“Getting to know the people with long COVID and be a part of their journey with this terrible condition is very special to me, and I think that’s true of many people working in this field.” Dr. Peluso

An infectious disease specialist, Michael Peluso MD helped create and run the LIINC long-COVID project at UCSF.

Dr. Michael Peluso, MD, is an infectious disease clinician and researcher, as well as the director and one of the co-creators of the large Long Term Impact of Infection with Novel Coronavirus (LIINC) project at UCSF.

In a recent Zoom interview, I talked with him about his work in long COVID and his thoughts on ME/CFS.

The Mighty LIINC Project

Health Rising has hailed UCSF’s LIINC project many times. With more than 1,000 participants, over 20,000 biospecimens collected, and a team of more than 60 researchers and staff, LIINC has evolved into a central hub in the long-COVID research community.

I’ve always been intrigued by how LIINC got started. It turned out that the UCSF researchers who started LIINC mostly hailed from the HIV world, and this has made a huge difference. Their presence is emblematic of how the emergence of long COVID has brought a new cadre of sophisticated researchers into the post-viral illness field. They were trying to find a way to wipe out HIV completely – not deal with a post-viral illness such as we know it – yet they very quickly glommed onto long COVID.

LIINC has become a central hub for long-COVID studies and clinical trials.

When I see creations like LIINC, I always ask myself: why don’t we have 5 or ten LIINCs? Why did LIINC happen at UCSF and not, say, at Stanford, or Harvard, or wherever? I still don’t know. Very early in the pandemic, though, as soon they realized that COVID-19 was soon going to be everywhere, Peluso said he and his mentors Stephen Deeks and Timothy Henrich met together by Zoom and created what would become LIINC.

LIINC grew beyond their wildest imaginations over time – yet, in retrospect, the fact that it grew so large was not surprising. This is the scale on which these researchers, many of whom have been embedded in the HIV research field, are used to operating. They also clearly enjoyed good institutional support.

The University of California at San Francisco (UCSF) approved what they were doing In the fastest IRB process Peluso’s ever seen, and they opened their doors in April, 2020 – just three months after the first case of long COVID. First the focus was on acute COVID, but within a couple of weeks, cases of long COVID began popping up. Peluso wasn’t involved in post-viral research and knew little about ME/CFS at the time, but the prospect wasn’t entirely new to him as he’d had trouble with an Epstein-Barr virus reactivation a decade or so earlier.

From the beginning, UCSF was ahead of the game regarding long COVID, and in June 2020, convened probably the first grand rounds presentation in the country on long COVID to doctors, pharmacists, residents, and medical students.

By the end of 2020, LIINC was focused almost entirely on long COVID. As long COVID evolved and came back again and again, so did the program, extending its standard followup from 4 months to 2 years and indefinitely, for those willing to be followed.

A Special Sense of Collaboration

Five years-plus into long COVID, I asked Dr Peluso if anything had surprised him. First, the introduction of a new virus into an “immunologically naïve” world – i.e., a world that had never experienced anything like it and therefore was not protected from it – was in itself a shocking experience.

Usually, when outbreaks occur, they’re sporadic and localized, which means they’re studied retroactively. The SARS-CoV-2 virus, on the other hand, not only impacted people worldwide but also continued to resurface. The downside of this is that so many people died or got ill and remain ill, but the upside is the ability to study the virus and what it’s doing in real time.

Peluso was heartened by the unusual sense of collaboration he’d found in the long-COVID field.

The other surprise was heartening. When I asked what was exciting him the most about the field, I thought Peluso would give me a technical answer such as the progress we’re making with viral persistence, but no – it was the level of collaboration and feeling of team that stood out for him.

“I think what’s most exciting to me, you know… just how sustained it’s been and a ‘huge collaborative spirit’ that doesn’t always pervade scientific endeavors. Peluso talked about “how much it feels like we’re all on the same team” and said that’s very special. “That’s not a given in science, academics, and life. We feel like we’re in the trenches together”.

He’s impressed by how invested the researchers are, stating there’s “an army of people now – clinicians and scientists and researchers and advocates and people with lived experience who are willing to grapple” with these complex and difficult diseases.

While he acknowledged that progress seems slow to people with these diseases, “in the scheme of science, it’s going at a pace that’s exciting. You know… it feels like every day when I open my email, I will see something new.”

Noting that most people in the field had never met each other before, Peluso called the 2023 Keystone International Symposium “galvanizing” and looked forward to its match this year, “Long COVID and Other Post-Acute Infection Syndromes” in New Mexico from Aug 10th-13th. (The conference was organized by Akiko Iwasaki, Avindra Nath, Hannah Davis, and Daniel M. Altmann. Peluso is the keynote speaker.)

Not that things are proceeding as quickly as we would want. Peluso emphasized that if long COVID were easy to solve, it would have been solved by now. People who aren’t committed to the long term shouldn’t be in this field.

