Researchers Are Using Viruses to Make Superbugs Commit Suicide

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The gene-editing technology called CRISPR has its origins as a bacterial immune system against viruses, a feature which could be turned against them in the future.

By arming bacteriophage viruses with the tools to force bacteria into falling on their own swords, scientists hope we will be able to develop powerful new ways to defeat antibiotic resistant pathogens and perhaps even shape our body’s microflora.

Research presented at the CRISPR 2017 conference in the US described the progress that has been made in modifying viruses that target specific bacteria with genes that make the host’s enzymes cut into its own DNA.

Clustered regularly interspaced short palindromic repeats – CRISPR for short – are sequences of DNA made of a repeating codes that form a long palindrome.

Bacteria produce them as a kind of immune system against viruses called bacteriophages, slipping bits of the virus’s genes scavenged out of the environment into the repeating codes.

With the viral DNA stored away in CRISPR sequences, any future infections can be detected quickly and a CRISPR-associated system (or cas) enzyme can then use the sequence as a beacon, latching onto the infecting virus genes and either snipping them selectively or tearing them to shreds.

About 25 years ago, researchers realised this cut-and-paste system of CRISPR sequences and cas enzymes could be used in the lab to edit sequences artificially, and a new engineering toolkit was born.

The technology has been in the news quite a bit in recent years as advances have been made in applying it to cancer treatments and even eliminating HIV infections.

While it might not be without certain risks, CRISPR gene editing has sparked a something of a minor revolution.

Bringing it back to its roots and turning it into a weapon against its creators has a sense of serendipity about it.

“I see some irony now in using phages to kill bacteria,” said the chief scientific officer of Locus Biosciences, Rodolphe Barrangou, at the CRISPR 2017 conference.

Using bacteriophages as a form of therapy to treat infection isn’t all that new, with trials dating as far back as the 1920s.

The use of phages is appealing because they are far more specific than antibiotics, targeting only specific types of bacteria and therefore posing no risk to our own health. The viruses can also penetrate the coatings of sticky film bacteria produce for protection and adherence.

Russia experienced a fair degree of success with phage therapy behind its Iron Curtain during the Cold War, but unable to patent the naturally occurring viruses and with the bacteria quickly adapting, red tape and limitations in technology have made it far easier to focus on antibiotics in the west.

With looming epidemics of superbugs on the horizon, attention is returning to bacteriophages as ways to kill bacteria, and CRISPR has put a new spin on the old idea.

A spin-off company from North Carolina State University, Locus Biosciences is testing the limits of CRISPR technology, including giving bacteriophages CRISPR sequences containing codes for antibiotic resistance genes.

Targeting bacteria with the genes, the CRISPR sequence would form a target for the bacteria’s own cas enzymes, effectively blocking resistance or even prompting the bacteria into chewing up its own DNA and self-destructing.

In recent years our eyes have been opened to how complex our relationship is with bacteria in our environment, and how dull our tools are for dealing with them.

Variations in our gut microflora has been linked with everything from Parkinson’s disease to autism to obesity, suggesting the species of bacteria we harbour could have major ramifications on many aspects of our health.

With its razor-honed surgical precision, it’s possible the technology could one day be used to select specific strains of bacteria in our gut, deleting them from the ecosystem and allowing us to edit our microbiomes.

Given we’re practically at the dawn of both CRISPR technology and our grasp on the complexity behind our body’s bacterial ecosystems, we can only speculate for the time being.

As antibiotics slowly lose their shine it’s probably worth paying close attention to radical new solutions such as these.

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Vaginal Bacteria Have Been Found to Neutralise HIV Treatment

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A study on the vaginal bacteria of South African women has revealed that a certain type of bacteria is able to break down a common drug used for the prevention of HIV.

Annually, more than 1 million women are infected with human immunodeficiency virus (HIV). HIV infection rates among women are a major health concern, as HIV can be passed from mothers to their children during pregnancy, childbirth ,and breastfeeding.

“I believe this will change the way we approach HIV prevention studies in women,” lead researcher Nichole Klatt, from the University of Washington, told ScienceAlert.

