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Cancer Drug Can Reactivate HIV

Melanie Ott

SAN FRANCISCO, CA—August 24, 2017

People living with HIV must take a combination of three or more different drugs every day for the rest of their lives. Unfortunately, by following this strict treatment plan, they can suffer from side effects ranging from mild dizziness to life-threatening liver damage. However, if they stop taking the drugs, the virus hiding inside their cells can spontaneously resurface.

In fact, the latent HIV, which can hide in cells for many years, is a critical barrier to a cure. Researchers are exploring two main strategies to tackle this problem––reactivate and destroy the latent virus (called “shock and kill”) or find a way to silence it for good.

In an effort to tackle both strategies, a team of scientists at the Gladstone Institutes studies drugs that disrupt latency and could eventually be used to treat infected patients. They recently discovered how a new drug called JQ1, which is currently in early-phase human cancer trials, can reactivate latent HIV.

The Key Is the Short Form
“Our discovery was born out of frustration,” explained Gladstone Senior Investigator Melanie Ott, whose study was published today in the journal Molecular Cell. “We already knew that the drug JQ1 targets a protein called BRD4, but our experiments were not yielding consistent results. Then, we started looking at different forms of the protein and, unexpectedly, found that a short form was the key to silencing HIV.”

By identifying this new role for the short form of BRD4, Ott’s team could finally explain a mechanism that controls HIV latency. They showed that the drug JQ1 targets and removes the short form of BRD4, which then allows the virus to make copies of itself.

“Many people in the field don't even know that a short form of BRD4 exists,” said Ryan Conrad, a postdoctoral scholar in Ott’s lab and first author of the study. “While uncovering the role of this protein in HIV, we discovered that it may also be involved in fighting other viruses related to HIV. Therefore, our findings could provide new insights into an ‘old’ cellular defense mechanism against invading viruses.”

The study could also impact a broader range of diseases, given that the drug JQ1 is already being tested as a way to target the BRD4 protein to treat cancer, heart failure, and inflammation.

A Holistic Approach to Curing HIV
Many scientists concentrate on the “shock and kill” strategy as a way to cure HIV, but more and more of them are shifting their focus to silencing the virus. The mechanism discovered at Gladstone can support both strategies—manipulating the BRD4 protein either to help HIV resurface or to strengthen the body’s capacity to suppress it.

“Silencing and reactivating HIV are often seen as competing approaches, but I think they could actually be combined to develop more effective therapies in the future,” added Ott, who is also a professor in the Department of Medicine at the University of California, San Francisco (UCSF). “You could start by shocking and killing the virus that’s easy to target, then use silencing mechanisms to slow the resurfacing of latent virus.”

This strategy could potentially allow patients to stop taking drugs, and for several years to elapse before the virus reactivates. By that time, the immune system could be strong enough to eliminate the virus as it surfaces.

“That's how I see the future of HIV cure research,” said Ott.

Scientists may not completely eliminate HIV overnight, but Ott’s team is working to find a way to target the virus so people who are infected can stop continuously taking pills.

Publication: Conrad RJ, Fozouni P, Thomas S, Sy H, Zhang Q, Zhou MM, Ott M. The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI/SNF Chromatin-Remodeling Complexes. Mol Cell. 2017 Aug 17. pii: S1097-2765(17)30549-X. doi: 10.1016/j.molcel.2017.07.025.

Ott Elected to The American Academy of Microbiology

Melanie Ott

SAN FRANCISCO, CA—June 1, 2017

Gladstone Senior Investigator Melanie Ott, MD, PhD, was elected as a fellow of The American Academy of Microbiology (AAM). She was chosen based on her outstanding contributions to microbiology research and her dedicated service to science and the public.

The AAM is the honorific leadership group within the American Society for Microbiology, the world’s oldest and largest life science organization. AAM fellows are elected through a highly selective, peer-review process, based on their records of scientific achievement and original contributions that have advanced microbiology. Each elected fellow has built an exemplary career in basic and applied research, teaching, clinical and public health, and industry or government service. Over the last 50 years, 2,500 distinguished scientists have been elected to the AAM.

“I am honored to be recognized by this remarkable distinction and delighted to be elected to such a prestigious academy,” shared Ott, who is also a professor of medicine at the University of California, San Francisco (UCSF).

Ott’s research focuses on how viruses—HIV, the hepatitis C virus, and most recently, the Zika virus—hijack human cells to promote their own survival. Her work has contributed greatly to what researchers understand about these viruses, and it has inspired new research in each of these fields.

Ott received her MD from the University of Frankfurt/Main in Germany and her PhD from the Picower Graduate School in Manhasset, New York. She has received several honors and awards, including two Young Researcher Awards from the European Conference on Experimental AIDS Research and the Hellman Award from UCSF, which supports the research of promising assistant professors with the capacity for great distinction in their research. She also received the Chancellor’s Award for Public Service from UCSF, which recognized her work as co-founder of a committee at Gladstone that promotes science education in local schools, specifically targeting underserved youth.

The AAM will recognize Ott, along with the 2017 Fellowship class, during a ceremony and reception on June 2, 2017, at the American Society for Microbiology’s ASM Microbe meeting in New Orleans.

Using Viruses to Find the Cellular Achilles Heel

Melanie Ott

SAN FRANCISCO, CA—January 22, 2015­—A study from researchers at the Gladstone Institutes has exposed new battle tactics employed by the hepatitis C virus (HCV). Published in the January 22 issue of Molecular Cell, the investigators created full protein interaction maps—interactomes—of where the virus comes into contact with the host proteins during the course of infection. Through these protein interactions, the scientists not only gained insight into the virus, they also uncovered a common set of host proteins that are targeted by various infections. Their results suggest that these proteins and the cellular processes they govern are the most crucial—in effect, the collective Achilles heel—for both the human body and its viral invaders.

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Melanie Receives 2014 Avant-Garde Award for HIV/AIDS Research

Melanie Ott

Three scientists, including Gladstone's Melanie Ott, MD, PhD, have been chosen to receive the 2014 Avant-Garde Award for HIV/AIDS Research from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health. The three scientists will each receive $500,000 per year for five years to support their research.

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Navigating the Road from DNA to RNA—and Beyond

Melanie Ott

In the latest issue of Molecular Cell, researchers in the laboratory of Gladstone Investigator Melanie Ott, MD, PhD, describe the intriguing behavior of a protein called RNA polymerase II (RNAPII). The RNAPII protein is an enzyme, a catalyst that guides the transcription process by copying DNA into RNA, which forms a disposable blueprint for making proteins. Scientists have long known that RNAPII appears to stall or “pause” at specific genes early in transcription. But they were not sure as why.

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Gladstone Scientists Link Hepatitis C Virus Infection to Fat Enzyme in Liver Cells

Melanie Ott

SAN FRANCISCO, CA—October 10, 2010—Scientists at the Gladstone Institute of Virology and Immunology (GIVI) have found that an enzyme associated with the storage of fat in the liver is required for the infectious activity of the hepatitis C virus (HCV). This discovery may offer a new strategy for treating the infection.

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