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More HIV Research Findings

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    Posted: July 10 2018 at 6:09pm
Scientists find method to help target HIV virus in human cells

2018-07-10 16:32:35

SYDNEY, July 10 (Xinhua) -- Scientists from Australia and Britain have discovered a new method which may help to target the HIV virus as it makes its way to infecting cells.

Scientists from the University of New South Wales (UNSW) in Australia, led by Associate professor Till Bocking, described on Tuesday how the HIV virus forms a protein shell called a capsid, to protect itself from the hosts defence mechanism as it infects the nucleus of a cell.

Using a new microscope technique developed at UNSW, the team discovered that the HIV virus uses a molecule from the host cell to strengthen its capsid.

"It's like a switch, when you bind this molecule, you stabilize the capsid, and release the molecule to open it up," Bocking said.

The molecule, called inositol hexakisphosphate, is abundantly present in mammals and has been seen to make the HIV capsid much stronger, stabilising it for 10 to 20 hours.

Because the infection process takes hours, it was crucial for scientists to find out how the virus was keeping stable within the cell.

"The HIV capsid has been intensively studied," leader of the British research team at Cambridge, Dr Leo James said.

"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."

To assist in their study, 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," Bocking said.

In the team's findings, 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.

While there currently no HIV therapies targeted at the HIV capsid, it is hoped that new therapies could improve treatment with reduced toxic effects.

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.............. 'And while we are on the subject:

The HIV Epidemic Is Not Over, And We're Not as Prepared as We Need to Be

There could be a resurgence.

MIKE MCRAE
20 JUL 2018

Authors of a commission into the state of the global AIDS epidemic warn policy makers and researchers to do a better job of collaborating if we're to have a hope of meeting targets.

More concerning still is their prediction that persistence of high HIV rates in many populations could spark a resurgence, and current funding and practices just aren't up to the challenge of dealing with it.

A Lancet Commission led by the International AIDS Society has published a report combining the expertise of more than 40 experts from around the globe, providing a snapshot of where we're currently at with one of history's most notorious epidemics.

And the news could be better. A lot better.

It's been roughly 40 years since acquired immunodeficiency syndrome – or AIDS – made the leap from being a rare and obscure illness to the start of a global pandemic.

Progress in prevention and treatments has been hampered by its stigma as a disease associated with vice, and in spite of a pharmacopeia of life-prolonging drugs and prophylactics, we still don't have an effective vaccine.

Based on figures collected between 2015 and 2016, just under 40 million people worldwide are infected with the virus, with 2 million newly diagnosed in 2016 alone.

Tragically, more than 35 million people have succumbed to the virus's debilitating effects on the immune system, a number that rises in spite of treatments that keep the virus's progress under control.

Thankfully, the rate of new infections is dropping. But for the Joint United Nations Programme on HIV/AIDS (UNAIDS), the decline is not fast enough. Right now its target is to see just 500,000 new cases per year by 2020, with an end goal of a complete eradication by 2030.

"The HIV pandemic is not on track to end," says the report.

The commission points the finger at complacency that "may have hastened the weakening of global resolve to combat HIV."

Putting it another way, the fear has died down and the drive to solve the crisis has waned.

"Global health is beginning to falter as democracy, civil society, and human rights deteriorate in many countries, and as development assistance for health has stalled," says lead commissioner and president of the International AIDS Society, Linda-Gail Bekker.

In some ways, the age old problem of AIDS as a stigmatised condition is still responsible.

Just under half of all new infections occur in people from marginalised groups, such as gay and bisexual men and intravenous drug users, and healthcare systems often struggle to reach and engage with these communities.

In sub-Saharan Africa, HIV infection rates peak in adolescent girls. There, AIDS is the fourth highest cause of death for young women.

Reaching young and diverse demographics with advice they trust is a challenge. The commission warns as the population gets older, we could see a resurgence in the number of new infections. Added to that is a rise in other complications.

Between 2012 and 2016, the number of people over the age of 50 living with HIV jumped by more than a third. Where communicable diseases were once the big problem, anti-retroviral therapies have extended the life of those living with HIV to the extent that other health conditions become a concern.

Recent research has found that HIV puts people at more than double the risk of cardiovascular disease, for example.

To meet these changes in the future and have a hope of meeting the UNAIDS targets, the commission suggests we need to step beyond what they refer to as an 'exceptionalist' approach.

In the past, funding and programs have targeted HIV in isolation.

While this has no doubt proven useful in cutting the rates of infection, the commission refers to models that demonstrate there is a greater benefit in combining HIV testing and treatment with other health services, such as screening for diabetes.

HIV funding has flat-lined in recent years, falling well short of the some US$26 billion estimated as necessary to meet targets.

Finding new ways to pool efforts and develop new strategies is vital if we're to finally see an end to the AIDS pandemic, something that might only be possible if we develop and successfully distribute an effective vaccine.

"The HIV response and the broader global health field must work together," says Bekker.

"Despite the remarkable progress of the HIV response, the situation has stagnated in the past decade. Reinvigorating this work will be demanding, but the future health and wellbeing of millions of people require that we meet this challenge."


