David Margolis knows viruses. He has spent his career working to eradicate the human immunodeficiency virus (HIV), which causes AIDS. The Sarah Graham Kenan Professor of Medicine, Microbiology and Immunology, and Epidemiology at the UNC School of Medicine, Margolis directs the HIV Cure Center at Carolina, where he and his team pioneered research into one of the most difficult problems in HIV research — how to get the virus out of latency so it can be eliminated and people can be truly cured.
Just this past spring, Carolina inked a second five-year, $20 million deal with the pharmaceutical company ViiV Healthcare Limited — enabling the HIV Cure Center to continue its groundbreaking research. But then a new virus disrupted that work: the global COVID-19 pandemic
Margolis had to temporarily shutter his HIV lab when the University transitioned to remote operations in March. Because the level of containment needed to study the highly contagious coronavirus is much higher than for HIV, he couldn’t pivot directly to COVID-19 research. Instead, he is using his skills as an infectious diseases clinician to assist with treatment trials.
The Well spoke with Margolis about SARS-CoV-2, the virus that causes the disease COVID-19, and the hope for treatment and a vaccine.
The Well: What are some differences between the human immunodefiency virus, or HIV, and the novel coronavirus?
Margolis: HIV becomes a part of the genetic code of a cell it infects. Coronavirus doesn’t do that. HIV is slowly progressive, but it almost always progresses in almost everyone it infects. With COVID-19, it’s flipped the other way around. It progresses quickly, but almost everyone is going to control it and eventually be better. In general, people do a very good job of becoming immune and recovering from coronavirus. The percentage of people that actually die is relatively small compared to HIV — a couple of percentage points. There will be some people who have underlying conditions that cause them to get very sick and die. And there are some people — it’s probably genetically based — who have this inflammatory reaction to the infection that damages their organ systems and they don’t recover. The problem is that when hundreds of millions of people are infected across the world, a couple of percentage points of that is a lot of people.
The Well: What explains that difference? Is it something about the mechanics of the coronavirus, how it interacts with human cells?
Margolis: This coronavirus interacts with human biological systems in a lot of different ways that we don’t understand. We understand that it enters the cell in part by binding to a specific receptor called ACE2, but it also sticks to the cell using other molecules. And so even that part of the life cycle is pretty complicated. There’s a lot of person-to-person difference in how people handle the virus infection. And you hear these stories of these unusual presentations, of people getting red toes or children getting this inflammatory illness that looks like what’s called Kawasaki disease in pediatrics. To be clear, that’s the minority of children. But why this person? Why this child? There’s a lot we don’t really understand yet.
The Well: Is that something that happened with HIV? Does it present differently in different people?
Margolis: Well, certainly HIV progresses at different speeds in different people, although it generally progresses. And in rare cases some people get very immunodeficient and get very sick within months of being infected. Usually it is a couple of years for that process to play out. So I think both diseases have sort of a typical classical presentation with some spectrum. But, again, we’ve only seen coronavirus for a few months, so maybe it’s not surprising to discover these unusual manifestations when you have millions of people infected, and it’s a brand new thing.
The Well: There is still no vaccine for HIV after all these decades. Why is there optimism that scientists will be able to develop a vaccine for coronavirus?
Margolis: I guess the first point is that most people control and eventually, we think, eliminate coronavirus from their systems. No one with HIV does. There are probably people who are exposed to coronavirus without getting infected or without getting systemically sick. There’s probably coronavirus replication in the nose of some people or the respiratory tract of some people, and their immune systems fight off the virus, and they don’t present with symptoms. And then they show up antibody-positive later. They’ve been exposed. So there are a lot of reasons to think that because there’s a pretty good immune response in the first place that a little bit of boosting of that would protect a lot more people.
