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HIV (the large spherical object in red) under attack by the immune system. Small Y-shaped antibodies are binding to its surface. Illustration by David S. Goodsell, the Scripps Research Institute.

Investigator's Corner: Guido Silvestri

Matthew Wood

Posted on Apr 13th, 2018


Postdoctoral Fellow Matthew Wood sat down with Guido Silvestri, MD, from Emory University, after his lecture as part of the Global Infectious Disease Seminar series.

Guido Silvestri, MD, is the Georgia Research Alliance Eminent Scholar in Comparative Pathology and Professor and Vice Chair of Laboratory Medicine at Emory University. His prolific work on the relationship between the immune system and HIV and SIV viruses spans 25 years and has helped shape our understanding of how HIV infection results in chronic disease. He spoke at CID Research summarizing some of the recent research from his lab on natural hosts of Simian Immunodeficiency Virus (SIV). SIV are a group of related retroviruses that jumped from African monkeys (natural hosts) to chimpanzees and eventually humans about 100 years ago, leading to the global HIV pandemic. Interestingly, despite high viral loads in the natural hosts, these monkeys remain healthy and do not develop any AIDS-like illness, providing insights into why some primates (like us) get AIDS while others do not. He also discussed some of the work being done in his division defining what kind of cells in our body HIV is hiding in when a patient is taking antiretroviral therapy. Identifying and eliminating these cells which remain latently infected represents a major obstacle in the path to a cure for HIV.

After getting your MD, what led you down the path of research science rather than just focusing on clinical work?

I did both for a while. I was a practicing doctor for 20 years but it was never my main occupation. While I was doing research, my clinical work occupied about 20% of my time. I liked defining a problem when a patient came in and working to solve that problem for them. But then, there’s the management of a chronic problem, and the reality is that it becomes the majority of your work with patients. This can get heavy after a while, or at least it did for me. Science is never heavy because every experiment is something new.

What would you say is one of the most important things we’ve learned so far from studying the natural hosts of SIV (African monkeys that can be infected by a virus similar to HIV and, unlike humans and chimps, do not ever become sick)?

Well it’s really the fact that most infectious diseases are a result of failed adaptation between the host and the microorganism. I don’t even know what the word pathogen really means, because we think of a pathogen as something that causes disease. But it really isn’t in the organism’s interest to cause a disease. In fact, most of the interactions are geared toward not causing disease. Often, either you have the host getting rid of the organism, or you have it adapting to the host and not causing disease, like in the mangabeys (sooty mangabeys are a natural host of SIV). It get’s interesting when you have these failed adaptations. This is how you get diseases like HIV, tuberculosis, malaria, and hepatitis, which can go on for years. With tuberculosis, you can even get infected and never develop any symptoms. So, I think the natural hosts have really helped us learn about how HIV is really a failed coexistence between the virus and host.

Your presentation highlighted some research on HIV cure approaches. The foundation for AIDS research (AMFAR) has set a goal for an HIV cure by 2020. What do you think are some of the most promising cure strategies that are currently being pursued?

One major reason for optimism in my mind is that more than ever before we understand the mechanisms dictating latency and latency reversal. I think down the road we will need to use these immunological mechanisms. We’re talking about CD4 cells (immune cells which act as targets for HIV infection, including many types of T cells) and CD4 cell biology. So when you think about CD4 cells this is an incredibly heterogeneous population of cells. You got naïve, central memory, stem cell memory, tissue memory, and then you have all these flavors within these groups that we keep describing. It comes down to understanding which cells are the ones perpetrating latency and maintaining these viruses in their genome for years and years in the body. I think we need to solve this immunological problem. Not the problem of how the immune system finds infected cells and kills them, but the problem of how the function of different CD4 cells dictates how the virus can remain latent within them.

I think we make progress by taking the time to understand these specific mechanisms. When you think of when AIDS started and we figured out it was a virus, some of the most important progress came from developing antiretroviral drugs. What made a difference was identifying the essential enzymatic reactions of the virus: reverse transcriptase, protease, integrase. We purified these enzymes, developed systems to screen enzyme inhibitors, modified these inhibitors to make them orally available as drugs, and that’s what ended up saving millions of lives. There were no short cuts there and it took about 10 years. I think we’re getting there with a cure.

About the Author

Matthew Wood is a Postdoctoral Fellow in the Sodora Lab. Matthew has always been interested in the complex interplay between microorganisms and their host species. Matthew joined the Sodora Lab knowing that his background with HIV biology and immunology could help those afflicted by infectious diseases that prevent people from living the health lives they're entitled to.

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