HIV infection

Ya-Chi Ho, MD, PhD, MMS, on Turning Off HIV-Driven Aberrant Transcription

In a continuing effort to better understand HIV infection, and ultimately find a cure, a research team led by Ya-Chi Ho, MD, PhD, MMS, have been conducting research on HIV-driven aberrant transcription. Their latest work was highlighted at the 10th Annual International AIDS Society Conference on HIV Science.1

Infectious Diseases Consultant caught up with Dr Ho after her session.

Dr Ho is an assistant professor of Microbial Pathogenesis and Medicine (Infectious Diseases) and an investigator in the HIV Reservoirs and Viral Eradication Transformative Science Group (Cure TSG) at Yale University School of Medicine in New Haven, Connecticut.

INFECTIOUS DISEASES CONSULTANT: Can you give us an overview of your session? How can HIV-driven aberrant transcription be turned off?

Ya-Chi Ho: In my session, I highlighted one of the neglected aspects of HIV treatment—that HIV continues to produce viral proteins that can induce chronic immune activation and immune exhaustion despite effective antiretroviral therapy (ART). This is because none of the ART can inhibit the HIV promoter, which drives viral protein production. Using single-cell RNA-Seq of blood samples from HIV-infected individuals and cell-line models, my research team and I demonstrated that the HIV promoter can drive cancer-related gene expression if the HIV provirus is integrated into certain cancer-related genes, inducing higher levels of cancer-related gene expression in these cells.2 This is called HIV-driven aberrant transcription.

We conducted a drug library screening and identified FDA-approved drugs that can inhibit HIV expression. We found that 3 FDA-approved drugs may inhibit HIV expression: spironolactone, mycophenalic acid (the active form of CellCept or mycophenolate mofetil), and a Janus kinase (JAK) inhibitor.

We showed in a cell line model that these drugs cannot only inhibit HIV viral expression but also inhibit HIV-driven aberrant host gene transcription. This study indicates that HIV expression can be targeted by FDA-approved drugs. The effect of these drugs on chronic immune activation and HIV integration site-related clonal expansion in the clinical setting remains to be examined.

ID CON: How might turning off HIV-driven aberrant transcription impact HIV status?

YCH: HIV suppressing agents, which inhibit HIV expression, can potentially reduce HIV-induced chronic immune activation and reduce HIV integration site-related clonal expansion. This means that an ideal drug may improve the health of people living with HIV (by reducing HIV-related aging, chronic immune activation, and related complications such as cardiovascular events). Further, reducing the expanding latent reservoir can contribute to HIV eradication.

If researchers can continue to find drugs that can lock HIV promoters into permanent silenced status, similar to how human endogenous retroviruses are silenced in humans, then a permanent silencing of HIV expression, ideally, can lead to a functional cure.

ID CON: What are the clinical implications of turning off HIV-driven aberrant transcription? How might this affect how HIV is managed?

YCH: This study indicates that some FDA-approved drugs—such as spironolactone, mycophenolic acid, and JAK inhibitors—can suppress HIV expression. This leads us to a new paradigm of HIV treatment. Instead of targeting viral proteins (such as reverse transcriptase, protease, and integrase), targeting HIV long terminal repeat (LTR) can interrupt not only HIV protein production but also chronic immune activation and potentially HIV-driven aberrant proliferation. While implementing this strategy into clinical settings remains to be examined, there are ongoing clinical trials exploring whether mycophenolic acid3 and JAK inhibitors4 may change HIV persistence. Further, some HIV-infected individuals are taking spironolactone as a part of the anti-androgen regimens. The impact of these HIV suppressing agents in the clinical setting should be explored.

ID CON: What else should HIV specialists know about turning off HIV-driven aberrant transcription?

YCH: HIV care providers may consider clinical observational studies or prospective clinical trials on the impact of HIV suppressing agents on chronic immune activation profiles, HIV expression, and the size of the latent reservoir.

ID CON: What is the key take-home message from your session?

YCH: ART does not kill HIV-infected cells and does not inhibit viral protein production in the infected cells. This is because the HIV promoter remains “on” and active, leading to stochastic reactivation, chronic immune activation, and HIV integration-site-related clonal expansion of the infected cells. Researchers found medications that can inhibit HIV expression in a laboratory setting. Further studies exploring the use of HIV-suppressing agents as a new therapeutic strategy to reduce immune activation and reduce the size of the latent reservoir should be encouraged.

Reference:

  1. Ho YC. Turning off HIV-driven aberrant transcription. Talk presented at: 10th Annual International AIDS Society Conference on HIV Science; July 21-24, 2019: Mexico City, Mexico. http://programme.ias2019.org/Programme/Session/13. 
  2. This manuscript is currently under review for publication.
  3. MMF for HIV Reservoir Reduction. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03262441. Accessed August 29, 2019. ClinicalTrials.gov identifier NCT03262441.
  4. Evaluating the Safety and Tolerability of Ruxolitinib in Antiretroviral-Treated HIV-Infected Adults. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02475655. Accessed August 29, 2019. ClinicalTrials.gov identifier NCT02475655.