(Long COVID appears to be far more complex than HIV/AIDS, which was effectively “solved”; i.e., treated not long after the technology had evolved enough to be able to capture the virus. The problem is not that long COVID or ME/CFS is going to be harder to treat than HIV/AIDS – at the moment, they are just harder to understand. They could be relatively easier or harder to treat once we understand what’s going on.

Peluso noted that the “s” in AIDS refers to a “syndrome”; i.e. at one point, HIV/AIDS was considered a collection of symptoms that occur together but do not have a clear cause or clear treatment regimen – just as long COVID and ME/CFS are now.)

Long COVID and ME/CFS are complex diseases, but Peluso believes the researchers still in the field know that – and are in it for the long game.

Pelsuo felt that the people who are still in the field are “really in it” and have a view to the “long game”, and that extends to diseases like ME/CFS. He said, “We’re all thinking about how we can apply what we’ve learned to ME/CFS”, post-Lyme syndrome, post-Ebola syndrome, etc.

Peluso learned a great deal about ME/CFS during a work he penned with Maureen Hanson. He agreed that there had been too little investment in ME/CFS and understood the ME/CFS patient community’s angst about the historical neglect shown to the field.

He also noted that so many of the technologies available today didn’t exist when ME/CFS showed up on the research radar in the 80s and 90s. Stating there could be differences upstream and convergences downstream (which create the similar symptoms) in the post-viral diseases, he believes it’s essential to study them side by side and that he’s seeing more interest in doing that.

Treatment

On the clinical side, Peluso described the multiple Paxlovid trials that attempted to treat long COVID by eradicating the virus using an antiviral, which was a longshot attempt but also a stage the field had to go through. The negative findings (which have yet to be fully assessed) had a silver lining – the long-COVID field weathered the disappointment, adjusted, and moved forward. He stated:

“You know there was a real possibility that you know the 1st few of these trials would report out and would have negative results, and then people would sort of throw up their hands and walk away. But that’s not at all been what’s happened right? What instead happened is that the 1st round of negative trials has opened the door to a much broader swath of future clinical trials… informed by what happened in the 1st round.”

Of course, the elephant in the clinical trials room is the RECOVER project, which, from what I can tell, appears to be sitting on several hundred million dollars. RECOVER’s current clinical trials program hasn’t exactly wowed anyone, but the RECOVER TLC meeting in Sept. 2024, with its recommendations for a fresh direction, created a great deal of excitement. Peluso called the vibe of that event very positive and a “great first step”.

Nine months later, RECOVER is continuing to move slowly and communicate fitfully, if at all, about its new approach and hasn’t said how it will proceed. Let’s hope that inertia hasn’t dragged the program back to the dark ages. RECOVER’s unique resources mean it has the potential to play a significant role in addressing long COVID.

Peluso noted how valuable the infrastructure that RECOVER has built up (more than 300 clinical research sites!) is, and how a similar network played an important role in finding treatments for HIV/AIDS.

Small, “Really Intense”, Pathogenesis Trials

LIINC excels in small, intense clinical trials that it believes will tell us what is happening in these diseases.

For its part, LIINC has been doing what Peluso called “really intense pathogenesis” trials to probe the biological underpinnings of long COVID.

These small proof-of-concept trials are injecting a kind of creative energy into the field. By tracking both clinical effectiveness and the broad physiological impact of a treatment, their goal is to zero in on biological targets.

Coming once again to lessons learned from their work in HIV/AIDS, Peluso noted how effective this approach has proven to be there. He gave an example of a single-arm (no placebo), 34-week, 10-person trial that combined experimental vaccines, monoclonal antibodies, and toll receptor agonists in an attempt to get rid of HIV once and for all. The kicker was that the participants had to go off their HIV/AIDS drugs to participate. (Now that’s intense!)

The virus should quickly come roaring back once the drug cocktail is stopped, but 7/10 people were able to control the virus (sans drugs) for months, and in some cases for over a year. That was exciting, but the real news was how much Peluso and company learned about how the immune system deals with the virus. Peluso said that the small study really “moved the needle” in helping to understand the virus.

That kind of stuff is LIINC’s bread and butter, and that’s what they’re bringing to long COVID.

VIPER!

By using large sample sets and standardized technology, VIPER hopes to uncover biomarkers for long COVID.

I asked Peluso about his rather trenchant assertion I saw somewhere that the long-COVID field cannot ignore any longer the fact that it doesn’t know who is in its studies; that is, long COVID is a large syndrome that shows great variability, yet studies and clinical trials often behave as if it’s one entity and are throwing all sorts of patients into the mix. That’s not a recipe for success in the medical field.

I noted that we’re five years into long COVID and it was amazing to me that we still can’t differentiate lung long COVID from kidney long COVID from ME/CFS-like COVID. I would have thought that would have been priority from day 1.

