HIV drugs are very good at what they do: They help stop the virus from replicating. So much so, they shrink virus levels to undetectable in the blood. Problem is, HIV hides away in sleepy pools that neither the immune system nor drugs can get to – both only target an actively replicating virus. But that long-held idea may have just been turned on its head, as a new landmark study has just found that HIV isn’t so dormant in these problematic reservoirs as once thought.

Described in the journal Nature, an international team headed by researchers at Northwestern University and the University of Oxford has found that, even when tests can’t detect it in the blood, HIV continues to replicate at low levels in a key part of our immune system called lymphoid tissue. And that’s actually a good thing, because it not only helps us understand how HIV persists in the body despite drug regimens, but also suggests it may be possible to target these areas in a bid to eliminate the reservoirs that stand between us and a cure.

While we’d known about these reservoirs for a long time, largely because the virus somehow bounces back as soon as drugs are stopped, scientists thought that these pools of cells were latently infected, basically meaning that the virus is lying dormant. That’s because in patients whose infection was suppressed by drugs, scientists failed to see genetic variants appear over time, which you would expect with a mutation-prone virus like HIV. In addition, scientists weren’t seeing the emergence of drug-resistant strains, which you would expect if drugs were exerting selection pressure.

But prior studies had only looked at blood samples, neglecting other compartments of the body, in particular the lymphoid tissue that tends to possess higher cell infection frequencies. So in the search for more informative data, researchers behind the present study took lymphoid tissue biopsies from three patients on treatment at three different time points, and subjected them to a new sequencing tool known as deep sequencing in order to probe the viral DNA present.  

^{Diagram of a lymph node. Naeblys/Shutterstock}

“Deep sequencing is able to detect mutations in the virus that are present at very very low numbers,” study author Helen Fryer told IFLScience. “We wanted to see if we could find mutational changes that are consistent with viruses going through cycles of replication. We know as HIV replicates, it makes mistakes pretty much every time it infects a new cell.”

And indeed, that was what they were able to find: The mutations observed were all indicating that the virus is evolving over time. The researchers propose this is because HIV is able to continually replicate at low levels when drug concentrations are low, for instance in lymphoid tissue where drugs have been found in lower amounts than the blood. These areas therefore represent “sanctuaries” from which HIV can continually replenish the viral reservoirs and then travel into the blood.

If scientists can therefore find a way to increase drug levels in these areas, then it might be possible to eliminate these viral reservoirs. But researchers need to work out exactly where these problem sites are and how to get the drugs there. In addition, Fryer points out that reservoirs may be different for patients on or off therapy, and finding that out would be important in our search for a cure.