Editor's Note: At the AIDS 2024 conference, Dr. Melanie Ott from the University of California, San Francisco, delivered a special report titled "The Sound of Silence: Tackling HIV Transcription to Achieve Remission," which garnered widespread attention. Following the conference, Infectious Diseases Frontier conducted an in-depth interview with Dr. Ott, where she elaborated on the significance of HIV transcription mechanisms in regulating viral reservoirs, which play a crucial role in the rebound of the virus after treatment interruption. Professor Ott highlighted that a novel strategy involving the use of transcription inhibitors in combination with existing antiretroviral therapy (ART) could potentially suppress transcriptional activity in reservoir cells, thereby delaying viral rebound and reducing immune activation, bringing new hope and breakthroughs to the field of HIV treatment.1. Infectious Diseases Frontier: You have proposed a strategy to achieve disease remission by intervening in HIV transcription. How did this idea come about, and what is its current standing in the field of HIV research?
Dr. Ott: Over the past two decades, we have been dedicated to exploring the mechanisms of HIV transcription and their potential applications in HIV treatment strategies. The HIV reservoir, a group of infected cells that persist in the body despite antiretroviral therapy, is crucial for regulating HIV relapse. Based on recent and long-term research findings, we now understand that the HIV reservoir is not completely transcriptionally silent, as was previously thought, but exhibits some level of transcriptional activity. This transcriptional activity is believed to be a key factor in the rebound of the virus after treatment interruption and is also the source of persistent immune activation, even under ART. Therefore, we are convinced that transcriptional therapy is an important aspect that urgently needs to be integrated into current ART regimens. Incorporating transcription inhibitors into ART regimens holds promise for effectively suppressing transcriptional activity in reservoir cells, potentially delaying viral rebound and alleviating immune activation.
2. Infectious Diseases Frontier: What key findings in your research support the feasibility of achieving disease remission by regulating HIV transcription? What significance do these findings have for the development of new HIV treatments?
Dr. Ott: The concept of transcription inhibitors is not entirely new; it was actively researched even before ART was established as an effective HIV treatment. However, with the advent and widespread use of ART, research on transcription inhibitors stalled. Fortunately, my colleague, Professor Susana Valente at the Scripps Research Institute in Florida, revived the study of Tat inhibitors (which target the HIV-specific transcription activator) about 12 years ago. This move essentially reignited exploration in the field of HIV-specific transcription inhibitors. Susana’s research revealed the significant potential of Tat inhibitors; they can effectively enhance the latency or transcriptionally inactive state of HIV reservoir cells, even in the absence of ART, thereby suppressing HIV transcription activity.
3. Infectious Diseases Frontier: What technical challenges do you face in achieving precise regulation of HIV transcription? How has your team overcome these challenges to advance your research?
Dr. Ott: The main challenge we face is that HIV can integrate into the human genome and cleverly mimic the behavior of normal genes. HIV exploits the human transcriptional machinery to regulate its own transcription and replication processes. However, there is a key difference between HIV-integrated genes and natural human genes: the HIV-specific transcription activator, Tat. Tat is a protein encoded by the virus that uniquely binds to the RNA structure of HIV and recruits a series of cofactors to initiate transcription. Therefore, we see Tat as a highly promising therapeutic target, and we believe that research targeting Tat could provide us with a new opportunity to combat HIV. By delving into the biological functions of Tat, we can develop highly specific inhibitors targeting HIV that do not interfere with normal human genes.
4. Infectious Diseases Frontier: How do you think the effectiveness of achieving disease remission through HIV transcription intervention can be effectively evaluated in clinical trials? What indicators or methods will be prioritized?
Dr. Ott: This is a rather straightforward approach because we can directly quantify the transcriptional activity of the virus in the reservoir, which could become an important measure of success in clinical trials. Additionally, we will closely monitor levels of chronic immune activation and inflammatory markers, which are generally higher in HIV-infected individuals compared to HIV-negative individuals. Therefore, I propose combining HIV-specific assays, such as HIV RNA quantification, with assessments of inflammatory markers to comprehensively evaluate the effectiveness and success of our treatment strategy.
5. Infectious Diseases Frontier: For future HIV treatment strategies, how do you think the method of regulating HIV transcription will integrate with other treatment methods (such as ART, immunotherapy, etc.) to achieve better treatment outcomes?
Dr. Ott: We have high hopes for Tat inhibitors as a strategy directly targeting the HIV-specific transcription mechanism. We are committed to developing these drugs and look forward to combining them with current ART regimens, especially in the early stages of HIV infection. Our goal is to validate in the future that combining Tat inhibitors with ART not only enhances the therapeutic effect of ART but also effectively delays viral rebound after treatment interruption, and potentially achieves the breakthrough of preventing viral rebound altogether.