It does seem that making an antibody to the spike protein on the outside of the envelope can be protective. The spike engages a part of the protein on the surface of human cells. That is part of the entry process of the virus binding to and entering the cell. So antibodies to that part of the spike seem to be protective. If that works for humans, you will have to make a vaccine that makes you generate a level of antibody that hangs around for long enough at an effective level to be really protective. Just like with every other vaccine that we have, including the flu vaccine.
There’s the concern that we make an antibody today, and the virus changes a little bit and we need a different vaccine. But there are two reasons to be hopeful that won’t happen. One is that in just a few months, the virus has spread across the entire world. Think about it: It started in one little place somewhere back in December or January and already it’s across the entire planet. Looking at all those viruses from a lot of different places, there are some genetic changes, but not very many. And so hopefully the virus won’t evade a vaccine, at least not very quickly. The other thing is that a lot of the new vaccine technologies that are all being rolled out to make a vaccine at “warp speed” are very amenable to being reengineered quickly. Just as we make different influenza vaccines every year with the new technologies, we could probably do that much more quickly.
The Well: There is no HIV vaccine, but HIV treatment has come a long way. What about a treatment for coronavirus?
Margolis: So the difference in coronavirus is we have a good immune response, but we don’t have very good drugs to stop coronavirus growing in you once it gets there. In HIV, we have very good drugs to stop it growing in you once it gets there. But we don’t have a vaccine to prevent your infection that works very well. We are always treating HIV-infected people that have had established infection in our work. We’re looking to eradicate established infection.
HIV therapy is now very well established. Therapy generally involves taking two or three drugs at the same time, often now in one pill once a day. It’s a combination therapy. Those small-molecule drugs all are designed to inhibit different stages of the HIV replication cycle that allow it to copy itself once it gets into a cell or copy itself as it’s going out of the cell. There are therapies that block the entry of HIV into a cell, but for various reasons they’re not used very much now. The simplest, most effective therapies all block parts of the life cycle either once the HIV has gotten in and is trying to copy itself or as it’s on the way out, trying to copy itself to make more viruses. So if you’re on those drugs, even if HIV gets into your system, it can’t copy itself. And it doesn’t establish infection. In HIV, what’s used most now for prevention are the drugs that stop its growth.
Maybe someday if we develop good enough, safe enough, effective enough coronavirus drugs, we could use those kind of drugs, too. But right now, we have perhaps one drug, remdesivir, that reduces the virus replication. It is somewhat effective but not hugely so as a single drug.
The Well: Is there any reason for optimism?
Margolis: The whole scientific and medical community has responded much more effectively and quickly to this new virus. Unfortunately, the public health preventions were not in place the way they should have been. That’s a different story. But the scientific and medical community are able to respond for two major reasons. One is the knowledge about virology and vaccine development and assay systems. Compared to 30 years ago, when HIV started, the science is light years ahead. Many of the technologies and techniques that were developed for HIV have been used for hepatitis C therapy and for other viral diseases and are now being turned to coronavirus. The other difference is the speed of information — all of these things basically published on the internet before they’re even reviewed scientifically. It’s a blessing and a curse. There’s just a flood of information. And while it’s a little difficult to deal with, it’s ultimately helpful. We have the ability to have the virus discovered in China and, weeks later, the sequence of the virus is being looked at by scientists all over the world.
I would say making an HIV vaccine is still looking like a very difficult thing to do, whereas I think there’s a lot more optimism for a coronavirus vaccine in the next year or so.
One of Margolis’ colleagues, Luther Bartelt, assistant professor in the UNC School of Medicine, and others in Infectious Diseases, Microbiology & Immunology and the Gillings School of Global Public Health have partnered with UNC Hospitals and the UNC Blood Donation Center to collect plasma from people who have tested positive and recovered from COVID-19. They’re using the plasma as a COVID-19 therapy in a study led by Dr. Bartelt. “The antibodies are like a sponge that would soak up and neutralize the virus to impede its ability to replicate,” Bartelt told a reporter in May. He also added that “once the plasma is collected, it can be frozen and used for up to a year.”
Read about whether you qualify and how to donate plasma.