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A lentiviral vector that activates latent human immunodeficiency virus-1 proviruses by the overexpression of tat and that kills the infected cells.
Hum Gene Ther. 2009 Nov; 20(11):1259-68.HG

Abstract

Despite the efficient HIV-1 replication blockage achieved with current highly active antiretroviral therapy (HAART) therapies, HIV-1 persists in the body and survives in a latent state that can last for the entire life of the patient. A long-lived reservoir of latently infected CD4(+) memory T cells represents the most important sanctuary for the virus and the greatest obstacle for viral eradication. In this work, we present an initial step toward a gene therapy approach aimed at the activation of latent provirus to induce the death of latently infected T cells. Latent HIV-1 infection is characterized by the failure of viral gene expression as a consequence of uninitiated or aborted transcription. We have constructed an HIV-1-based lentiviral vector (p5p53RTAT3) that expresses the viral trans-activating protein Tat in a drug-regulated manner and p53 in a Rev-dependent manner. We have demonstrated that the Tat-expressed protein from p5p53RTAT3 vector reactivates latent HIV-1 proviruses in J1.1 and ACH-2 cell lines and promotes p53-induced apoptosis in the presence of Rev. Our system was able to trigger the trans-activation of the provirus 5' long terminal repeat (LTR), stimulate the expression of the Rev protein from a tat-defective provirus, and provoke apoptosis selectively in the cells transfected with a tat-defective HIV-1 provirus in contrast to those with no HIV-1 provirus. However, the Rev-dependent p53 killing of latently infected cells was not effective enough for complete elimination of the awakened HIV-1 viruses. In summary, we have developed a vector system that is efficient in activating latent HIV-1 proviruses but that needs further improvement to kill infected cells.

Authors+Show Affiliations

Departamento de Biología Experimental, Universidad de Jaén, Jaén, Spain. d.f.onion@bham.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19604078

Citation

Macías, David, et al. "A Lentiviral Vector That Activates Latent Human Immunodeficiency Virus-1 Proviruses By the Overexpression of Tat and That Kills the Infected Cells." Human Gene Therapy, vol. 20, no. 11, 2009, pp. 1259-68.
Macías D, Oya R, Saniger L, et al. A lentiviral vector that activates latent human immunodeficiency virus-1 proviruses by the overexpression of tat and that kills the infected cells. Hum Gene Ther. 2009;20(11):1259-68.
Macías, D., Oya, R., Saniger, L., Martín, F., & Luque, F. (2009). A lentiviral vector that activates latent human immunodeficiency virus-1 proviruses by the overexpression of tat and that kills the infected cells. Human Gene Therapy, 20(11), 1259-68. https://doi.org/10.1089/hum.2009.059
Macías D, et al. A Lentiviral Vector That Activates Latent Human Immunodeficiency Virus-1 Proviruses By the Overexpression of Tat and That Kills the Infected Cells. Hum Gene Ther. 2009;20(11):1259-68. PubMed PMID: 19604078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A lentiviral vector that activates latent human immunodeficiency virus-1 proviruses by the overexpression of tat and that kills the infected cells. AU - Macías,David, AU - Oya,Ricardo, AU - Saniger,Luisa, AU - Martín,Francisco, AU - Luque,Francisco, PY - 2009/7/17/entrez PY - 2009/7/17/pubmed PY - 2010/9/24/medline SP - 1259 EP - 68 JF - Human gene therapy JO - Hum Gene Ther VL - 20 IS - 11 N2 - Despite the efficient HIV-1 replication blockage achieved with current highly active antiretroviral therapy (HAART) therapies, HIV-1 persists in the body and survives in a latent state that can last for the entire life of the patient. A long-lived reservoir of latently infected CD4(+) memory T cells represents the most important sanctuary for the virus and the greatest obstacle for viral eradication. In this work, we present an initial step toward a gene therapy approach aimed at the activation of latent provirus to induce the death of latently infected T cells. Latent HIV-1 infection is characterized by the failure of viral gene expression as a consequence of uninitiated or aborted transcription. We have constructed an HIV-1-based lentiviral vector (p5p53RTAT3) that expresses the viral trans-activating protein Tat in a drug-regulated manner and p53 in a Rev-dependent manner. We have demonstrated that the Tat-expressed protein from p5p53RTAT3 vector reactivates latent HIV-1 proviruses in J1.1 and ACH-2 cell lines and promotes p53-induced apoptosis in the presence of Rev. Our system was able to trigger the trans-activation of the provirus 5' long terminal repeat (LTR), stimulate the expression of the Rev protein from a tat-defective provirus, and provoke apoptosis selectively in the cells transfected with a tat-defective HIV-1 provirus in contrast to those with no HIV-1 provirus. However, the Rev-dependent p53 killing of latently infected cells was not effective enough for complete elimination of the awakened HIV-1 viruses. In summary, we have developed a vector system that is efficient in activating latent HIV-1 proviruses but that needs further improvement to kill infected cells. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/19604078/A_lentiviral_vector_that_activates_latent_human_immunodeficiency_virus_1_proviruses_by_the_overexpression_of_tat_and_that_kills_the_infected_cells_ L2 - https://www.liebertpub.com/doi/10.1089/hum.2009.059?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -