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Immune cells engineered in lab to resist HIV infection, Stanford study shows

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Researchers at the Stanford University School of Medicine have found a novel way to engineer key cells of the immune system so they remain resistant to infection with HIV, the virus that causes AIDS.

A new study describes the use of a kind of molecular scissors to cut and paste a series of HIV-resistant genes into T cells, specialized immune cells targeted by the AIDS virus. The genome editing was made in a gene that the virus uses to gain entry into the cell. By inactivating a receptor gene and inserting additional anti-HIV genes, the virus was blocked from entering the cells, thus preventing it from destroying the immune system, said Matthew Porteus, MD, an associate professor of pediatrics at Stanford and a pediatric hematologist/oncologist at Lucile Packard Children’s Hospital.

“We inactivated one of the receptors that HIV uses to gain entry and added new genes to protect against HIV, so we have multiple layers of protection — what we call stacking,” said Porteus, the study’s principal investigator. “We can use this strategy to make cells that are resistant to both major types of HIV.”

He said the new approach, a form of tailored gene therapy, could ultimately replace drug treatment, in which patients have to take multiple medications daily to keep the virus in check and prevent the potentially fatal infections wrought by AIDS. The work was done in the laboratory, and clinical trials would still be needed to determine whether the approach would work as a therapy.

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“Providing an infected person with resistant T cells would not cure their viral infection,” said Sara Sawyer, PhD, assistant professor of molecular genetics and microbiology at the University of Texas-Austin and a co-author of the study. “However, it would provide them with a protected set of T cells that would ward off the immune collapse that typically gives rise to AIDS.”

The study was published in the Jan. 22 issue of Molecular Therapy.

One of the big challenges in treating AIDS is that the virus is notorious for mutating, so patients must be treated with a cocktail of drugs — known as highly active antiretroviral therapy or HAART — which hit it at various stages of the replication process. The researchers were able to get around that problem with a new, multi-pronged genetic attack that blocks HIV on several fronts. Essentially, they hope to mimic HAART through genetic manipulation.

The technique hinges on the fact that the virus typically enters T cells by latching onto one of two surface proteins known as CCR5 and CXCR4. Some of the latest drugs now used in treatment work by interfering with these receptors’ activity. A small number of people carry a mutation in CCR5 that makes them naturally resistant to HIV. One AIDS patient with leukemia, now famously known as the Berlin patient, was cured of HIV when he received a bone marrow transplant from a donor who had the resistant CCR5 gene.

Scientists at Sangamo BioSciences in Richmond, Calif., have developed a technique using a protein that recognizes and binds to the CCR5 receptor gene, genetically modifying it to mimic the naturally resistant version. The technique uses a zinc finger nuclease, a protein that can break up pieces of DNA, to effectively inactivate the receptor gene. The company is now testing its CCR5-resistant genes in phase-1 and -2 trials with AIDS patients at the University of Pennsylvania.

The Stanford scientists used a similar approach but with an added twist. They used the same nuclease to zero in on an undamaged section of the CCR5 receptor’s DNA. They created a break in the sequence and, in a feat of genetic editing, pasted in three genes known to confer resistance to HIV, Porteus said. This technique of placing several useful genes at a particular site is known as “stacking.”

Incorporating the three resistant genes helped shield the cells from HIV entry via both the CCR5 and CXCR4 receptors. The disabling of the CCR5 gene by the nuclease, as well as the addition of the anti-HIV genes, created multiple layers of protection.

Blocking HIV infection through both the CCR5 and CXCR4 receptors is important, Porteus said, as it hasn’t been achieved before by genome editing. To test the T cells’ protective abilities, the scientists created versions in which they inserted one, two and all three of the genes and then exposed the T cells to HIV.

Though the T cells with the single- and double-gene modifications were somewhat protected against an onslaught of HIV, the triplets were by far the most resistant to infection. These triplet cells had more than 1,200-fold protection against HIV carrying the CCR5 receptor and more than 1,700-fold protection against those with the CXCR4 receptor, the researchers reported. The T cells that hadn’t been altered succumbed to infection with 25 days.

