Case study links inflammation to HIV persistence in specific scenarios

A years-long case study has potentially identified another factor with which HIV treatment efforts must contend: Inflammation could be a linchpin in the virus’ overexpression in some people. 

The findings come from the treatment of a person living with HIV. The study, led by the HIV Dynamics and Replication Program at the National Cancer Institute at Frederick and the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases and supported by Frederick National Laboratory scientists, was recently reported in Nature Medicine. 

The study subject presented with advanced HIV and several secondary medical concerns and received antiretroviral drugs, the standard treatment for the virus. His immune system regained some function, and his conditions began to improve—but then he was stricken by a wave of new neurological symptoms. 

The team suspected progressive multifocal leukoencephalopathy (PML), a rare but serious inflammation in the brain, driven by immune reconstitution inflammatory syndrome (IRIS). IRIS involves excessive inflammation and is sometimes seen in immunosuppressed people after treatment that restores their immune system’s capabilities. It can occur when the body has an outsized reaction to an existing secondary infection. 

In this case, the team determined that a common and typically benign human polyoma virus (JC virus), an infection of the central nervous system, provoked the individual’s recharged immune system and trigged PML-IRIS. Doctors treated the individual with corticosteroids. His health improved, but months later, HIV levels in his body unexpectedly spiked despite antiretroviral treatment. The virus had seemingly become resistant. 

The individual’s PML-IRIS also returned, brought about by lingering JC virus. Doctors again gave corticosteroids but, after the treatment, noticed something strange: without any change to the previously ineffective antiretroviral drug regimen, the HIV levels in his body dropped sharply. 

Borne out of reach 

It was a clear indicator that inflammation can affect HIV’s behavior. From there, the team pinpointed HIV-infected T cells, a type of white blood cell, as the key. 

“T cells that were going to fight the JC virus were HIV-infected themselves, and so when these T cells were activated to fight the JC virus, there was a large expansion of these cells,” said Robert Gorelick, Ph.D., head of the HIV Molecular Monitoring Core at Frederick National Laboratory and a coauthor on the paper. 

The first round of corticosteroids stopped much of that expansion as part of treating the PML-IRIS, but like a battalion of soldiers stationed in recaptured territory, some of those T cells stayed in the individual’s central nervous system—so the HIV piggybacking in them stayed, too. 

That was important because “the levels of antiretroviral therapies in that compartment of the body are actually suboptimal,” said Christine Fennessey, Ph.D., head of the Viral Evolution Core at the Frederick National Laboratory and an investigator on the study. Largely unaffected, HIV was able to copy itself and spread in those T cells. 

Eventually, a strain with a drug-resistance mutation became dominant, leading to the marked spike in HIV levels the team witnessed as the individual’s PML-IRIS returned. 

But when doctors readministered the corticosteroids—which reach the central nervous system better than antiretroviral drugs—they quashed the JC virus infection, reducing the need for T cells. As the infected T cells began to taper, the source of the drug-resistant HIV abated. That in turn diminished the HIV levels, without changes to the antiretroviral drug regimen.  

In the end, doctors placed the individual on second-line antiretrovirals that suppressed the drug-resistant virus and helped bring the HIV levels more under control. His health again improved and remained largely stable for five years (the end of the period reported in the study). 

“One of the things that really sticks out to me at least is that we need to develop better [antiretroviral] drugs that have better penetrance into the central nervous system, because that’s obviously an area where low-level HIV replication could occur and these viruses could escape from our normal [antiretroviral] therapies,” Fennessey said. 

She added there may also be implications for HIV treatment, such as placing a person directly on second-line antiretrovirals when it becomes clear they have a secondary infection with a risk of PML-IRIS. Future work could determine if the experience of this HIV-infected patient is observed in others who face a similar clinical scenario. 

A complete picture 

Frederick National Laboratory brought multiple resources from its AIDS and Cancer Virus Program to bear on the study, in support of the lead investigators. 

Fennessey’s team performed the single-genome sequencing that identified the mutations in the drug-resistant HIV and indicated that the drug-resistant strain had got its footing in the central nervous system. Meanwhile, Gorelick’s group handled the highly sensitive assays to measure virus levels in the individual’s body. Both helped to fill in pieces of the puzzle, and both Fennessey and Gorelick say it was a gratifying experience. 

“There were some fine minds working on this,” Gorelick said. “It’s nice to see how the work that you did contributed to the bigger story.” 

Adding to that, Fennessey said, “This story is a really nice complete picture. There’s a beginning, a middle and an end. … This was a very satisfying study to be a part of.”