The microbicide drug, tenofovir, is widely used to combat the spread of HIV, and works by inhibiting the process that allows HIV to replicate. While tenofovir routinely protects men against HIV infection, women using the same drug might not see the same results.

But what exactly does the vagina have to do with drug administration?

In Africa, tenofovir is being applied in a gel directly into the vagina. Taking a tablet isn’t always ideal in Sub-Saharan Africa, and the focus of prevention here is to stop the spread of HIV at the site of infection during sex.

Other studies have revealed that the vagina may contain bacteria that acts as a sort of ‘biological condom’, protecting against the infection of HIV and STIs.

To investigate the potentially negative effects these bacteria are having on tenofovir, Klatt and her team collected vaginal swabs from 688 South African women as they participated in a clinical trial into the efficiency of an intravaginal gel against HIV infection.

The team found that there were two major types of vaginal bacteria present in the sample group – one contained Lactobacillus, and the other contained Gardnerella vaginalis.

Of the two major types of vaginal bacteria, the women with non-lactobacillus bacteria had a reduction of HIV infection of only 18 percent, while those with Lactobacillus had a reduction in HIV infection rate of 61 percent when using the gel – a threefold increase in protection.

The scientists investigated further, and discovered that G. vaginalis could metabolise and breakdown the active form of the drug, rendering it useless in the fight against the spread of HIV.

“These data demonstrate that vaginal microbiota must be accounted for and to improve efficacy of HIV prevention, novel interventions to enhance Lactobacillus and decrease Gardnerella and other BV-associated bacteria are needed,” Klatt told ScienceAlert.

The scientists hope that the results will inform the ways in which the drug is administered based on the bacteria present in a patient’s vagina.

“We are now excited to be forging the way ahead in pharmacomicrobiomics studies in HIV and other diseases. Specifically, we are assessing other drugs that bacteria may interact with in the vagina, and the specific mechanisms underlying this,” says Klatt.

“We are also developing systems to assess drug-microbiota interactions in other diseases such as IBD and cancer, where mechanisms underlying variable drug efficacy are unknown.”

The research is published in Science.

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Fasting could slow the development of a common type of childhood leukaemia

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Fasting can slow the development of one of the most common forms of childhood leukaemia, new research has found.

Based on tests in mice, going without food on a regular schedule was enough to halt the progress of two types of acute lymphoblastic leukaemia (ALL), and there’s hope that the findings could be used to develop treatments for cancer in humans, too.

ALL is caused by the body overproducing immature white blood cells called lymphoblasts that gradually replace healthy ones – and while the cancer does occur in adults, it most commonly occurs in children.

But when mice with ALL were restricted in their eating patterns, researchers from the University of Texas Southwestern Medical Centre noticed a significant drop-off in the disease’s effects. 

“We found that in models of ALL, a regimen consisting of six cycles of one day of fasting followed by one day of feeding completely inhibited cancer development,” says lead researcher Chengcheng Zhang.

“Mice in the ALL model group that ate normally died within 59 days, while 75 percent of the fasted mice survived more than 120 days without signs of leukaemia.”

To test how fasting could be used to stop the disease, the researchers used fluorescent, coloured proteins to keep track of the cancer cells.

After seven weeks, virtually no cancerous cells were detected in the fasting mice, while an average of 68 percent of cells were found to be cancerous in the mice that hadn’t been fasting.

Part of the treatment’s success seems to be related to the hunger-inhibiting hormone leptin, which is created by fat tissue.

Previous research has shown that fasting can reduce leptin levels, and ALL patients often show weakened leptin receptor activity, so the researchers paid close attention to both factors during their study.

They found that intermittent fasting in mice increased leptin receptor activity, and they think this fact is significant in the success of their treatment.

“We found that fasting decreased the levels of leptin circulating in the bloodstream as well as decreased the leptin levels in the bone marrow,” explains Zhang. “These effects became more pronounced with repeated cycles of fasting.”

“After fasting, the rate at which the leptin levels recovered seemed to correspond to the rate at which the cancerous ALL cells were cleared from the blood,” he adds.