Porteus said he views the work as an important step forward in developing a gene therapy for HIV.

“I’m very excited about what’s happened already,” he said. “This is a significant improvement in that first-generation application.”

He said a potential drawback of the strategy is that while the nuclease is designed to create a break in one spot, it could possibly cause a break elsewhere, leading to cancer or other cell aberration. He said it’s also possible the cells may not tolerate the genetic change.

“It’s possible the cells won’t like the proteins they’re asked to express, so they won’t grow,” he said.

But he said he believes both problems are technically surmountable. He said the researchers’ next step is to test the strategy in T cells taken from AIDS patients, and then move on to animal testing. He said he hopes to begin clinical trials within three to five years.

Though the method is labor-intensive, requiring a tailored approach for each patient, it would save patients from a lifelong dependence on antiretroviral drugs, which have adverse side effects, Porteus noted.

He said he also hopes to adapt these techniques for use against other diseases, such as sickle cell anemia, one of his areas of interest. Porteus works with patients in the Pediatric Bone Marrow Transplant service at Packard Children’s.

In addition to Sawyer, he collaborated with Richard Voit, a former Stanford graduate student who is now an MD/PhD candidate at the University of Texas Southwestern Medical Center, and Moira McMahon, PhD, a former postdoctoral scholar at Stanford who is now at the University of California-San Diego.

The study was supported by a grant from the American Foundation for AIDS Research and by a Laurie Krauss Lacob Faculty Scholar Award from the Lucile Packard Foundation for Children’s Health.

Information about Stanford’s Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu.

BY RUTHANN RICHTER

Source: Stanford School of Medicin

Misc News/Press Release

Govt declares 7-days State Mourning, 2-days public holiday in Himachal

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Atal-Bihari-Vajpayee passes away

Shimla:The Himachal Pradesh Cabinet Ministers, the Chief Minister Jai Ram Thakur, the Governor Acharya Devvrat, and several leaders of the Bhartiya Janata Party and oppositions mourned the sad demise of former Prime Minister Atal Bihari Vajpayee (93).

He passed away today in All India Institute of Medical Sciences (AIIMS), Delhi after a long illness.

The State Government has declared seven days State Mourning. The national flag would remain to fly at half mast.

The State Government has also declared public holidays for 17th and 18th August 2018.

He was born in Gwalior on December 25, 1924, and joined the Rashtriya Swayamsevak Sangh in 1939. was one of the founding members of the BJP.

He Vajpayee was thrice elected the prime minister between 1996 and 1999 and was the only non-Congress prime minister to complete the full term of five years, from 1999 to 2004.

He was also conferred prestigious Bharat Ratan award too.

Nation has today lost a great leader and a noble soul. This loss cannot be compensated. Himachal Pradesh had been a special place for Atal Ji and he always considered it as his own home as he used to come and stay at Prini in Kullu District frequently

, in their condolence message, the Ministers said.

He was a statesman and a visionary leader, whose demise is a great loss to the nation. He said that Shri Vajpayee always considered Himachal Pradesh as his second home and has a house at Prini in Kullu district, 

Chief Minister Jai Ram said in his condolence message.

The Chief Minister also shared an old picture taken with Shri Vajpayee.

Chief Minister said that the idea to construct Rohtang tunnel connecting landlocked hinterland Lahaul valley with rest of the world was conceived in 1998 by Shri Vajpayee and the project was announced by him on June 3, 2000. He said that this project was nearing completion and would be the biggest gift of Shri Vajpayee to the State.

He said that it was National Democratic Alliance (NDA) government led by Shri Atal Bihari Vajpayee that Himachal Pradesh got a special package for industrial development in 2003. He said that this resulted in an industrial investment of thousands of crores of Rupees and employment opportunities to lakhs of the youth of the State.

Jai Ram Thakur said one of the largest educational programs in the world, ‘Sarva Shiksha Abhiyan’ was launched during his Prime Ministership. The program was a product of strong willpower of this statesman, he added.

