Gene May Hold Key to Controlling Tuberculosis, Hepatitis and HIV

According to authors of a new study published in the journal Nature Immunology, a gene called the ariadne homolog 2 (Arih2) may hold the key to treating and potentially controlling chronic infections such as HIV, hepatitis B and tuberculosis.

Upper left: liver, heart and lung tissue of ARIH2-sufficent and -deficient mice. Upper right: ARIH2-sufficent and -deficient mice (Lin AE et al). Bottom: the red line on the lower image points to the location of the ARIH2 gene on the short arm of chromosome 3 (genecards.org)

Identified in 2011, Arih2 gene is fundamental to the function of the immune system. It is believed to make critical decisions about whether to switch on the immune response to an infection.

The study results have implications for the treatment of chronic overwhelming infections, such as HIV, that exhaust and switch off the immune system, as well as for chronic inflammatory conditions such as rheumatoid arthritis and sepsis.

“Arih2 is found in dendritic cells, the sentinels of the immune system that play an essential role in raising the alarm about the presence of foreign invaders in the body. Arih2 is responsible for the most fundamental and important decision that the immune system has to make – whether the immune response should be initiated and progressed or whether it should be switched off to avoid the development of chronic inflammation or autoimmunity. If the wrong decision is made, the organism will either succumb to the infection, or succumb to autoimmunity,” said study senior author Dr Marc Pellegrini of the Walter and Eliza Hall Institute of Medical Research and the University of Melbourne.

“Although our immune system works well against many infections, some organisms have developed mechanisms to evade or counteract the immune system, allowing them to persist in the body. During evolution, some organisms have evolved ways of exhausting our immune system to the point where the immune system just switches off, and this is what happens in HIV, hepatitis B and tuberculosis,” Dr Pellegrini explained.

He said these organisms counter the immune response – exhausting T cells which are stimulated over and over again by the infection and becoming exhausted or paralyzed. With this current discovery, what we should be able to do is circumvent these mechanisms and reinvigorate the immune response temporarily to boost the immune system and help clear these infections.

“The research team was now looking at the effect on the immune response of switching off Arih2 for short periods of time during chronic infections. We are investigating how manipulating Arih2 and associated pathways promotes immunity in chronic overwhelming infections, where we know the immune response is inadequate,” said study co-author Dr Greg Ebert of the Walter and Eliza Hall Institute of Medical Research.

He said Arih2 had significant promise as a drug target. Arih2 has a unique structure, which we believe make it an excellent target for a therapeutic drug, one that is unlikely to affect other proteins and cause unwanted side-effects. Because Arih2 is critical for survival, we now need to look at the effect of switching off the gene for short periods of time, to see if there is a window of opportunity for promoting the immune response to clear the infection without unwanted or collateral damage or autoimmunity.

Dr Pellegrini said it would take many years to translate the discovery to a drug that could be used in humans. We are very excited about this discovery. Arih2 is the one of the most important genes involved in the most fundamental and vital decisions that the immune system has to make: whether or not to switch on the immune response to an infection.

“This discovery has significant implications for manipulating the immune response to infections and suppressing chronic inflammation or autoimmunity because we can target this gene to try to push immune responses in one or other direction – either promoting it or suppressing it. It is probably one of the few genes and pathways that is very targetable and could lead to a drug very quickly.”

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Bibliographic information: Lin AE et al. ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system. Nature Immunology, published online 25 November 2012; doi: 10.1038/ni.2478