HIV medicines may eliminate beneficial gut bacteria
People living with HIV have a markedly increased risk of developing cardiovascular disease. A new study from the University of Gothenburg indicates that this may partly be due to the way both the virus and HIV treatments affect the gut flora.
Access to effective HIV drugs has improved considerably. Despite this, mortality among people with HIV remains high compared to the general population, partly due to an increased risk of cardiovascular disease. In parts of southern Africa, HIV infection is believed to account for up to a quarter of all cardiovascular disease.
"The underlying cause is unclear. One hypothesis is that the effects of the virus on the immune system disrupt our interaction with the gut bacteria. This, in turn, can lead to chronic inflammation that contributes to the development of atherosclerosis," says Karolina Sjöberg Jabbar, lead author of the study and researcher at the Wallenberg Laboratory for Cardiovascular and Metabolic Research at the University of Gothenburg.
Distinct effects in different countries
The study was conducted in collaboration with two leading American research institutes and published in the journal Nature Microbiology.
Researchers analysed stool samples to map bacteria and viruses in the gut of 327 people with HIV and 260 HIV-negative controls from Uganda, Botswana, and the USA. The aim was to understand how both HIV drugs and the virus itself influence the gut microbiome.
The results showed that HIV affected the composition of the gut microbiome differently across the countries studied. The researchers also found similarities, such as an increase in genes that help bacteria colonise the intestinal lining.
"A major part of our immune system is located in the gut. These changes were directly linked to the disease’s effects on the immune system, namely the reduction of white blood cells targeted by HIV," says Karolina Sjöberg Jabbar.
Inhibits an enzyme the virus needs
HIV attacks the immune system’s white blood cells (CD4-positive T lymphocytes), making the body more vulnerable to infections. HIV is a retrovirus, meaning its genetic code consists of RNA. To replicate using the human cell’s machinery, the virus must convert its RNA into DNA.
For this process, HIV uses an enzyme called reverse transcriptase, which is essentially absent in humans. Most common HIV drugs work by inhibiting this enzyme.
However, certain gut bacteria also produce reverse transcriptase, using it to defend themselves against viruses – specifically phages. Bacteriophages are a type of virus commonly found in the gut, in even larger numbers than bacteria and human cells. They play an important role in transferring genetic material between bacteria and can both benefit and destroy them.
"This means that some gut bacteria rely on the same enzyme for their own defence that HIV depends on for its replication," says Karolina Sjöberg Jabbar.
Impairs gut bacteria’s defence
An interesting finding was that HIV drugs, like the virus itself, affected the gut microbiome differently across geographical regions. Among participants in Uganda and Botswana who used efavirenz, a common HIV drug that inhibits reverse transcriptase, major changes were observed.
Most notably, there was a sharp decline in the bacterium Prevotella. This decrease was linked to uncontrolled spread of phages that specifically infect the Prevotella genus, normally kept in check by the bacterium’s immune defence.
Through experiments and simulations, researchers discovered that the drug not only inhibited reverse transcriptase in HIV but also in Prevotella, leaving it less protected against viral infections by phages. Among participants in the USA using the same drug, no similar changes were observed.
Reduced health benefits from fibre
Differences in the effect of HIV drugs on the gut microbiome across regions are likely explained by dietary habits. Prevotella is common in Uganda and Botswana and thrives on a high-fibre diet. In people with a Western, low-fibre diet, the bacterium is much less prevalent.
Prevotella is important for our gut microbiome because it specialises in breaking down fibre into simpler sugars that other gut bacteria can utilise. These bacteria, in turn, produce short-chain fatty acids that are beneficial to human health.
A reduction in Prevotella can therefore lead to the loss of other beneficial gut bacteria and a decline in the overall ability to break down fibre, as seen among participants in Uganda and Botswana using efavirenz.
Although they shared the same dietary habits as other participants in these countries, they could no longer benefit from the positive health effects of a fibre-rich diet. They also had a disproportionately high incidence of atherosclerosis, despite low prevalence of common cardiovascular risk factors such as high blood pressure and elevated blood lipids.
"These changes may be due to disruptions in the gut microbiome caused by HIV treatment. Cardiovascular disease is rising sharply in Africa, and HIV is a key risk factor. Our findings suggest that specific drugs may have contributed to this development through their impact on the gut microbiome," she says.
Should be tested in different countries
Karolina Sjöberg Jabbar believes the study’s findings highlight the importance of evaluating drugs in different geographical contexts, not just Western ones.
"Our study shows that drugs can have different side effects in different populations depending on their gut microbiota, which in turn is influenced by diet and lifestyle. This is a factor that may need to be considered when choosing treatment," she says.
"The other key message for me is that disturbances of the interaction between viruses, bacteria, and human cells in the gut can lead to cascading effects with major implications for our health. Research has only begun to scratch the surface of these complex relationships,"she adds.
The study was conducted by researchers at the University of Gothenburg, the Broad Institute, which is part of MIT and Harvard, and the Ragon Institute of Mass General Brigham, MIT, and Harvard.
TEXT OCH PHOTO: KARIN ALLANDER
