There are millions living with HIV and researchers have been working towards making a successful vaccine against the deadly infection for the past 35 years with no success. Now a new blueprint is being developed to prevent the infection.

A team of researchers from Duke University and Harvard have worked towards making a vaccine that can imitate a rare process in the immune system that is seen in persons with HIV. This process can help reduce the viral load of the body, explain the researchers.

The study results were published in the latest issue of the journal Science.

Researchers warn that this may be the first step in the development of an effective vaccine against the infection and there may be many bridges to cross before the final vaccine is ready for human use and is tried in large scale clinical trials.

Barton Haynes, director of the Duke Human Vaccine Institute, who was the lead author of the study said in a statement, “For the first 20 years after the virus was discovered, the field tried to make a vaccine using the techniques that all the successful measles, mumps, rubella, polio vaccines had been made within the past. And none of those worked.” He explained that the virus is constantly changing and thus every vaccine developed failed to generate antibodies that could fight the infection off.

The researchers explained in their work that in around 20 percent of the persons infected with HIV, the immune system makes a special protein called “broadly neutralizing antibodies” (bnAbs). These antibodies are powerful enough to remove the viruses in regions that remain same despite mutations. This means that the HIV may mutate but the antibodies would still be able to attack and remove them and not allow the viruses to replicate. These antibodies cannot cure a person with HIV however because some reservoirs of viruses remain within certain cells where the antibodies fail to reach them.

There have been studies where animal models of HIV have been injected with these antibodies and results showed that new infections could be prevented by these injections. This protection however did not last and was too short lived explain the researchers. To make an effective vaccine the researchers needed a shot that would provide long term protection from HIV infection.

Thus for this new study the team used technology of computer modelling and followed it up with lab testing to see if the mice and monkeys could train their immune systems to create these antibodies and fight off the infection. Haynes said, “We show a new way to design the HIV vaccine to guide the broadly neutralizing antibodies to go down paths they rarely go down on their own.”

They wrote that they “hypothesized that vaccination with immunogens that bind with moderate to high affinity to bnAb B cell precursors, and with higher affinity to precursors that have acquired improbable mutations, could initiate bnAb B cell lineages and select for key improbable mutations required for bnAb development.” They wrote in their results section, “…our immunogens elicited antibody responses in macaques and knock-in mice that exhibited the mutational patterns, structural characteristics, or neutralization profiles of nascent broadly neutralizing antibodies.”

They first designed HIV-1 envelope immunogens (moieties that could mimic the cover of an HIV-1 virus and stimulate the immune response). These immunogens were bound to bound precursor B cells at the CD4 binding site or else at the V3-glycan bnAb lineage. They then vaccinated lab macaques with the CD4 bound antibodies, They also used genetically modified mice called “knock in mice”. These mice had genes to secrete the needed bnAb. From these mice the isolated bnAbs were found to neutralize the HIV-1 global isolates. These bnAbs were found to kill the HIV-1 isolates despite their mutations, the team noted.

Other experts have lauded this approach saying that the body would be the best manufacturer of the antibodies that could fight off the HIV infection. This work is one third completed with development of essential antibodies that could fight off the infection. They hope to soon have the tools for an effective HIV vaccine.

The team wrote in conclusion, “…this study demonstrates a rational strategy for sequential immunogen design to circumvent the difficult roadblocks in HIV-1 bnAb induction by vaccination…This strategy of selection of specific antibody nucleotides by immunogen design can be applied to B cell lineages targeting other pathogens where guided affinity maturation is needed for a protective antibody response.”

Dr. John Mascola, director of the Vaccine Research Center at the National Institutes of Health (NIH) in a statement said that this new vaccine could be 80 to 90 percent effective and estimates that it would be ready for trials in large clinical trials in another five years.

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The Wistar Institute was awarded two major grants totaling more than $12 million from the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, to fund an international multidisciplinary clinical research consortium spearheaded by Wistar’s HIV Research Program. The consortium, including several partner institutions in the U.S. and abroad, will investigate the impact of opioid use disorder (OUD) and medications for opioid use disorder (MOUDs) on immune recovery in response to antiretroviral therapy (ART) in HIV-infected people.

Both HIV infection and chronic opioid exposure are associated with immune activation, which leads to T-cell depletion and progression to acquired immunodeficiency syndrome (AIDS).

OUD is commonly treated with drugs that either activate (agonists) or block (antagonists) the opioid receptor. “Yet, we have a very limited understanding of how the medications we use to treat OUD impact disease progression and the response to ART in people living with HIV,” commented Montaner.

The overarching goal of this research is to investigate the role of opioid receptor involvement in modulating the levels of immune activation, and the effects of different classes of MOUDs, in people living with HIV. Effectively controlling immune activation after ART in persons taking MOUDS can directly impact health and mortality.

