Scientists disarm HIV to prevent it damaging the immune system

HIV particles showing the core and the envelope
Researchers have found a way to prevent HIV from damaging the immune system, in a new lab-based study published in the journal ‘Blood’. The research could have important implications for the development of HIV vaccines.

AIDS, which results from infection by HIV, is the third most common cause of death in low-income countries, killing around 1.8 million people a year worldwide. An estimated 2.6 million people became infected with HIV in 2009. No vaccine against the virus currently exists.

Usually, when a person becomes infected with a virus or bacteria, the body’s innate immune response provides an immediate defence. However, some researchers believe that HIV causes the body’s innate immune system to overreact, weakening the immune system’s next line of defence - the adaptive immune response.

Now, in research funded by the Wellcome Trust and the National Institutes of Health, scientists from Imperial College London and Johns Hopkins University have shown that HIV is unable to damage the immune system if cholesterol is removed from the virus’s membrane. When the researchers removed the cholesterol, they found that this stopped HIV from triggering the innate immune response.

This led to a stronger adaptive response, orchestrated by immune cells called T cells. These results support the idea that HIV overstimulates the innate response and hence weakens the immune system.

Dr Adriano Boasso, a Wellcome Trust Research Career Development Fellow at Imperial College London, said: "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.

“This may be one reason why developing a vaccine has proven so difficult. Most vaccines prime the adaptive response to recognise the invader, but it’s hard for this to work if the virus triggers other mechanisms that weaken the adaptive response.”

Cell membranes contain cholesterol, which helps the membrane remain fluid. The cholesterol in the cell membrane is not connected to cholesterol in the blood, which is a risk factor for heart disease. HIV envelops itself in the membrane of the cell that it infects and uses it to interact with particular types of cell.

Normally, a subset of immune cells called plasmacytoid dendritic cells (pDCs) recognise HIV quickly and react by producing signalling molecules called interferons. These signals activate various processes, which are initially helpful but damage the immune system if switched on for too long.

In collaboration with researchers at Johns Hopkins University, the University of Milan and Innsbruck University, Dr Boasso’s group at Imperial has discovered that if cholesterol is removed from HIV’s envelope, it can no longer activate pDCs. As a consequence, T cells, which orchestrate the adaptive response, can fight the virus more effectively.

The researchers removed cholesterol using varying concentrations of beta-cyclodextrin, a derivative of starch that binds cholesterol. Using high levels of this molecule, they produced a virus with a large hole in its envelope.

This ’perforated’ virus was not infectious and could not activate pDCs but was still recognised by T cells. Dr Boasso and his colleagues are now looking to investigate whether this inactivated virus could be developed into a vaccine.

“It’s like an army that has lost its weapons but still has flags, so another army can recognise it and attack it,” he said.

Boasso A et al. Over-activation of plasmacytoid dendritic cell inhibits anti-viral T cell responses: a model for HIV immunopathogenesis. Blood 2011.