Does COVID-19 Persist?

— An unexpected idea gains traction and may provide clues about long COVID

A computer rendering of COVID virus particles in the bloodstream.

Does COVID-19 persist in the body?

With reporting long COVID symptoms like brain fog and fatigue, the idea of viral persistence has gained traction.

"At the beginning of the pandemic, we never expected to have these discussions about SARS-CoV-2 persistence," said Michael Peluso, MD, MHS, of the University of California San Francisco. "It was just not part of our framework for coronaviruses."

Early papers identified SARS-CoV-2 antigens in blood or tissue, but many were small studies evaluating immunocompromised people, Peluso noted. "None addressed the specificity of the assay, and a common criticism was that this could all be a false-positive signal," he told ľֱ.

But in research published last month in , Peluso and colleagues studied plasma samples from 171 immunocompetent people who had COVID, using an to measure the concentration of SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid. These samples were compared with 250 pre-pandemic samples from people who never had COVID.

The researchers found that a quarter of COVID-infected people had SARS-CoV-2 antigens in their blood for up to 14 months after infection. The most common was spike.

"This allowed us to demonstrate more definitively than prior work that post-acute antigen persistence is occurring in at least a subset of people post-COVID and that it can be detected by a blood assay," Peluso said. "Now we need to better understand whether we can tie measurements on this assay to long COVID phenotypes or other post-acute complications, which will require a much larger study."

Hypotheses about the root causes of long COVID often fall into one of : autoimmunity triggered by SARS-CoV-2 infection; reactivation of latent viruses like Epstein-Barr (EBV); damage from ongoing inflammation; or viral persistence. Viral persistence suggests that some people don't fully clear the coronavirus after acute infection and pieces linger in a .

"A large body of work now supports that months or years after acute SARS-CoV-2 infection, evidence of persistent viral antigens -- spike and nucleocapsid -- and viral RNA are detected in various tissues in people, based on autopsy and biopsy studies," observed Akiko Iwasaki, PhD, of Yale University in New Haven, Connecticut.

"We do not currently understand the molecular nature of persistent viral RNA," Iwasaki told ľֱ. Viral RNA may reflect fragments of the viral genome that persist, meaning they are not replication competent. But it's possible viral RNA represents the whole genome capable of replication, she observed.

"If replicating virus is causing harm -- like long COVID -- then antivirals may be able to target such viral reservoirs and be used as a therapy," Iwasaki pointed out. "If only viral remnants are present -- fragments of viral RNA or proteins -- antivirals like Paxlovid [nirmatrelvir/ritonavir] will not be able to clear it."

Removing viral proteins could be done by antibodies, but removing viral RNA would be more difficult, she added.

While evidence for persistent antigen is growing, persistent virus has rarely been detected and only in small quantities, noted Avindra Nath, MD, of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

"Yes, viral antigen can be detected," Nath said. "But presence of viral antigen doesn't mean that it's completely replicating virus. They're two separate things."

A Very Broad Condition

What causes long COVID may not be the same for everyone, noted David Putrino, PhD, of the Icahn School of Medicine at Mount Sinai in New York City. "It's a very broad condition" with many subtypes, he told ľֱ.

"I think most serious people who are researching long COVID understand that one of the subsets emerging is people who may have a persistent viral infection," Putrino said.

"For the longest time, it's been a taboo topic. We've been told by virologists for years that certain viruses don't persist and don't hide out in tissue," he added. "It's becoming abundantly clear now that coronaviruses can do this."

Ongoing trials are testing what role, if any, viral persistence may play in long COVID. At Yale, the trial is studying a 15-day course of nirmatrelvir/ritonavir in 100 patients, with results expected this year. , an NIH study of 900 people, is testing nirmatrelvir/ritonavir for and is expected to be complete in 2025.

In the trial, Peluso's team is testing AER002, a monoclonal antibody. "The goal is to probe the antigen persistence mechanism by intervening with a treatment that should be able to neutralize circulating spike protein and promote clearance of infected cells that are expressing spike protein on their surface," he said.

"It's only by trying to alter the biology that we can really determine whether SARS-CoV-2 persistence is driving long COVID symptoms and whether targeting persistence will help," he added.

In a feasibility study, Putrino's lab will study two repurposed HIV antivirals, emtricitabine/tenofovir (Truvada) and maraviroc. "Maraviroc has had some early published evidence that it does have some antiviral action on SARS-CoV-2 in the body," he noted. "Truvada also has some weaker evidence showing it has action on SARS-CoV-2, but more importantly, it has strong evidence that it can act quite aggressively on persistent EBV," which may be a factor in a subset of long COVID patients.

Solving long COVID involves "looking in every direction, not just narrowing down into one direction of viral persistence or immune dysregulation," Putrino pointed out.

"That's where we need to go," he said. "It's a complicated problem. If the problem was simple, it would be solved by now."

  • Judy George covers neurology and neuroscience news for ľֱ, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.