The NIDA support of this initiative will fund two clinical studies:

• The first grant provides $8,373,891 over five years for an international trial conducted among the U.S., Vietnam and France, in collaboration with the Vietnam Ministry of Health, the Perelman School of Medicine at the University of Pennsylvania, the Institute of Applied Medicine and Epidemiology (a French-led initiative to expand access to HIV/hepatitis prevention and treatment services), and the Pasteur Institute.

  The goal of this three-arm randomized trial, conducted in Vietnam and co-led by Montaner and David Metzger, Ph.D., a research professor and director of the HIV Prevention Research Division at the Perelman School of Medicine at the University of Pennsylvania, is to evaluate the impact of long-term opioid receptor stimulation or blockage with MOUDs on immune reconstitution in HIV-infected people who inject drugs and are initiating ART. Early preliminary data suggest that chronic opioid receptor engagement by an opioid receptor agonist while on ART may result in increased immune activation and inflammation associated with increased levels of persistent HIV, when compared to a full opioid receptor antagonist. To verify this hypothesis, the study will assess recovery outcomes and adherence to therapy 48 weeks after initiation of ART in 225 participants with OUD who receive either methadone (opioid receptor agonist), extended-release naltrexone (antagonist) or buprenorphine (partial agonist).

• A second, complementary grant will provide $3,889,138 over five years for mechanistic studies on local persons living with HIV on ART and taking MOUDs. Collaborators on this research are the Perelman School of Medicine at the University of Pennsylvania, Jonathan Lax Treatment Center, and the Icahn School of Medicine at Mount Sinai. The study will assess the preliminary observation that greater myeloid activation and HIV persistence are present in people receiving opioid receptor agonists when compared to people treated with opioid receptor antagonist naltrexone.

  Blood and tissue samples from individuals living with HIV who are receiving ART and treatment with different MOUDs will be used to study the mechanisms that regulate persistent immune activation and residual HIV expression.

“We expect the results of this major collaborative effort, which has its hub in Philadelphia, to have broad clinical implications in informing the best pharmacologic strategy for the management of opioid use disease in HIV-infected people starting ART,” said Montaner. “This is directly relevant in light of the opioid epidemic ongoing in our nation and will help ensure that the right medications are used for both HIV and OUD, with the ultimate objective of saving lives in the future.”

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The cell polarity protein Par3 controls mechanic changes in the skin and plays an important role in cell division. Malfunction can lead to DNA damages. The balance of the system is of great importance: while too much differentiation leads to loss of stem cells and therefore premature aging, too many cell divisions can be a cause of skin cancer. The new study by a team around Sandra Iden about how polarity regulators control cellular mechanics in the skin was now published in Nature Communications.

The skin serves as a crucial barrier to the outside world. Its task is not only to keep pathogens or toxic chemicals out of the body, but also to keep water inside and maintain hydration. In order to function properly, the skin epidermis constantly needs to keep a balance of cells it sheds off and new cells that replenish the lost ones. The skin epidermis is made up of several layers with different functions. Skin stem cells are responsible for the self-renewing capacity of the skin.

In a previous study, the researchers showed that inactivation of the polarity protein Par3 resulted in a decline of stem cells, impaired skin homeostasis and premature skin aging. Back then, however, the underlying mechanisms remained unclear. ‘We were now able to show that Par3 has a direct influence on the homeostasis of the skin by controlling the mechanical properties of keratinocytes, the main skin epithelial cell,’ said leading scientist of the study Dr Sandra Iden. The polarity protein Par3 controls the mechanical properties of the main skin epithelial cells, called keratinocytes. It has functions that are conserved from worms and flies to mammals. Par3 also regulates barrier function and cell division orientation.

The recent work started with two separate approaches. One of the first authors, Martim Dias Gomes, said: ‘We realized that inactivating Par3 leads to failures in cell divisions, resulting in DNA damage responses.’ At the same time, his colleague and co-first author Soriba Letzian was working on another project: ‘We challenged mouse skin with UV light – but observed an unexpected DNA damage response already in absence of the harmful light, when Par3 was missing. That was the moment we realized that the DNA damage response and the aberrant cell divisions might be tightly linked,’ he said. Based on these results, they teamed up and together examined possible causes of these mitotic failures.

As they now show, Par3 is an important regulator of contractility of keratinocytes, which is required to maintain the accuracy of cell division events. The absence of Par3 led to mitotic errors, causing an alert signal and a cascade of DNA damage responses that then fuelled premature differentiation, and potentially the skin stem cell decline. These findings were surprising, as during the development of epithelial tissues Par3 was considered to serve tissue function rather through orienting mitotic spindles.

These new findings thus revealed that core polarity proteins like Par3 steer mechanochemical networks essential to keep a healthy self-renewal capacity. ‘We are glad that we were able to contribute a piece of the puzzle of how the skin epithelium is maintained intact, and hope that this will serve future medical applications,’ Sandra Iden concludes.

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