StpC-based gene therapy targeting latent reservoirs of HIV-1.
The ability of HIV-1 to form latent reservoirs presents a major obstacle to eradication. One approach to elimination of the latent reservoir is induction therapy, whereby cells harboring latent virus are activated and therefore initiate virus replication. We have constructed a lentiviral vector encoding Herpesvirus saimiri subgroup C saimiri transformation-associated protein (StpC), which has been shown to modulate HIV-1 replication, under the control of a cytomegalovirus promoter in order to determine the ability of StpC to upregulate latent HIV-1. We have included a suicide gene, herpes simplex virus thymidine kinase (TK), under the control of the HIV-1 long terminal repeat (LTR) promoter. We hypothesized that upon StpC expression in latently infected cells induction of virus replication and subsequent production of viral transactivators of the LTR will activate expression of the tk gene, sensitizing the cells to the nucleoside analogue ganciclovir (GCV). Transduction of the latently infected cell line J1.1 resulted in increased virus replication. In the presence of GCV transduced cells exhibited decreased HIV-1 replication, inhibition of cell proliferation, and increased apoptosis. This prototype vector serves as a proof of concept of the utility of gene-based induction agents and suicide genes as a new method for targeting reservoirs of latent HIV-1.
Turner
Lorianne Stehouwer
LS
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA. lsturner@temple.edu
Tsygankov
Alexander Y
AY
Henderson
Earl E
EE
D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011533:Proviruses / Q000235:genetics / Q000502:physiology*; D012367:RNA, Viral / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017735:Virus Latency / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
D019380:Anti-HIV Agents; D016655:HIV Core Protein p24; D010750:Phosphoproteins; D012367:RNA, Viral; D014764:Viral Proteins; C092384:tyrosine kinase interacting protein, Saimiriine herpesvirus 2; D013937:Thymidine Kinase; D015774:Ganciclovir