While fasting was capable of stopping the development of ALL, the technique wasn’t as effective against another type of blood cancer that’s more common in adults, called acute myeloid leukaemia (AML).

In tests with a mouse model of AML, the activity of leptin receptors was unaffected by fasting, which could explain why restricted eating doesn’t seem to help against this different form of leukaemia. 

Of course, these tests have so far only been run on mice, so there’s no guarantee that the same results would be seen in people.

But if scientists are able to develop a similar treatment for humans with ALL, there’s one big advantage to this approach – deliberately skipping meals doesn’t involve taking any drugs, so clinical trials can start sooner without any extensive testing of pharmaceuticals.

The researchers are now keen to test their findings further, with a view to ultimately figuring out how to simulate fasting mechanisms in the body, so that patients with the disease don’t have to give up food to get better.

“It will be important to determine whether ALL cells can become resistant to the effects of fasting,” says Zhang.

“It also will be interesting to investigate whether we can find alternative ways that mimic fasting to block ALL development.”

The research has been published in Nature Medicine.

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A new antibody therapy appears to have permanently blocked HIV infection in monkeys

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A new type of antibody therapy appears to have completely blocked the primate equivalent of HIV in infected monkeys.

More than two years after the treatment, the monkeys are now drug free, have no symptoms, and there are almost no traces of the virus in their systems. The results are so impressive that clinical trials have already begun with human patients in the US.

“We have good reasons to believe that the therapy will work similarly in humans,” said lead researcher Lutz Walter from the German Primate Centre in Göttingen. “It would be a breakthrough for the future treatment of HIV patients.”

In the trial, rhesus macaques infected with simian immunodeficiency virus (SIV) – the primate version of HIV – were given a standard antiretroviral drug for 90 days, before being treated with an antibody called Vedolizumab for 23 weeks.

After completing the therapy, all monkeys showed sustained control of the infection, and there were almost no traces of the virus in their blood or gastro-intestinal tissues.

Impressively, two years later, the “viral load remained low, the immune system intact, and the rhesus macaques healthy”, a press release explains. The monkeys, for now at least, are in “sustained remission“.

“This finding could become a blueprint for an alternative therapy for HIV, which could make it so someone would not need to continuously take antiretroviral drugs,” said one of the researchers, Aftab Ansari, from Emory University School of Medicine and Yerkes National Primate Research Centre in the US. “It could also help us craft more effective vaccines.”

Once HIV infects someone, it immediately hides in their gut, hijacking a group of immune cells called CD4+ T-cells and using them to replicate itself and spread around the body. 

Antiretroviral drugs are already the most common form of treatment for patients with HIV, and taken regularly, they can help to keep this infection under control for decades . But they never remove HIV from the body altogether, so they have be taken permanently, and often cause side effects such as chronic inflammation, poisoning symptoms, and accelerated ageing.

That’s why researchers are trying to combine this approach with the use of antibodies, to develop a treatment that’s longer lasting.

Antibodies are a specific type of protein that our bodies produce in response to a certain antigen. They’re the proteins used in vaccines that tell our immune systems “Hey, I recognise this virus and it’s not good” – and researchers have spent years actively trying to develop antibodies that take down HIV.

But although there have been impressive results in the past, they’ve all been short-lived, and required ongoing injections of antibodies, because HIV is a master at hiding and disguising itself in its hosts.

Which is why this new approach is so promising.

“The aim of the study was to find a new therapeutic approach for the treatment of infections with immunodeficiency viruses, which would permanently prevent the proliferation of the viruses even after only temporarily application,” said Walter.

To figure this out, the team took 18 rhesus macaques infected with SIV and gave all of them antiretrovirals for 90 days, before giving 11 of them Vedolizumab every three weeks, and seven of them a generic antibody to serve as a control group.

Three of the monkeys in the treatment group were discounted from the study because their immune system fought back against Vedolizumab, but the other eight went on to have the virus pretty much erased from their system – while still maintaining healthy levels of T-cells in the body. This means the drug wasn’t just wiping out the immune system.

