title: The viral protein Tat can inhibit the establishment of HIV-1 latency.
abstract: The establishment of HIV-1 latency can result from limiting levels of transcription initiation or elongation factors, restrictive chromatin modifications, transcriptional interference, and insufficient Tat activity. Since the viral protein Tat can counteract many of these factors, we hypothesized that the presence of exogenous Tat during infection might inhibit the establishment of latency. This was explored using a Jurkat model of latency establishment and reactivation. PCR and reverse transcriptase PCR (RT-PCR) confirmed the latent state in this model and showed evidence of transcriptional interference. To address our hypothesis, cells undergoing infection were first exposed to either purified recombinant Tat or a transactivation-negative mutant. Only the former resulted in a modest inhibition of the establishment of latency. Next, Jurkat cells stably expressing intracellular Tat were used in our latency model to avoid limitations of Tat delivery. Experiments confirmed that intracellular Tat expression did not affect the susceptibility of these cells to viral infection. Eight weeks after infection, Jurkat cells expressing Tat harbored up to 1,700-fold fewer (P < 0.01) latent viruses than Jurkat cells that did not express Tat. Additionally, Tat delivered by a second virus was sufficient to reactivate most of the latent population. Our results suggest that inhibition of the establishment of latent infection is theoretically possible. In a hypothetical scenario of therapy that induces viral gene expression during acute infection, activation of viruses which would otherwise have entered latency could occur while concurrent highly active antiretroviral therapy (HAART) would prevent further viral spread, potentially decreasing the size of the established latent reservoir.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montréal, Quebec, Canada. mark.wainberg@mcgill.ca
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Donahue
authors.forename: Björn D
authors.initials: BD
authors.lastname: Kuhl
authors.forename: Richard D
authors.initials: RD
authors.lastname: Sloan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D017735:Virus Latency; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus