Study shows how HIV is shielded from Immune Attack

Scientists from UNSW Sydney and the UK have discovered that the human immunodeficiency virus (HIV) hijacks a small molecule from the host cell to protect itself from being destroyed by the host's immune system.

The finding, as well as details of the new strategy that enabled it, are published as back-to-back papers in eLife. They identify a new target for antiviral therapy against HIV and provide a method for testing and measuring new drugs designed to target the capsid.

UNSW Ph.D. student Chantal Márquez is involved in both studies and is the first author of the paper describing the new method.

HIV forms a protein shell—called a capsid—that shields its genetic material from host defence mechanisms as it enters the cell and makes its way to the nucleus to establish infection.

Using a new single-molecule microscopy technique—developed at UNSW's Single Molecule Science in the Faculty of Medicine—the research teams found that HIV specifically incorporates a small molecule from the host cell—inositol hexakisphosphate—to strengthen its capsid. The host inadvertently provides the key for the virus infecting it to lock down the protective shell, keeping the genetic cargo safe until it is released into the nucleus.

"The HIV capsid falls apart within minutes once it's isolated from the virus," said Associate Professor Till Böcking, who led the UNSW team involved in both studies.

"Our strategy lets us study exactly how a native capsid breaks apart in real-time without taking it out of the viral membrane."

With the help of Associate Professor Stuart Turville of the Kirby Institute, the team engineered viruses with fluorescent tags to monitor the viral capsid using fluorescence microscopy.

"We can now see the effect of different molecules on the capsid, and pinpoint precisely when it cracks open and begins to collapse," says Associate Professor Böcking.

"Capsids need to be much more stable inside a cell because the infection process takes hours, not minutes—so we wanted to find out what keeps it stable inside a cell," says Dr. David Jacques of Single Molecule Science, who is an author of both studies.

The researchers found that inositol hexakisphosphate, which is abundantly present inside mammalian cells, makes the capsid much stronger, stabilizing it for 10-20 hours.

"It's like a switch. When you bind this molecule, you stabilize the capsid, and release the molecule to open it up," explains Associate Professor Böcking.

"The HIV capsid has been intensively studied, but the question of how it can simultaneously be both stable and poised to 'uncoat' has been one of the great unanswered questions in HIV biology," says Dr. Leo James, leader of the research team at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.

Most of the currently approved HIV therapies target enzymes needed at different stages of the virus' life cycle, but none of them are directed at the HIV capsid. New drug alternatives could improve the treatment of HIV with reduced toxic effects.

Source: https://medicalxpress.com/news/2018-07-hiv-shielded-immune.html

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New antibody attacks 99% of HIV strains

Scientists have engineered an antibody that attacks 99% of HIV strains and can prevent infection in primates.

 It is built to attack three critical parts of the virus - making it harder for HIV to resist its effects.

The work is a collaboration between the US National Institutes of Health and the pharmaceutical company Sanofi.

The International Aids Society said it was an "exciting breakthrough". Human trials will start in 2018 to see if it can prevent or treat infection.

Our bodies struggle to fight HIV because of the virus' incredible ability to mutate and change its appearance.

These varieties of HIV - or strains - in a single patient are comparable to those of influenza during a worldwide flu season.

So, the immune system finds itself in a fight against an insurmountable number of strains of HIV.

Super-antibodies

But after years of infection, a small number of patients develop powerful weapons called "broadly neutralising antibodies" that attack something fundamental to HIV and can kill large swathes of HIV strains.

Researchers have been trying to use broadly neutralising antibodies as a way to treat HIV or prevent infection in the first place.

The study, published in the journal Science, combines three such antibodies into an even more powerful "tri-specific antibody".

Dr Gary Nabel, the chief scientific officer at Sanofi and one of the report authors, told the BBC News website: "They are more potent and have greater breadth than any single naturally occurring antibody that's been discovered."

The best naturally occurring antibodies will target 90% of HIV strains.

