Investigators at the Wistar Institute have identified biomarkers that could discriminate HIV-infected post-treatment controllers, that is, HIV-infected individuals who do not experience viral rebound after analytical treatment interruption (ATI).

The findings, which were published in the June 29, 2021, issue of Nature Communications, have multiple implications for HIV clinical trials.

The most obvious use for biomarkers that can predict viral rebound after ATI is that they would make HIV cure clinical trials safer.

They may also give new insights into the comorbidities that occur at high levels in HIV patients.

ATI is the only way to see whether a treatment has enabled patients to gain long-term control over the virus.

But it is associated with risks.

The biggest risk is "to the individual, because the virus will come back," Mohamed Abdel-Mohsen told BioWorld Science. But the approach "also does have risk to the community... The person who is viremic can transmit virus and infect other people."

Abdel-Mohsen is an assistant professor in The Wistar Institute Vaccine & Immunotherapy Center, and the senior author of the Nature Communications paper.

Previous studies of viral rebound after ATI have focused on the virological side of the issue, in particular, the size and location of the viral reservoir that seeds rebound.

But "what is always missing is the host side of this equation," he said.

To understand those factors, Abdel-Mohsen and his team looked at post-treatment controllers, rare individuals that do not experience rebound after treatment interruption.

Post-treatment controllers are exceedingly rare -- the known number of such individuals in North America is fewer than 70.

But because they have had full-blown viremia, and their immune system learns to control HIV -- unlike elite controllers, who are able to control the virus without ever being treated -- they are the closest model for functional cure studies, Abdel-Mohsen said.

Learning more about how such individuals do what they do could give insights into how to turn other individuals into post-treatment controllers.

In their studies, the scientists looked at metabolites and glycans – the carbohydrates that coat cells – to search for a set of such molecules that might predict both the timing of rebound in noncontrollers, and those individuals that did not rebound at all.

They identified a set of such markers that was able to predict time to rebound and controllers with high accuracy.

Some of those markers, Addel-Mohsen said, were active markers that appeared to not just correlate with rebound, but play a role in determining its timing.

Looking at the roles of those biomarkers, Abdel Mohsen and his colleagues then realized that they overlapped with previously identified molecules that play a role in HIV comorbidities.

"People living with HIV are still suffering from a higher level of comorbidities," Abdel Mohsen said. "While the lifespan may be coming close to those of HIV-negatives, the quality of life is not the same."

The biomarker set identified by the Wistar team is functionally linked to tryptophan, glutamate and bile acid metabolism.

Tryptophan catabolism, in particular, has been linked to HIV comorbidities as well as gut microbial dysbiosis. "To my knowledge, this is the first evidence that host pathways that have been associated with both gut microbial dysbiosis and comorbidities are also associated with rapid rebound," he said.

Research on rebound and post-treatment control has focused on viral factors, while investigations of comorbidities tend to concentrate more on host factors. But Abdel-Mohsen argued that the relationship between them "is something we need to account for in our search for a cure," he said. Rebound and comorbidities are "two sides of the same coin, not two different coins."

Finally, the link between the two phenomena also has basic implications for clinical trials.

Clinical trial investigators – not just in the HIV field – tend to want to test their interventions on patients that, other than the main focus of the trial, are relatively healthy. Cancer trials, for example, often exclude patients with brain metastases. And HIV trials exclude those with comorbidities.

The results now published in Nature Communications, though, suggest that such exclusions may lead to skewed trial populations and so prevent valuable insights into the biology of viral control.

"When investigators recruiting avoid recruiting someone with comorbidities," he said, "we might be ignoring a very big, important thing here."