Shaping the Future of AIDS Research

Melanie Ott, MD, PhD, is Director of the Gladstone Institute of Virology and Senior Vice President of the Gladstone Institutes, and a professor of medicine at University of California, San Francisco. Arriving at Gladstone in 2002, Dr. Ott’s work has focused on HIV and hepatitis C and expanded into other viruses such as Zika, influenza, and SARS-CoV-2. She has focused much of her work on HIV transcription and identifying new molecular targets for treatments and cure, new diagnostics, and the potential for pan-viral therapeutics. She is a recipient of NIH MERIT and DP1 Avantgarde Awards, an elected member of the Association of American Physicians, and a Fellow of the American Academy of Microbiology.

Looking at the field of HIV research today, where do you see the greatest unmet needs?

Maybe the greatest unmet needs have shifted a little bit in the last few weeks. I think we have a very robust HIV research program here in the US. It has always been exemplary for the rest of the world. There was a lot of emphasis on sticking with it until the end—until the cure. And I think this is still a very important aspect. We both know that we are still missing a vaccine, which would make a huge difference in the world. But we also still have people worldwide that are under antiretroviral therapy, which have been miracle drugs but not quite the answer for everything. We are seeing comorbidities arising early and in people under antiretroviral therapy, and I think we have to tackle this.

I would say we also cannot ignore the global South and withdraw our support there. I think we have been an example to the world, helping to get Africa under treatment with the PEPFAR program. And if it were to fall away, it would not only cause Africa and African people great problems, but also us because the virus will be basically allowed to run free, evolve and develop. And we have all seen this with COVID and all the variants that are constantly arising—if you let a virus go free somewhere, more dangerous viruses are going to come out of it.

How do you see the intersection of HIV research with other infectious diseases?

This is a very important question and very close to my heart. For example, HIV is a chronic disease. It’s a virus that integrates into our genome and that is not going away. It causes issues over time. And now we have COVID, for example, which is a disease that gets cleared, but still we have a lot of people with long COVID who have very similar symptoms sometimes or underlying immune dysfunctions that we have seen in HIV, for example.

So, there are broad lessons we can learn that apply to every viral disease. But there are also very specialized lessons we can learn from HIV. And I would say that HIV has been really paving the way for antivirals to become a pillar of treatment for viruses. It was thought that viruses are mainly countered with vaccination, but now we know that antivirals play a huge role because they have been instrumental in HIV. Other examples are the use of broadly neutralizing antibodies, also largely pioneered in HIV, and now also deployed and generated for many other dangerous viruses.

I would also add T cell biology. When we study how HIV behaves in a host cell, which is typically a T cell, we also learn something about the biology and immunology of those T cells, which has huge implications in other fields of research—cancer and autoimmune diseases, to mention just a couple.

Well, CAR T cells were originally developed for HIV and now they’re a huge pillar in cancer therapy. It just shows that a robust and long-term research investment in one virus not only benefits the study of that one virus but also benefits other virus research, emerging viruses, and other fields of biology and medicine.

I know that your lab has started doing a bit of work on artificial intelligence. How do you envision the role of AI, precision medicine, and other emerging technologies in accelerating the field of HIV research?

I fully embrace them. We have probably the fastest acceleration of knowledge because we have the
ability to generate huge amounts of data. The gene sequencing revolution over the last few years has taken us from sequencing one genome for $3 billion to sequencing many genomes for about $300 per genome. So, we are sitting on an enormous amount of valuable data and information that we need technologies like AI to take full advantage of and translate into tangible therapies or information for vaccines or other things.

We have a whole data science institute here at Gladstone that is leading here in that area. So there is definitely a lot of movement. We also started very early on to reach out to our technology partners in Silicon Valley and we have a close collaboration with Google in different areas. All of this is important for us to maximize what we can do with data and biology in order to make a difference for people who are affected by diseases.

Having supported and worked with amfAR as a reviewer for many years, how would you characterize the work that amfAR has done in HIV research?

Well, absolutely critical. I think your willingness to take risks is a very important thing because as we all know, the grants that we get from NIH [National Institutes of Health] are usually grants that are very certain and low risk, where basically everything is already done. That is good because it gives you some stability, but at the same time I think we need amfAR to help fund these early projects and to take risks that might not pay off, but there might be a very high reward. And I’ve always admired amfAR for their focus on young people, on emerging talent, because this is absolutely critical for research on HIV and other diseases to thrive.

You’re a leader in the field and have been a researcher for many years. What keeps you motivated?

I think what keeps me absolutely excited, especially at the current time, are the possibilities that are out there, because of the acceleration … the technologies that we are now applying, the way we can now characterize, for example, the reservoir of cells that remain in people despite antiretroviral treatment that tells us so much about what needs to be done in order to get this under control. I am very interested in transcription—the generation of new virus RNA, really an engine in the virus that constantly churns out new messages that translate into new proteins and new viruses. And that process has kept me busy for the last 30 years.

Currently I’m particularly excited because we know that transcription might be a critical way to manipulate the virus into giving up, basically. And I’m excited by the fact that we know now that the virus is not really truly dormant in peo­ple. That explains a lot of the comorbidities and the inflammation that is ongoing in people, but I think we have unique opportunities to interfere with that continuous activity. And that might make a real difference for people. So, I’m very excited by taking 30 years of basic biology and applying it to a new aspect of treatment that in combination with existing treatments could make a tangible difference.

One final question: If you could make one bold prediction about HIV research by the end of 2025, what would that be?

I would not be surprised if in the next one to two years we will see really innovative new additions to current treatments. And that can go in many different directions, such as immunology. There’s a lot of research ongoing on broadly neutralizing antibodies. I would say that cure research on the molecular level is very exciting. And we also have gene therapy, which we have not talked about—the people who have been cured and the road­map that has been laid out for us, which is very much precision, individualized, personalized medicine, and probably not affordable for a large amount of people. I think we are much more open to gene therapy approaches, which were a bit like science fiction until recently. CRISPR [genetic scis­sors] has definitely changed the level of acceptance of gene therapy and increased its precision.

I think we have so much in the pipeline due to sustainable funding and to organizations like amfAR taking risks and betting on new ideas. There are a lot of options on the table and we will potentially have to combine different approaches to make them really effective.

Click Here to read more from the May 2025 issue of amfAR INNOVATIONS.

---