Barton F. Haynes, a Duke University immunologist who wasn’t involved with the study, told the LA Times that the antibody “allowed animals to control the infection” on their own. “That’s what was tantalising and surprising.”

Even better, Vedolizumab is already used in humans in Europe and the US to treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, so it doesn’t need to go through the extensive safety testing that most new drugs would need to.

The antibody works by attacking a specific receptor on T-cells that are known to be susceptible to HIV infection – in inflammatory bowel diseases this helps to calm down an over-active immune response. And in monkeys with SIV, it seems to wipe out all the T-cells that HIV is hiding in, while leaving healthy ones intact.

More research is needed to be done now to verify exactly what Vedolizumab is doing to infected T-cells, and extensive clinical trials will have to take place before we know whether this works in humans.

But so far, it’s looking pretty promising. And Phase I clinical trials testing the same combination of Vedolizumab and antiretrovirals in 15 HIV-infected humans have already begun in the US, with the researchers looking to extend them to more countries soon.

The research has been published in Science. 

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Union Cabinet approves amendments to HIV and AIDS (Prevention and Control) Bill, 2014

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The Union Cabinet under the chairmanship of Prime Minister Narendra Modi has given its approval to introduce official amendments to the HIV and AIDS (Prevention and Control) Bill, 2014 which has been drafted to safeguard the rights of people living with HIV and affected by HIV.

The Bill seeks to address HIV-related discrimination, strengthen the existing programme by bringing in legal accountability and establish formal mechanisms for inquiring into complaints and redressing grievances. The Bill seeks to prevent and control the spread of HIV and AIDS, prohibits discrimination against persons with HIV and AIDS, provides for informed consent and confidentiality with regard to their treatment, places obligations on establishments to safeguard rights of persons living with HIV and create mechanisms for redressing complaints. The Bill also aims to enhance access to health care services by ensuring informed consent and confidentiality for HIV-related testing, treatment and clinical research.

The Bill lists various grounds on which discrimination against HIV positive persons and those living with them is prohibited. These include the denial, termination, discontinuation or unfair treatment with regard to employment, educational establishments, health care services, residing or renting property, standing for public or private office, and provision of insurance (unless based on actuarial studies).  The requirement for HIV testing as a pre-requisite for obtaining employment or accessing health care or education is also prohibited.

Every HIV infected or affected person below the age of 18 years has the right to reside in a shared household and enjoy the facilities of the household. The Bill also prohibits any individual from publishing information or advocating feelings of hatred against HIV positive persons and those living with them. The Bill also provides for Guardianship for minors. A person between the age of 12 to 18 years who has sufficient maturity in understanding and managing the affairs of his HIV or AIDS affected family shall be competent to act as a guardian of another sibling below 18 years of age to be applicable in the matters relating to admission to educational establishments, operating bank accounts, managing property, care and treatment, amongst others.

The Bill requires that “No person shall be compelled to disclose his HIV status except with his informed consent, and if required by a court order”. Establishments keeping records of information of HIV positive persons shall adopt data protection measures. According to the Bill, the central and state governments shall take measures to prevent the spread of HIV or AIDS; provide anti-retroviral therapy and infection management for persons with HIV or AIDS; facilitate their access to welfare schemes especially for women and children; formulate HIV or AIDS education communication programmes that are age appropriate, gender sensitive, and non-stigmatizing; and lay guidelines for the care and treatment of children with HIV or AIDS. Every person in the care and custody of the state shall have right to HIV prevention, testing, treatment and counseling services. The Bill suggest that cases relating to HIV positive persons shall be disposed’ off by the court on a priority basis and duly ensuring the confidentiality.

There are no financial implications of the Bill. Most of the activities are being already undertaken or can be integrated within the existing systems of various Ministries under training, communication and data management, etc. The Bill makes provision for appointment of an ombudsman by state governments to inquire into complaints related to the violation of the Act and penal actions in case of non-compliance. The ombudsman need not be a separate entity, but any existing state government functionary can be deputed or given additional charge.

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