Many of us know hydrogen sulfide as a bad-smelling gas – when teachers produced the gas using Kipps devices in the classroom, we blocked our nostrils. However, as unpleasant as it is, gas also has a positive side. It is useful in medicine, as the research of the last 5-6 years shows. And now researchers at the Indian Institute of Science in Bengaluru have identified an important role for hydrogen sulfide – in the fight against 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 Center for Infectious Disease Research, in association with the Bangalore Medical College and Research Institute, was published in the journal eLife.
AIDS kills around 600,000 people every year; there were 1.9 million new infections in 2019. The only treatment available is antiretroviral therapy (ART), which has not been very effective as the virus manages to evade drugs and rebounds after treatment. The researchers note in their paper that “the persistence of latent but self-replicating HIV in cellular reservoirs is a major obstacle to cure.”
Scientists have investigated why this happens. Generally, the human body generates gases such as nitric oxide, carbon monoxide and hydrogen sulfide, which work against bacterial and viral infections. They realized that while nitric oxide and carbon monoxide were known to help suppress HIV, the effect of hydrogen sulfide was “completely unexplored”. Therefore, scholars – Virender Kumar Pal, Ragini Agrawal, Srabanti Rakshit, Pooja Shekar, Diwakar Tumkur Narasimha Murthy, Annpurna Vyakarnam and Amit Singh – decided to examine it closely.
“We discovered an unexpected role for hydrogen sulfide in HIV latency and reactivation,” they say in the paper, which details how it happens. ART has an unfortunate side effect of a buildup of toxic molecules, increasing oxidative stress and interfering with the work of an enzyme called CTH, which produces hydrogen sulfide – an enemy of the virus. The “genetic silencing” of CTH alters the functioning of mitochondria, the powerhouse of cells, and triggers the reactivation of HIV.
Simply put, ART alters the production of hydrogen sulfide in the cells of the patient’s body. The virus waits for therapy to end, then returns with a vengeance.
The task facing researchers was to find a way to bring hydrogen sulfide back to the battlefield. If the body can’t produce it, then maybe external inputs can help.
At this point, a particular molecule comes into play. Scientists call it “morpholin-4-ium 4-methoxyphenyl (morpholino) phosphinodithioate”, but it is better known as GYY4137. For fifteen years, this molecule has been known to slowly release hydrogen sulphide. In a 2014 article published in the American journal National Library of Medicinetitled “GYY4137, a novel water-soluble molecule releasing hydrogen sulfide,” the authors describe it as “a pharmacological tool to explore the biological functions of hydrogen sulfide.”
An older German study had shown that a chemical called N-acetylcysteine, known to suppress HIV reactivation, worked in part by releasing hydrogen sulfide molecules. The IISc researchers decided to work with GYY4137, a better chemical, for the production of hydrogen sulfide.
In the IISc research paper, the authors say they found that “use of a slow-release hydrogen sulfide donor, GYY4137, suppressed HIV reactivation and decreased virus replication.”
To study the effects of a gaseous molecule on HIV, researchers had to build and validate new model systems. Detecting hydrogen sulfide in the cells was also a challenge – they had to use an indirect approach, measuring heat (calorimetric) and light (fluorometric) emissions in the cells to infer the hydrogen sulfide content. The researchers studied the effects of natural hydrogen sulfide generation in HIV-infected cells and when the cells were supplemented with GYY4137.
“Our data show that if hydrogen sulfide deficiency reactivates HIV-1, the hydrogen sulfide donor GYY4137 can potently inhibit residual levels of HIV-1 transcription during suppressive antiretroviral therapy and block virus reactivation. upon stimulation,” the authors state.
the IISc internal magazine, Corequotes one of the researchers, Amit Singh: “We observed a direct effect of hydrogen sulfide on the suppression of HIV reactivation and replication as well as all of its other beneficial effects, such as maintaining mitochondrial health. and the dissipation of oxidative stress in our [cellular] models.”
According to Core article.
Now hydrogen sulfide is recorded as a useful gas not only in the treatment of AIDS, but also elsewhere. Localized delivery of hydrogen sulfide at physiological concentrations helps improve mitochondrial function, alleviates oxidative stress, and supports anti-inflammatory functions. Conversely, depletion of endogenous hydrogen sulfide (produced by the body) elevates the activities of enzymes that produce “reactive oxygen species” or ROS, which are molecules that are either oxidizing agents, or those that become oxygenated radicals. ROS react with carbohydrates, lipids, proteins and nucleic acids to damage cells. Hydrogen Sulfide, like a cop on patrol, keeps these thugs under control. (ROS also brings benefits such as wound repair, but that’s another matter.)
“In recent years, hydrogen sulfide has been reported to exhibit a diverse range of pharmacological effects in biological systems,” says the 2014 article in the National Library of Medicine. Other studies also speak of the beneficial role of gas in medicine. For example, a study published in 2017 in Frontiers in pharmacology speaks of the “beneficial role of hydrogen sulfide” in the treatment of Parkinson’s disease.
May 29, 2022