HIV Damages and Sneaks Through

posted: 14/04/2010

HIV damages the cell walls of the genitals’ mucous membrane, and this lets HIV slip through to infect the vulnerable cells below, we have now learnt from a study. Most experts thought that HIV got through the mucous membrane itself, where these already had surface damage. This new scientific finding steers scientists who are creating microbicides and vaccines, to design these so they block contact between a very specific HIV protein and those in genital mucous membranes.

Microbicide hopes raised
This is an example of basic laboratory research into learning exactly how HIV attacks and works that may help solve a big HIV prevention problem. Women lack a HIV prevention method that they can control. Microbicides and vaccines are the best hope, but none have succeeded. This research gives microbicide and vaccine researchers a clear target to focus on. A few years down the line, we may see more hopeful signs of workable microbicides and vaccines appearing.

All sexual transmission of HIV occurs through mucous membranes. These researchers have basically found out that HIV has a protein that makes genital mucous membranes easier to pass through and cause infection. Previously researchers into HIV transmission had thought that transmission was most likely to occur either when the mucous membrane was damaged (for example through trauma or ulcers), or when many activated immune cells were present (such as during a sexually transmitted infection like gonorrhoea).

Disease progression?
The same ‘damage the cell walls and then sneak past’ strategy used by HIV for infecting people is thought by some experts to also help explain HIV disease progression and the development of some serious conditions, such as atherosclerosis (hardening and narrowing of the arteries).

How HIV does it
This study found that HIV weakens the integrity of surface cells, even when they are undamaged.

"It makes the electrical barrier resistance of epithelial cells decrease. By doing that, the virus can cross the barrier," said lead researcher Charu Kaushic, associate professor in the Centre for Gene Therapeutics at McMaster University, Ontario, Canada.

How does HIV actually get underneath epithelial cells to infect other cells that are susceptible to HIV? "It's not the cells on top," Kaushic said. "It is the immune cells underneath that have all the receptors that HIV likes to latch on to and that allow the virus to replicate and establish infection. But it has to cross the epithelial barrier first!"

Aisha Nazli, a researcher in Kaushic's laboratory, noticed every time she put HIV on epithelial cells, their electrical resistance went down significantly. It happened every time she tried this.

Protein break through

Kaushic said the surface protein of the virus (the gp120 surface protein) causes the epithelial barrier to break. "The surface protein signals to the inside of the epithelial cells by binding to it", she said. "The epithelial cells start making inflammatory proteins which cause these cells to go on their self-destructive pathway."

The researchers say if viral load and exposure time are enough, HIV can probably disrupt any mucosal barrier in the body, although infection may not necessarily occur every time.

"This is a significant step forward in defining where prevention strategies, such as microbicides and vaccines, need to focus. Instead of trying to stop HIV from infecting the target cells underneath the epithelium, we need to think about ways to stop the virus from attaching to epithelial cells themselves," said Charu Kaushic.

Source

Nazli A et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathogens 6 (4): e1000852, 2010. (full article, free access)

HIV Genes Decoded

posted: 06/08/2009

Scientists say they have decoded the entire genetic structure of HIV-1 which is the key type of HIV. They hope this will lead to a better understanding of how HIV works, and it could speed the development of new types of treatment.

The new research in the USA was published in Nature and it decoding the genes is an important breakthrough. It is a task that would have been impossible just a few years back. HIV, like the viruses which cause influenza, hepatitis C and polio, carries its genetic information as single-stranded RNA rather than double-stranded DNA.The information enclosed in RNA is more complex than information in double-stranded DNA.

RNA's intricate patterns revealed

RNA is folds itself into intricate patterns and structures. Decoding the full genome therefore opens up genetic information that could not be seen before and may explain why the virus acts as it does.

Double-stranded DNA depends on building blocks called nucleotides to carry information. These are the familiar A, C, T and G of the genetic code. However by contrast RNA has just one strand and depends on complex folding patterns to carry information, as well as nucleotides.

"There is so much structure in the HIV RNA genome that it almost certainly plays a previously unappreciated role in the expression of the genetic code," Weeks said.

"The technique is thus akin to zooming out on a map and getting a broader view of the landscape at the expense of fine details," Hashim Al-Hashimi of the University of Michigan wrote in a commentary in Nature.

This will help researchers make better drugs, said Weeks. New drugs are often engineered to fit into specific structures on a virus, blocking it from attaching to a cell, for instance, or gumming up its works so it cannot replicate.

But RNA viruses are especially hard to defend against.

New drug type possibilities

Weeks said the new imaging technique will help researchers find new approaches. "In the short term it almost certainly is going to make it easier to design short, interfering RNAs," he said. These drugs, known as siRNAs for short, stop RNA from functioning and can interfere with defective cells or bacteria and viruses.

Companies such as Merck and Co. and Silence Therapeutics Plc are working to use this approach.

"SiRNAs can be very potent," Weeks said. "They are expensive to make but they are relatively easy to design."

New SHAPE method for RNA

His team developed a new chemical method called SHAPE to make an image not only of the RNA's nucleotides, but of the shapes and folds of the RNA strands.

Other imaging methods such as X-ray crystallography can capture the precise position of each atom, but only one small area at a time. SHAPE gets a bigger picture, but not at the atomic level, Weeks said. The team, from the University of North Carolina, said they planned to use the information to see if they could make tiny changes to the virus.

Tiny Tweaks to HIV Virus

"If it doesn't grow as well when you disrupt the virus with mutations, then you know you've mutated or affected something that was important to the virus," says Ron Swanstrom, professor of microbiology and immunology. "We are also beginning to understand the tricks the genome uses to help the virus escape detection by the human host."

Manchester welcomes news

Dr David Robertson from the University of Manchester welcomed this "definitive analysis". "What this may reveal is some of the proteins operating at a level below the structures, which may have all sorts of functions within the virus. More generally, if we can unpick the structures then we can compare the systems of different viruses and gain new understanding of how they work."

Keith Alcorn of the HIV information service NAM added: "Encouraging the virus to mutate is not a new idea, but it is one of a number of options on the table. How important this information will be for the development of new drugs remains to be seen, but it is a useful addition to what we know."

Source and Source

RNA image