Chief Minister said that it was during the tenure of Shri Vajpayee that the Golden Quadrilateral, the lifeline of trade in India came into being. In addition, ‘Pradhan Mantri Gramin Sadak Yojna’ (PMGSY) aimed at linking the 5 lakh villages of India to cities by all-weather roads, which in particular proved a boon to the hilly states like Himachal Pradesh, he added.

Shri Vajpayee was the great son of India in a real sense, who, with his simplicity and humility, ruled the hearts of millions of people. He always believed in value-based politics and always adhered to it. He said that Shri Vajpayee would always be remembered and respected by the people of the country for his simplicity, humanity and benevolence,

the Governor said in his message of condolence.

Further, leaders of the opposition are also paying their respects and praying to the Almighty to grant peace to the departed soul.

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Landslide on Shimla-Dhalli bypass hit apple trucks & traffic plan, road likely to remain closed for 2-3 days

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Mehli-Shimla bypass

Shimla – A huge landslide on Shimla-Dhali bypass road (NH-5) between Mehli and Malyana on Thursday afternoon has come in a time when the apple growers have begun to reap their crops and transport to markets. It is the peak season for the growers. The Shimla-Dhali bypass is like a lifeline for the growers in the upper areas of the district.

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As per the Traffic Police, Shimla, it may take about two to three days to clear the road and open it for traffic again. The landslide also uprooted three to four trees. There were no reports of anything being buried under the debris and rocks.

All vehicles on both sides of the road remained stuck in long jams before they had to turn back to take alternative routes.

This blockage has made another road inaccessible for the trucks – the Mehli-Shoghi bypass, which branches off from the Shimla-Dhali bypass. The Shimla Police had to change the traffic plan according to which the trucks arriving from the upper area of the district would have to take the Dhalli-IGMC-Lakkar Bazaar road during the night hours only.

As per the police, the trucks going towards the upper Shimla area would have to use the bifurcation at Khalini Chowk and take Khalini-Chhota Shimla-Dhalli route during night hours only.

As per the district administration, the work to clear the road is underway, but it might take a couple of days before it could be opened for traffic.

At the same time, the blockage of roads due to landslips at various other places has brought local vehicles as well as trucks carrying apple crop to halt, leading to a distress among the growers. Bad weather could delay the restoration work.

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Lack of emergency in making emergency announcement troubles schoolchildren, parents

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school in shimla remained closed

Shimla: On August 13, 2018, the district administration of Shimla like all other districts decided to keep the schools close owing to a heavy and continuous spell of rain. It continued raining on Sunday night and till early morning it had caused several landslides and uprooting of trees. The roads were blocked all over the city including the circular road.

As it was still raining on Monday morning, it was announced that the schools were to be kept closed for the day.

However, by the time this announcement was made, the majority of school students had already reached the school or on their way to school. The cabs had returned after dropping children at their respective schools.

It was still raining heavily when the schools sent children back home.

We had taken our seats in our classroom when the teacher told us that the school was to remain closed for the day,

said a student of a reputed private school while he was returning to the home on feet.

I received an SMS regarding the announcement when my children had already left for the school. The school said they had sent them back, but they did not reach home. There is no mean to communicate with them, and I fear they might have got stuck somewhere due to traffic jams,

said a mother of two while waiting for her children at a shop in Tutikandi.

The schoolteachers, when inquired about the same said they were also unaware of the announcement and had reached the school by the time this announcement reached them.

There were several other parents who were waiting for the safe return of their respective children. They believed, the schools should not have sent children back in heavy rain if they had arrived at school.

The campus would have been a safer place when it was raining heavy and roads were already blocked at several places,

said another woman while she inquired classmates of her son.

I had returned after dropping children at the school. I begin to receive calls from the parents to go back and bring the children back as the schools were closed. The Khalini-Shimla road was already closed due to a fallen tree, and even I was stuck in traffic,

said a cab driver.

It appears the State Government need to evolved faster and insured ways to reach the public via official announcements in times of emergencies like bad weather and natural disasters. Had this announcement reached an hour ago, which was possible as it had been raining heavily all night, the children and parents would not have faced such huge inconvenience.

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