Feature: Immune paradox

This feature appeared in the November/December 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Almost as long as HIV patients have been receiving antiretroviral therapy (ART) to suppress their viral load and correct the associated immunodeficiency, clinicians have being noticing something a bit strange: in some patients, the restored immune response leads to new immunopathology that arises despite control of the infection. It seems that in these individuals, the immune system itself is causing new problems.

This aspect of immune recovery in HIV patients, called immune restoration disease (IRD) has been the main focus of Professor Martyn French’s research for over a decade at the Royal Perth Hospital and University of Western Australia.

“We actually first described this phenomenon in Perth some years ago and it is now recognised as a major problem throughout the world in HIV sufferers from resource-poor countries who are starting ART,” he says.

The disease is usually encountered in people who are very immune-deficient when they start the therapy and who are co-infected with an opportunistic pathogen. Between 10 and 40 per cent of such patients show a pathogen-specific immune response that may cause severe disease.

Tuberculosis (TB) due to infection with Mycobacterium tuberculosis is the most common cause of IRD in HIV-infected patients during the initial months of ART, with other common pathogens including Cryptococcus, herpes viruses, and hepatitis B and C virus.

“For example, in South Africa it is very common for people to present with HIV and TB, and people treated for both can develop a condition that is commonly referred to as TB-associated immune reconstitution inflammatory syndrome [TB-IRIS],” says French.

“This is basically a form of IRD where the disease is actually caused by the immune system recovering, rather than by immunodeficiency. It seems that the body’s fight to clear the mycobacterial infection in the presence of an ART-driven immune recovery leads to an exaggerated inflammatory response that itself causes quite serious illness.”

At the Australasian Society for Immunology Scientific Meeting held in Perth in December, French will talk about this mechanistic phenomenon that occurs when mycobacteria interact with the immune system during ART.

He will also highlight that this TB disease can take two forms: one where you unmask an undiagnosed case of TB with the ART treatment; and the other when you seem to cause a paradoxical relapse of recently treated TB.

His discussions will be based largely on results from a major study that French’s group contributed to in Cambodia looking at the immunopathogenesis of TB-IRIS. This was done in collaboration with scientists in Melbourne, Sydney and Phnom Penh and funded by AusAID and the NHMRC.

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Immune backlash

The Cambodian findings essentially showed that IRD associated with M. tuberculosis infection involves both T cell responses to mycobacterial antigens and responses by the innate immune system.

“It seems that those HIV patients with treated TB who develop TB-IRIS on ART show innate responses in addition to the expected T cell response,” says French.

“There was also a group of patients that presented with TB after starting ART, in whom the immune response induced by ART was a really strong T cell response to the mycobacterial antigens. So in the patients where you unmask the TB, the T cell response seems to dominate, whereas in those where there seems to be a paradoxical relapse of the TB [already treated before ART], the innate responses predominated.”

In answer to the obvious question, French’s team has no idea yet as to why this is. Some recent evidence indicates that it may be related to the severity of the prevailing immune deficiency prior to the HIV therapy, so the immune system in people with very high pathogen loads launches this massive all-out attack against the TB antigens when suddenly boosted by the ART. This leads to a hyper-inflammatory response to the infection.

Around the world this type of abnormal immune response to treated TB is known as paradoxical TB-IRIS, because instead of getting better, paradoxically, the infection seems to get worse. According to French, the terminology comes from the old TB literature, well before HIV, when TB physicians noticed that some TB patients actually got worse when treated.

Nobody understood what was causing that either, and it quite possibly reflects a similar mechanism – with dead and dying bacteria from the TB treatment inducing a hyper-inflammatiory reaction. French notes that “in the HIV patients it is probably far worse, because on top of that you are restoring the immune system by treating the HIV.”

About 20 per cent of people with HIV and TB will develop this complication and careful patient management is needed to minimise the severity and symptoms of the inflammation. Work on prevention and treatment strategies for IRD continues worldwide and recent studies also indicate some beneficial effects from steroid administration in severe cases.

This is encouraging because while death rates are not so high with TB-IRIS as long as the morbidity is controlled, ART-treated HIV patients presenting with Cryptococcus, the second most common pathogen associated with IRD in HIV patients, fare much worse. More than one-third of these patients are likely to die due to severe meningitis, highlighting why IRD has become so important worldwide as an HIV-related issue.

“In resource-poor countries with high levels of HIV infection, the ART was often stopped because the effect was mistakenly thought to be toxicity from the drugs, when in fact it is a beneficial effect of the ART, but just one that is undesirable. The recommended approach now is to continue the ART and manage the inflammation.”

French and his colleagues Professor Patricia Price, Dr Sonia Fernandez, Dr Andrew Lim and Dr Silvia Lee, who have also worked on the immunology of HIV and HCV infection for many years, hope to understand the mechanistic nature of the immune responses being activated by ART in the presence of different pathogens and eventually find new ways to tame the hyper-inflammatory response.

Learning more about the immune activation going on in these co-infected patients could also provide novel insights about HIV disease itself and, ultimately, how to develop new treatments for this ever-challenging virus infection.

This feature appeared in the November/December 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.