When HIV and TB coexist: Digging into the roots of IRIS

HIV (green dots) budding from a white blood cell. (CDC)
HIV (green dots) budding from a white blood cell. (CDC)

Millions of people worldwide suffer from co-infection with tuberculosis (TB) and HIV. While prompt antibiotic and antiretroviral treatment can be a recipe for survival, over the years, physicians have noticed something: two or three weeks after starting antiretrovirals, about 30 percent of co-infected patients get worse.

The reason: immune reconstitution inflammatory syndrome, or IRIS. Doctors think it represents a kind of immune rebound. As the antiretrovirals start to work, and the patient’s immune system begins to recover from HIV, it notices TB’s presence and overreacts.

“It’s as though the immune system was blanketed and then unleashed,” says Luke Jasenosky, PhD, a postdoctoral fellow with Anne Goldfeld, MD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It then says, ‘I can start to see things again, and there are a lot of bacteria in here.'”

Though potentially severe, even fatal, IRIS may actually be a good sign: there is evidence that patients who develop it tend to fare better in the long run. But why does it arise only in some patients?

To find out, Goldfeld, Jasenosky, Viraga Haridas, PhD (another fellow in the Goldfeld lab), and a global collection of collaborators turned to one of the world’s largest TB/HIV co-infection treatment studies, the Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) trial. Their data suggest that patients who develop IRIS start out with a different profile of immune cells, one that fuels a robust response to TB.

An experiment in nature

The CAMELIA trial was intended to settle a debate in the HIV field: should doctors delay HIV treatment in co-infected patients to give the TB treatment a chance to work or start patients on antiretrovirals shortly after antibiotics? The trial researchers published their unambiguous answer—start antiretrovirals early—in 2011.

But as Goldfeld notes, CAMELIA was also meant to be a window into the basic biology of co-infection.

“It was an unprecedented opportunity to answer questions that couldn’t be answered in a laboratory model,” she says. “Our work provides an explanation of an experiment in nature. By carefully analyzing how patients reconstituted their immune system with antiretroviral therapy when they had TB, we discovered important changes in immune reconstitution in patients who experienced IRIS.”

Defining good inflammation

“We’re defining a kind of ‘good’ inflammation, one that may lead us to future therapies designed to recapitulate it and assist the immune system in overcoming TB.”

To better understand the roots of IRIS, the CAMELIA team looked at T cells and cytokines in blood samples from 154 CAMELIA participants, 50 of whom developed IRIS. The samples were drawn before, during and at several time points up to eight months after starting antiretroviral therapy. Findings were published last month in the journal AIDS.

In the patients who developed IRIS, CD4+ T cells—a critical component of the immune system—were already in a significantly more activated state before antiretroviral treatment, despite heavy suppression by HIV. After starting antiretrovirals, IRIS patients’ CD4+ T cells progressively tilted in favor of an “effector memory” response—a kind of immune response critical for control of TB infection.

“The IRIS in a sense remodeled the T cell compartment of these patients into one that’s more fit for fighting TB,” Goldfeld explains. “The immune profile we uncovered could help define biomarkers for effective TB vaccines in the future.”

This remodeling helps explain a potential link between survival and IRIS. It’s the outward display of an immune system that, once liberated by the antiretrovirals, turns its full attention to the TB infection, and starts producing cells and cytokines geared toward defeating it.

“We’re defining a kind of ‘good’ inflammation,” Goldfeld says, “one that may lead us to future therapies designed to recapitulate it and assist the immune system in overcoming TB.”

Haridas, Jasenosky and Goldfeld thank the following for their support of this study: Wallis Annennberg and the Annenberg Foundation, John Moores, the French AIDS agency (ANRS (12164)), the NIH (R21AI076023), and AmFAR with support from NIAID/NIH- IeDEA (U01AI069907-07).