Source:   https://www.sciencealert.com/hiv-commission-failing-targets-advice-changingexclusionary-approach

the BBC also carries a similar story:   https://www.bbc.co.uk/news/health-44884593
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Scientists unveil promising new HIV vaccine strategy

Date:
    November 26, 2018
Source:
    Scripps Research Institute
Summary:
    A new candidate HIV vaccine surmounts technical hurdles that stymied previous vaccine efforts, and stimulates a powerful anti-HIV antibody response in animal tests. The new vaccine strategy is based on the HIV envelope protein, Env. This complex, shape-shifting molecule has been notoriously difficult to produce in vaccines in a way that induces useful immunity to HIV.

FULL STORY

A new candidate HIV vaccine from Scripps Research surmounts technical hurdles that stymied previous vaccine efforts, and stimulates a powerful anti-HIV antibody response in animal tests.

The new vaccine strategy, described in a paper on November 23 in Science Advances, is based on the HIV envelope protein, Env. This complex, shape-shifting molecule has been notoriously difficult to produce in vaccines in a way that induces useful immunity to HIV.

However, the Scripps Research scientists found a simple, elegant method for stabilizing Env proteins in the desired shape even for diverse strains of HIV. Mounted on virus-like particles to mimic a whole virus, the stabilized Env proteins elicited robust anti-HIV antibody responses in mice and rabbits. Candidate vaccines based on this strategy are now being tested in monkeys.

"We see this new approach as a general solution to the long-standing problems of HIV vaccine design," says principal investigator Jiang Zhu, associate professor in the Department of Integrative Structural and Computation Biology at Scripps Research.

Copies of Env study the surface of HIV; their chief function is to grab hold of host cells and break into them to initiate infection. Since Env plays this crucial role in infection, and is the viral structure with the most exposure to the immune system of an infected host, it has been the main target of HIV vaccine efforts. The idea has been to inoculate people with the whole Env protein or subunits of it to stimulate the production of Env-binding antibodies, in the hope that these antibodies will prevent HIV from infecting host cells in future exposures to the virus.

So far, of course, no HIV vaccine has been effective in large-scale clinical trials. Many researchers believe that an HIV vaccine can work if it presents Env proteins to the immune system in a way that closely resembles the shape of Env on a real virus before it has infected a cell. But presenting Env correctly has been a huge challenge.

On an HIV virus, Env protrudes from the viral membrane in tight clusters of three, called trimers, and these complex structures adopt radically different shapes before and after infecting cells. HIV vaccine researchers, despite years and tens of millions of dollars of experimentation, have failed to find a broadly applicable method for stabilizing Env trimers in the desired, pre-infection shape.

"The trimer-stabilization solutions that have been reported so far have worked for a few HIV strains but have not been generalizable," Zhu says. "Env trimer 'metastability', as we call it, has really been a central problem for trimer-based HIV vaccine design."

Zhu, trained as a biophysicist, sought a more general solution to the Env stability problem, and in a paper in 2016 he and his Scripps Research colleagues reported that modifying a short, springy section of Env called HR1 might do the trick -- it allowed Env to stay in the pre-infection, "closed" shape.

In the new study he and his team showed that this strategy does indeed work for Env trimers from diverse HIV strains circulating in different parts of the world. This "uncleaved prefusion-optimized" (UFO) approach, as they call it, yields Env trimers that are stabilized in the closed shape and can be produced efficiently, with surprisingly little need for purification, in the types of cells normally used in biotech manufacturing.

"By now in my lab we've made this modification to Envs from 30 to 40 different HIV strains, and in most of the cases it has worked like a charm," Zhu says.

He and his colleagues further optimized their vaccine strategy by genetically linking their stabilized Env trimers, up to 60 at a time, to individual nanoparticles that mimic the globular shape of a whole virus. In this way the vaccine molecule, though artificial and lacking the genetic material for viral replication, seems to the immune system very much like a real invading virus and stimulates a stronger reaction.

In mice, Zhu and his team found, a sample Env-on-nanoparticles vaccine, within just eight weeks, elicited antibodies that in lab tests successfully neutralized a naturally circulating HIV strain -- of a type that prior candidate vaccines generally have failed against.

"This is the first time any candidate HIV vaccine has induced this desired type of antibody response in mice," Zhu says. Similarly unprecedented results were obtained in rabbits, demonstrating that the nanoparticle-based approach is clearly superior to the use of isolated Env proteins -- it elicits a significantly stronger response and does so much more quickly.

Further tests are now underway in 24 monkeys at the National Institutes of Health-sponsored Southwest National Primate Center in San Antonio, Texas.

Zhu and Scripps Research have licensed their HIV vaccine technology to a startup company, Ufovax LLC, which is sponsoring the ongoing tests. "We're now testing two candidate vaccines based on Env trimers from different HIV strains, plus a third candidate vaccine that is a cocktail of three Env-based vaccines," says Ji Li, Ufovax CEO. "We think this new approach represents a true breakthrough after 30 years of HIV vaccine research."

Story Source:

Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.

Journal Reference:

    Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward, David Nemazee, Dennis R. Burton, Ian A. Wilson, Jiang Zhu. HIV-1 vaccine design through minimizing envelope metastability. Science Advances, 2018; 4 (11): eaau6769 DOI: 10.1126/sciadv.aau6769

Cite This Page:

Scripps Research Institute. "Scientists unveil promising new HIV vaccine strategy." ScienceDaily. ScienceDaily, 26 November 2018. <www.sciencedaily.com/releases/2018/11/181126105516.htm>.

Source and photo:   https://www.sciencedaily.com/releases/2018/11/181126105516.htm
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