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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-

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

Rs 2572 crore for Himachal’s irrigation and drinking water schemes

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HP irrigation and drinking water schemes

Shimla: The State Government today said that it has earmarked an amount of Rs 2572 crore for providing irrigation and drinking water facilities in Himachal Pradesh during the current financial year.

The endeavour, the Government said, was to bring more area under irrigation facility so that farmers could go for crop diversification instead of traditional crops.

The Chief Minister, while addressing a public meeting at Kelodhar in Seraj assembly constituency of Mandi district, provided the information.It is Chief Minister’s first visit to Kelodhar after elections.

Further, it was announced that the Kandha-Bah-Batand road would be strengthened.

Earlier, the Chief Minister performed ‘bhumi pujan’ of Kandha-Bah-Batand road (Phase-II) to be constructed at a cost of Rs. 358.53 lakh.

He laid the foundation stones of IPH Office building and residence at Kelodhar to be constructed at a cost of Rs. 74.36 lakh and of Science Block building of Government Senior Secondary School Kelodhar on which about Rs 1.50 crore would be spent.

The Government announced Rs 15 lakh for Kelodhar Panchayat for various developmental works, Rs 10 lakh each for GP Bara, GP Saroha and GP Parwara. He also announced Rs 3 lakh for Mahila Mandal Kelodhar.

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British-era Bantony Castle Shimla to become Rs. 25 crore cultural centre     

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Bantony Castle Shimla Picture

CM said the building is also an example of beautiful anglo-gothic architecture. However, this fact appears to be incorrect as the Castle is built in the mock-Tudor style

Shimla: As a ray of hope for the Bantony Castle, Shimla, the Himachal Pradesh Government has announced Rs. 25 crores for the renovation of the British-era structure in order to develop as a tourist attraction.

This was stated by Chief Minister Jai Ram Thakur while inaugurating the five-day long State level Gram Shilp Mela which was organized by the State Language Art and Culture Department here on May 17, 2018.

Bantony Castle is one of the historic and monumental buildings of Shimla town and has a very rich history. spread over around 20,000 square meter area between Circular Road and Mall Road.

The Chief Minister said the building is also an example of beautiful anglo-gothic architecture. However, this fact appears to be incorrect as the Castle is built in the mock-Tudor style, part chalet and crowned with sloping roofs with mini-towers.

Nevertheless, he further said that since this building was strategically located on the Mall Road thus could be an added attraction for the tourists.

 This complex as a whole would be developed in such a way that it not only becomes a tourist attraction but also a centre of rich cultural diversity of the State.  

The previous Congress Government had, in 2017, announced that it will be turned into a Heritage museum with a restaurant and recreational park.

Artisans from different parts of the State received an opportunity to exhibit their artefacts at the Gram Shipi Mela. The government said it would also organize District level Gram Shilp Melas besides Inter-state Gram Shilp Melas to promote the artefacts of the State.

It was further informed that the State Government has announced a new scheme named ‘Aaj Purani Rahon Se’ for exploring folklores, historic events and cultural tourism in the State. The government has also decided to introduce miniaturized cultural souvenirs of Himachal Pradesh such as musical instruments, Chamba Rumal, Kangra paintings etc.

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Will tar 1100 km roads, construct 600 km new motorable roads, 750 km cross drainage, 35 bridges in 2018: HP Govt

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HP PWD target for 2018

Shimla: During review meeting of Himachal Pradesh Public Works Department held today, the Government informed that it has set up a target of construction of 600 km new motorable roads, providing cross drainage facilities on 750 km road length, metalling and tarring of 1100 km roads, construction of 35 bridges and providing road connectivity to 40 villages during the current financial year.

The Government said all the formalities regarding the allocation of road and bridge projects would be completed within a stipulated period to facilitate work- allocation within 51 days to concerned executing agencies.  

The e-tendering is expected to speed up the process of allocation of projects.

It has been felt that delay in Forest clearances was one of the major bottlenecks for starting of different road and bridge projects. Therefore, the Government would take up the matter with the Union Government to expedite forest clearances for these projects,

said the Chief Minister, who was presiding over the meeting.

It was informed that the target has been fixed to execute 414 works with a total length of 2400 km, under PMGSY with an outlay of Rs 600 crore during the current financial year.

On completion, 150 habitations would be connected with roads. Similarly, the target has been fixed to complete 209 works under Rural Infrastructure Development Fund (RIDF)-NABARD, which include 77 works in Shimla zone, 20 in Mandi Zone, 70 in Kangra zone and 4 in Hamirpur Zone, it was informed.

HPPWD review meeting 2018

During HPPWD review meeting 2018

It was informed that that out of 90 black spots identified in the State, 58 had been rectified and work on remaining black spots was in progress.

The State Government has allocated Rs. 200 crore for maintenance and repair of roads in the State besides Rs. 50 crore additionality for providing drainage facilities on the roads, claimed the Government.

Additional Chief Secretary Manisha Nanda said that 34394 officers and officials were working in the Public Works Department and “were doing their best” to ensure best road connectivity to the people of the State.  

The State today has total 35638 km of roads providing road connectivity to the remotest part of the State, informed the Engineer-in-Chief R.P Verma.

Opposed to the work-culture of the HP PWD, the Chief Minister, who holds Department, is claiming that regular monitoring and inspection of roads and bridges constructed particularly under NABARD, Central Road Fund etc. will be ensured.

 He said that for this, standard quality parameters should be laid down and responsibility of the defaulters must be fixed and strict action taken against the person, which rarely happens.

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