Many of us know hydrogen sulphiide as a gas that smells bad — when teachers produced the gas using Kipps apparatus in the classroom, we plugged our nostrils. However, disagreeable as it is, the gas has a positive side too. It is useful in medicine, as research in the last 5-6 years shows. And now, researchers at the Indian Institute of Science, Bengaluru, have identified a big role for hydrogen sulphide — in fighting AIDS — as the gas suppresses the growth of the HIV virus.
This finding by IISc researchers from the Department of Microbiology and Cell Biology and the Centre for Infectious Disease Research, in association with the Bangalore Medical College and Research Institute, hasbeen published in the journal eLife.
AIDS kills about 600,000 people annually; there were 1.9 million new infections in 2019. The only available treatment is the anti-retroviral therapy (ART), which has not been very effective since the virus manages to evade the drugs and rebounds post treatment. The researchers note in their paper that “the persistence of latent but replication-competent HIV in cellular reservoirs is a major barrier to cure”.
The scientists looked into why this happens. Typically, the human body generates gases such as nitric oxide, carbon monoxide and hydrogen sulphide, which act against bacterial and viral infections. They realised that while it was known that nitric oxide and carbon monoxide help suppress HIV, the effect of hydrogen sulphide was “completely unexplored”. Therefore, the researchers — Virender Kumar Pal, Ragini Agrawal, Srabanti Rakshit, Pooja Shekar, Diwakar Tumkur Narasimha Murthy, Annpurna Vyakarnam and Amit Singh — decided to take a close look at it.
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“We discovered an unexpected role of hydrogen sulphide in HIV latency and reactivation,” they say in the paper, which details how that happens. ART has an unfortunate side-effect of a build-up of toxic molecules, increasing the oxidative stress and getting in the way of the work of an enzyme called CTH, which produces hydrogen sulphide — an enemy of the virus. The ‘genetic silencing’ of CTH impairs the functioning of mitochondria, the powerhouse of cells, and triggers HIV reactivation.
Simply put, ART impairs the production of hydrogen sulphide in the patient’s body cells. The virus waits out the therapy and then comes back with a vengeance.
The task before the researchers was to find a way of bringing hydrogen sulphide back into the battlefield. If the body cannot produce it, then maybe external inputs can help.
At this stage, one particular molecule enters the picture. Scientists call it ‘morpholin-4-ium 4-methoxyphenyl (morpholino) phosphinodithioate’, but it is better known as GYY4137. For about 15 years now, this molecule has been known to slow-release hydrogen sulphide. In a 2014 paper published in the US journal National Library of Medicine, titled ‘GYY4137, a novel, water-soluble, hydrogen sulphide releasing molecule’, the authors describe it as “a pharmacological tool to explore the biological functions of hydrogen sulphide”.
An older German study had shown that a chemical called N-acetylcysteine, known to suppress HIV reactivation, worked partly by releasing hydrogen sulphide molecules. The IISc researchers decided to work with GYY4137, a better chemical, for hydrogen sulphide production.
In the IISc research paper, the authors say they found that “using a slow-releasing hydrogen sulphide donor, GYY4137, suppressed HIV reactivation and diminished virus replication”.
Studying the effects of a gaseous molecule on HIV required the researchers to build and validate new model systems. Detecting hydrogen sulphide in cells was a challenge too — they had to use an indirect approach, measuring the heat (calorimetric) and light (fluorometric) emissions in the cells to infer hydrogen sulphide content. The researchers studied the effects of natural generation of hydrogen sulphide in HIV-infected cells and when the cells were supplemented with GYY4137.
“Our data show that while hydrogen sulphide deficiency reactivates HIV-1, the hydrogen sulphide donor GYY4137 can potently inhibit residual levels of HIV-1 transcription during suppressive anti-retroviral therapy and block virus reactivation upon stimulation,” the authors say.
IISc’s internal magazine, Kernel, quotes one of the researchers, Amit Singh: “We observed a direct effect of hydrogen sulphide on suppressing HIV reactivation and replication along with all its other beneficial effects, such as maintenance of mitochondrial health and dissipation of oxidative stress in our [cellular] models.”
This opens the door to supplementing anti-retroviral therapy with chemical donors of hydrogen sulphide to lock HIV in a state of deep latency, potentially improving the lives of millions infected with the virus, says the Kernel article.
Now, hydrogen sulphide is recorded to be a useful gas not just in treating AIDS but elsewhere too. Localised delivery of hydrogen sulphide in physiological concentrations helps improve the function of mitochondria, mitigates oxidative stress and supports anti-inflammatory functions. Conversely, the depletion of endogenous (body-produced) hydrogen sulphide elevates the activities of enzymes that produce ‘reactive oxygen species’ or ROS, which are molecules that are either oxidising agents or those that become oxygen radicals. ROS reacts with carbohydrates, lipids, proteins and nucleic acids to cause cell damage. Hydrogen sulphide, like a patrolling cop, keeps these thugs under check. (ROS also brings benefits such as wound repair, but that is another matter.)
“In recent years, hydrogen sulphide has been reported to exhibit a diverse range of pharmacological effects in biological systems,” says the 2014 paper in the National Library of Medicine. Other studies also speak of the beneficial role of the gas in medicine. For example, one study published in 2017 in Frontiers in Pharmacology speaks of the “favourable role of hydrogen sulphide” in treating Parkinson’s Disease.
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