Researchers at the University of Texas Southwestern Medical Center recently discovered the mechanisms by which a small protein produced by the human immunodeficiency virus (HIV) manipulates the host’s cellular machinery, interfering with gene expression and the immune system and eventually leading to AIDS. Such findings could contribute to the development of new therapeutic targets for HIV or the improvement of current ones.
The research article, “HIV Tat controls RNA Polymerase II and the epigenetic landscape to transcriptionally reprogram target immune cells,” was published in the online journal eLife.
HIV can be present in the organism without causing any symptoms for many years, eventually taking over the host’s cellular machinery in order to further its existence. This mechanism of evasion from the immune system response and the takeover of immune cells, eventually leads to the onset of AIDS and consequent susceptibility to opportunistic infections and specific cancers.
HIV encodes a small protein named Tat that is known to facilitate viral transcription and has been suggested to modulate the cellular gene expression; however, the target genes of Tat and its mechanism of action have never been fully understood and described.
Now, researchers investigated how this protein has such an important impact in the HIV ability to manipulate genes and the host cellular machinery in its own benefit, while also evading antiretroviral therapy. The team found that Tat binds to about 400 human genes and either activates or represses them in order to create the ideal environment for HIV. Moreover, it also inactivates the body’s immune system.
“We observed that HIV methodically and precisely manipulates the host’s genes and cellular machinery,” said the study’s lead author, Dr. Iván D’Orso, in a UT Southwestern news release. “We also observed that HIV rewires cellular defensive pathways to benefit survival of the virus. The human genes and pathways that Tat manipulates correlate well with symptoms observed in these patients, such as immune system hyperactivation, then weakening, and accelerated aging.”
Although a vaccine that targets the Tat protein has been deemed well-tolerated in a Phase 2 clinical trial at the National Institute of Health in Rome, D’Orso said it might take many years until it is proven that the vaccine works. However, this study’s results clearly suggest that blocking Tat activity may have therapeutic value for HIV treatment.