Removing cholesterol from HIV’s membrane stops it damaging the immune system, bringing the idea of a vaccine that uses this way of making an inactive virus a step closer. You can read how scientists at Imperial College London and Johns Hopkins University and colleagues came to these conclusions in the latest issue of the journal Blood which was published online ahead of print last week.
Many researchers believe the reason HIV infects humans so successfully is because when it enters the body it causes the immune system’s first line of defence, the so-called “innate immune system” to overreact. This is a problem because when the innate immune system overreacts it weakens the second line of defence, the “adaptive immune response”, which otherwise would be powerful enough to cause HIV significant harm.
As first author Dr Adriano Boasso from Imperial College London explained to the press:
“HIV is very sneaky. It evades the host’s defences by triggering overblown responses that damage the immune system. It’s like revving your car in first gear for too long. Eventually the engine blows out.”
He said this could be one reason why it’s so hard to make a vaccine for HIV. Most vaccines boost the adaptive response to recognize and attack the foreign agent, but if the first thing that agent does is activate processes that weaken the adaptive response, then what do you do?
So he and his colleagues looked for a way to disarm HIV and prevent it taking that first step of triggering the innate immune response and so give the adaptive response a chance.
Viruses are not complete cells like bacteria: they survive and replicate by invading host cells and taking over their resources to do their bidding. One of the first things HIV does when it invades a host cell is steal its membrane to make its own “envelope”. This contains cholesterol (not the same one that clogs up arteries) which helps to keep it fluid so the virus can interact with other cells and continue with its work.
In the meantime, other things are also going on. When HIV first enters the body, a group of cells, the plasmacytoid dendritic cells (pDCs), recognizes the virus and immediately starts signalling, using molecules called interferons. These signals trigger immune responses that are helpful to start with, but if left switched on, begin to damage the immune system.
HIV makes sure they stay switched on, and it appears that it needs that fluid membrane containing cholesterol to do it, or so this study would suggest.
To test this, the team, including members from the University of Milan and Innsbruck University, removed cholesterol from the HIV envelope. They found this stopped the activation of pDCs, which in turn allowed the second line of defence, the T cells, to stay strong and orchestrate the adaptive response to fight off the virus effectively.
They used a compound called beta-cyclodextrin (bCD), a derivative of starch that binds cholesterol, at varying concentrations to effect graded withdrawal of cholesterol. High concentrations of bCD made big holes in the HIV envelope. These made the membrane so permeable that the virus could not activate the pDCs, but it could still be recognized by the T cells.
“It’s like an army that has lost its weapons but still has flags, so another army can recognise it and attack it,” said Boasso.
“Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions [virus particles], rendered HIV a more powerful recall immunogen for stimulating memory CD8 T cell responses in HIV-exposed uninfected individuals,” he and his co-authors write in their paper.
They conclude their findings support the idea that HIV overstimulates the innate response, and this in turn weakens the immune system.
They now want to find out whether this inactivated virus could be turned into a vaccine.
HIV/AIDS is the third biggest cause of death in low income countries, and kills 1.8 million people a year worldwide.
Funds from the Wellcome Trust and the National Institutes of Health (US) helped pay for the study.
Written by Catharine Paddock PhD