D016372:RNA, Antisense; D054321:rev Gene Products, Human Immunodeficiency Virus; D015215:Zidovudine; D019469:Indinavir; D016047:Zalcitabine