Noting that the field was understandably concerned about being too exclusive at the outset, Peluso suggested that the field had underdeveloped the pipelines for biomarker development. He said, “As a consequence of that, now, we’re in a situation where we don’t really know how to select people for the next round of trials.”

Peluso noted some studies are assessing patients based on their symptom presentations (phenotypes), but clearly that’s not sufficient – but that brought VIPER, LIINC’s new pilot biomarker program into the mix.

VIPER is a disruptive biomarker program aimed at turbocharging the biomarker search for long COVID. Because labs currently develop their own biomarkers using select groups of patients (which are likely not representative) and rarely compare long-COVID patients to recovered COVID-19 patients, the long-COVID biomarker search is basically a mess. What it needs is an integrated infrastructure that methodically checks out and is able to validate possible biomarkers – and that’s what VIPER is.

Once again, UCSF’s team’s experience with HIV/AIDS is informing their work. VIPER’s most immediate predecessor is RAVEN (the HIV Reservoir Assay Validation and Evaluation Network), which has successfully uncovered biomarkers in HIV/AIDS. While the pilot VIPER project is focused on finding a biomarker for coronavirus persistence, its ultimate goal is to uncover biomarkers across the various mechanisms at play in long COVID.

It aims to achieve this by intensively sampling long-COVID patients from sites across the U.S. and then using standardized procedures to test the samples for potential biomarkers as they emerge.

The holy grail would be a surrogate biomarker, like what was found in HIV/AIDS, which can track the progression of the disease. Once that was achieved in HIV/AIDS, the jig was basically up. As soon as the drug companies knew they could accurately track how well their drug was doing,, they poured resources into the HIV/AIDS field, and it didn’t take long to find drugs that could impact the disease.

While the technique that broke the code in HIV/AIDS – assessing its viral RNA loads – doesn’t work in long COVID, Peluso believes that viral persistence is driving long COVID in a subset of patients. Identifying which patients are affected is not yet possible – hence the first stage of the VIPER project.

A Look into the Crystal Ball 

“It feels like every day when I open my email, I will see something new.”

When Peluso looked five years into the future he hoped to see – given a sustained commitment from the NIH and others – he saw the ability to reverse the disease for a substantial percentage of patients.

My last question was a tough one – I asked him to look into his crystal ball and say what he expected to happen over the next five years.

He hopes that we will identify treatments that actually reverse the disease in a substantial percentage of patients with long COVID.

Doing that will require a couple of things, though: sustained investment, full engagement from the NIH, full support from the FDA, an engaged patient community, and a growing long-COVID research community.

It sounded to me like the field was seeding itself, that researchers in the field now are excited and committed but that the field needs to grow and that requires more funding. When I mentioned the dramatic funding cuts that occurred recently at the NIH, Peluso was clear: “We can’t do this without the NIH“.

Currently, the NIH is facing a significant setback due to the Trump administration’s cancellation or pausing of over $4 billion in funding within the past six months. The 2026 budget bill asks for a 40% reduction in NIH funding, or $18 billion in cuts.

The NIH’s funding for 2026, though, will be determined by Congress which, at least when it comes to the NIH, has continued to act in a bipartisan fashion. Congress completes the appropriations process and passes the final funding bill, typically by the end of the federal fiscal year on September 30, 2025.

During its first four years, the Trump administration attempted to cut the NIH budget by 18%, 3%, 13%, and 0%, but was rebuffed by Congress, which actually increased NIH funding slightly. Let’s hope it does so again!

Dr. Peluso, Solve M.E., and the Bezisterim Clinical Trial

Dr. Peluso discusses the Bezisterim long-COVID clinical trial, which aims to combat brain fog and fatigue, with Emily Taylor and others during Solve M.E.’s upcoming webinar on July 22nd. The potential impact on ME/CFS will be discussed.

Sign up for the webinar here. 

This trial was made possible by ME/CFS/long-COVID advocacy which dramatically increased funding for these diseases in the Congressionally Directed Medical Research Program. (The Trump administration has proposed a 57% cut in funding for the CDMRP (sigh!) Let’s hope Congress keeps this vital funding up!).

Health Rising’s Quickie Summer Donation Drive Update

With the drive entering its final stages, we are over 80% of the way to our goal!

Peluso reflected on an unusually inspired community of researchers at work.

What caught my eye about Dr. Peluso’s talk was the unusual level of enthusiasm, commitment and collaboration he’s found in the field. As patients immersed in our day-to-day struggles to keep our heads above water, it’s easy to forget that dedicated professionals are working hard on our behalf, and are actually excited (Peluso – “I’m excited every day to open my emails”) about their work.

As we wait, hope, and pray that answers will come sooner rather than later, Peluso’s interview buoyed my spirits a bit. I hope it had the same effect on you.