Health complications that often plague people living with HIV, and can prove fatal, might be reduced with the help of a drug already used to treat
kidney disease – if it works as well in people as it does in monkeys.
The finding provides the first direct proof that microbes that leave the gut and travel to the rest of the body – a process called microbial translocation – is the mechanism that triggers these health complication in people with HIV.
Chronic activation of the immune system and inflammation are key triggers for the development of AIDS in many people with HIV, even if they are doing well on anti-retroviral drugs. That's because these immune responses in turn trigger a constellation of diseases normally associating with ageing, such as cardiovascular disease.
One hypothesis is that
HIV damages the gut wall, allowing bacteria to leak out into the rest of the body, including the blood and other organs. Outside the gut, these bacteria prompt an inflammatory response that can lead to a cascade of other diseases.
Gut barrier
Earlier research found that people with HIV who had a leakier gut were more likely to die from these diseases. "Gut barrier integrity and immune activation predicts mortality; the leakier the gut, the sooner the patient dies," says
Peter Hunt at the University of California, San Francisco, who conducted that research.
To find out whether microbial translocation is responsible,
Ivona Pandrea at the University of Pittsburgh, Pennsylvania, and her colleagues gave a drug called sevelamer, every day for three months, to monkeys newly infected with the simian equivalent of HIV. Sevelamer is used to manage symptoms of chronic kidney disease, because it binds to unwanted phosphates in the gut, which the kidneys can no longer remove. But
it can also bind to bacterial proteins, keeping them inside the gut where they can do no harm.
The team took blood samples from the monkeys at regular intervals to look for molecules that indicate activation of the immune system, as well as measuring the viral load of HIV, and compared these to a control group that did not receive the drug.
The researchers saw a dramatic reduction in systemic immune activation and inflammation, and a slight reduction in viral replication, in the group given sevelamer, compared to the control. "It suggests that early control of microbial translocation may improve the outcome of HIV infection and limit non-infectious [diseases] associated with AIDS such as cardiovascular disease," Pandrea says.
However, it may not be easy to get the same response in people.
No significant benefit
Four separate teams have tried different drugs including sevelamer to reduce microbial translocation and immune activation in humans, so far with no significant benefits, according to results presented at the
Conference on Retroviruses and Opportunistic Infections which was held in Boston in March.
But Hunt thinks this may just be down to timing. The monkeys were treated early in the acute phase of their disease, soon after they were infected, whereas people in the studies had all been infected for many months or even years.
People infected with HIV have few signs of microbial translocation during the first six months of infection as it takes time for the virus to kill off epithelial cells and weaken the gut wall so that bacteria can leak through – so treating them early could be more effective.
Alternatively, a combination of treatments might work, Hunt says, possibly using a probiotic to modulate the gut microbiome, and an anti-inflammatory drug to dampen the immune response and problems associated with immune activation.
Journal reference:
Journal of Clinical Investigation, DOI: 10.1172/JCI75090.