"We're getting 99% coverage, and getting coverage at very low concentrations of the antibody," said Dr Nabel.

Experiments on 24 monkeys showed none of those given the tri-specific antibody developed an infection when they were later injected with the virus.

Dr Nabel said: "It was quite an impressive degree of protection."

The work included scientists at Harvard Medical School, The Scripps Research Institute, and the Massachusetts Institute of Technology.

'Exciting'

Clinical trials to test the antibody in people will start next year.

Prof Linda-Gail Bekker, the president of the International Aids Society, told the BBC: "This paper reports an exciting breakthrough.

"These super-engineered antibodies seem to go beyond the natural and could have more applications than we have imagined to date.

"It's early days yet, and as a scientist I look forward to seeing the first trials get off the ground in 2018.

"As a doctor in Africa, I feel the urgency to confirm these findings in humans as soon as possible."

Dr Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases, said it was an intriguing approach.

He added: "Combinations of antibodies that each bind to a distinct site on HIV may best overcome the defences of the virus in the effort to achieve effective antibody-based treatment and prevention."

Source: https://www.bbc.com/news/health-41351159

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Gonorrhea researchers identify novel route to vaccine, new antibiotic

Researchers have identified a protein that powers the virulence of the bacteria that causes gonorrhea, opening the possibility of a new target for antibiotics and, even better, a vaccine.

The findings, published today in PLOS Pathogens, are especially important since the microbe, Neisseria gonorrhoeae, is considered a "superbug" because of its resistance to all classes of antibiotics available for treating infections.

Gonorrhea, a sexually transmitted disease that results in 78 million new cases worldwide each year, is highly damaging if untreated or improperly treated.

It can lead to endometritis, pelvic inflammatory disease, ectopic pregnancy, epididymitis and infertility. Babies born to infected mothers are at increased risk of blindness.

"The infections very often are silent," said Oregon State University researcher Aleksandra Sikora. "Up to 50 percent of infected women don't have symptoms, but those asymptomatic cases can still lead to some very severe consequences for the patient's reproductive health, miscarriage or premature delivery."

The need for better antibiotic therapy, and a vaccine, is pressing. N. gonorrhoeae strains resistant to the last effective treatment options have emerged, and failures in treatment are occurring.

Sikora and her research team at the OSU/OHSU College of Pharmacy and Ann Jerse's lab at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, collaborated to discover a novel lipoprotein that N. gonorrhoeae uses to defeat the body's first line of innate immune defense.

The body relies on enzymes known as lysozymes that, as their name suggests, thwart bacteria by causing their cell wall to lyse, or break apart. Lysozymes are abundant both in epithelial cells, which make up the tissue on the outside of organs and the inside of body cavities, and in the phagocytic cells that protect the body by ingesting foreign particles and bacteria.

In turn, many gram-negative bacteria -- characterized by their cell envelope that includes a protective outer membrane -- have developed ways of defeating lysozymes. Prior to the work by Sikora's team, however, only one lysozyme-fighting protein had been discovered in the Neisseria genus.

Now that new targets have been identified, they can be explored as bullseye candidates for new antibiotics or a vaccine -- if the lysozyme inhibitor can itself be inhibited, then the bacteria's infection-causing ability is greatly reduced.

Sikora and her collaborators named the new protein SliC, short for surface-exposed lysozyme inhibitor of c-type lysozyme.

Studying SliC's function in culture as well as in a gonorrhea mouse model -- mice were infected with N. gonorrhoeae, then checked for SliC expression at one, three and five days -- researchers determined the protein was essential to bacterial colonization because of its anti-lysozyme role.

"This is the first time an animal model has been used to demonstrate a lysozyme inhibitor's role in gonorrhea infection," Sikora said. "Together, all of our experiments show how important the lysozyme inhibitor is. This is very exciting."

Source: https://www.sciencedaily.com/releases/2018/07/180705143834.htm

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