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Does cholesterol hold the key ...

Posted Sep 20 2011 4:16am
Does cholesterol hold the key to a vaccine against Aids? Scientists find way to stop HIV damaging the immune system

Sad if this is seen as further demonization of cholesterol. It in fact demonstrates the importance of cholesterol

Scientists have found a way to prevent HIV from damaging the immune system and say their discovery may offer a new approach to developing a vaccine against Aids.

Researchers from the United States and Europe working in laboratories on the human immunodeficiency virus (HIV) found it is unable to damage the immune system if cholesterol is removed from the virus's membrane.

"It's like an army that has lost its weapons but still has flags, so another army can recognise it and attack it," said Adriano Boasso of Imperial College London, who led the study. The team now plans to investigate how to use this way of inactivating the virus and possibly develop it into a vaccine.

Usually when a person becomes infected with HIV, the body's innate immune response puts up an immediate defence. But some researchers believe HIV causes the innate immune system to overreact. This weakens the immune system's next line of defence, known as the adaptive immune response.

For this study -- published yesterday in the journal Blood -- Boasso's team removed cholesterol from the membrane around the virus and found that this stopped HIV from triggering the innate immune response. This in turn led to a stronger adaptive response, orchestrated by a type of immune cells called T cells.

Aids kills around 1.8 million people a year worldwide. An estimated 2.6 million people caught HIV in 2009, and 33.3 million people are living with the virus.

Major producers of current HIV drugs include Gilead Bristol Myers Squibb, Merck, Pfizer and GlaxoSmithKline.

Scientists from companies, non-profits and governments around the world have been trying for many years to make a vaccine against HIV but have so far had only limited success.

A 2009 study in Thailand involving 16,000 volunteers showed for the first time that a vaccine could prevent HIV infection in a small number of people, but since the efficacy was only around 30 per cent, researchers were forced back to the drawing board.

An American team working on an experimental HIV vaccine said in May that it helped monkeys with a form of the Aids virus control the infection for more than a year, suggesting it may lead to a vaccine for people.

HIV is spread in many ways -- during sex, on needles shared by drug users, in breast milk and in blood - so there is no single easy way to prevent infection.

The virus also mutates quickly and can hide from the immune system, and attacks the very cells sent to battle it. "HIV is very sneaky," Boasso said in a statement. "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 may be why developing a vaccine has proven so tricky. "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."

HIV takes its membrane from the cell that it infects, the researchers explained in their study. This membrane contains cholesterol, which helps keep it fluid and enables it to interact with particular types of cell.

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

Working with scientists Johns Hopkins University, the University of Milan and Innsbruck University, Boasso's team found that if cholesterol is removed from HIV's envelope, it can no longer activate pDCs. As a result, T cells, which orchestrate the adaptive response, can fight the virus more effectively.

SOURCE





An antibiotic found in liver of sharks 'could revolutionise human medicine'

And it's a cholesterol type molecule!

An antibiotic found in sharks could be used as drug to treat human viruses and revolutionise medicine, new research has found.

The compound, found in the liver of the predator, could be used as a new type of drug to treat a broad spectrum of diseases from dengue and yellow fever to hepatitis B, C and D.

The antibiotic, squalamine, is already known to be safe for use in humans as an antiviral agent.

Dr Michael Zasloff, from Georgetown University who led the study, said: ‘To realise that squalamine potentially has broad antiviral properties is immensely exciting, especially since we already know so much from ongoing studies about its behaviour in people.’

They found that in both lab and animal experiments squalamine produced antiviral activity against the human pathogens found in the diseases such as some forms of hepatitis which cannot currently be treated.

Along with offering medical advances this discovery may solve the mystery of how sharks with primitive immune systems can so effectively fight viruses that plague all living creatures.

Dr Zasloff said: ‘I believe squalamine is one of a family of related compounds that protects sharks and some other “primitive” ocean vertebrates, such as the sea lamprey, from viruses. ‘Squalamine appears to protect against viruses that attack the liver and blood tissues, and other similar compounds that we know exist in the shark likely protect against respiratory viral infections, and so on.

‘We may be able to harness the shark's novel immune system to turn all of these antiviral compounds into agents that protect humans against a wide variety of viruses. ‘That would be revolutionary. While many antibacterial agents exist, doctors have few antiviral drugs to help their patients, and few of those are broadly active.’

Dr Zasloff discovered squalamine in 1993 and it has already been used in clinical trials to treat cancer and several eye disorders.

‘I was interested in sharks because of their seemingly primitive but effective immune system. No one could explain why the shark was so hardy,’ he said. When he started to ‘play’ with the compound he found that it inhibited the growth of rapidly growing blood vessels, such as those found in tumour growth and certain retinal diseases.

Since 1995 it has been synthesised in the laboratory rather than taking any natural shark tissue.

Dr Zasloff remained interested in how the natural cholesterol type molecule, which has a net positive electrical charge, acted as an immune agent in sharks.

When it enters cells, and it can only access certain cells including those in blood vessels, capillaries and the liver, squalamine ‘kicks off’ positively-charged proteins that are bound to the negatively charged surface of the cells inner membrane.

Some of these displaced proteins are used by viruses to replicate and without the protein a virus's life cycle is disrupted, the microbe is rendered inert and the cell containing it is destroyed.

This means that squalamine seems to be designed to fight certain viral infections, Dr Zasloff claimed. He said: ‘To me, the key to squalamine is that once in the body it times its action to match the life cycle of most viruses. ‘Most viruses take hours to complete their life cycle, the same time period that squalamine renders tissues and organs viral resistant after administration. ‘In addition, it acts fast to stop viral replication, clearing the body of these predators within hours.

‘Furthermore, because squalamine acts by making the host's tissues less receptive for infection, rather than by targeting a specific viral protein, the emergence of viral resistance would not be anticipated.’

In tissue culture studies squalamine was shown to inhibit the infection of human blood vessel cells by the dengue virus and human liver cells infected with hepatitis B and D, which can cause liver failure and cancer.

In animal studies, scientists from across the USA discovered that squalamine controlled infections of yellow fever, Eastern equine encephalitis virus, and murine cytomegalovirus, and in some cases cured the animals.

The study was published in the Proceedings of the National Academy of Sciences Early Edition online yesterday.

SOURCE
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