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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

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Video: Massive Landslide in Sirmaur Caught on Camera, NH 707 Closed for Traffic

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Sirmaur landslide nh 707

Sirmaur-Incessant rains have caused another massive landslide in the Sirmaur district on National Highway 707. A 100 to 150 meters stretch of Paonta Sahib – Shillai road near Kali Dhank, Badwas, caved in within a few minutes.

According to the initial information received, no loss of lives or damage to any vehicle was reported as a minor slide from the hill had alerted the people.

The landslide completely damaged several electricity poles, causing a blackout in some parts of the region.

The district police is re-directing all traffic from Paonta Sahib to Shillai to the Puruwala-Kilod-Jong-Kafota-Shillai route.

Further, all traffic movement towards Shimla from the region has also been re-directed.

The HP Meteorological Department has issued a yellow alert for the state till August 2th, while widespread rain has been predicted till August 4th. 

The Met has also issued an alert for flash-floods for Chamba, Mandi, Kullu, Shimla, and Solan districts.

It’s pertinent to mention that furious monsoon has already claimed over 200 lives and caused damages to property worth hundreds of crores in Himachal Pradesh.

During the last two days, as many as 21 people had died due to landslides and flash floods triggered by cloudbursts. Some of the persons who were swept away or buried were yet to be traced.

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Himachal: Cloudbursts, Landslides Claim 9 Lives in 48 Hours, 7 Still Missing, Met Issues Alert Till August 1st  

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monsoon damage in himachal pradesh 2021

Shimla-Monsoon continues to pummel Himachal Pradesh with deadly ferocity, leading to more cloudbursts, landslides, and flash floods. Several rivers and rivulets are in spate. Incessant rains could bring more destruction as the HP Meteorological Department has forecast widespread heavy rains till August 1st. While a red alert was issued for July 28, an orange alert has been issued for July 29 and July 30 and a yellow alert for July 31st and August 1st.

An advisory has been issued for locals and tourists to not venture near the river banks and avoid unnecessary travel as incessant rains could lead to more landslides, flash floods, and uprooting of trees.  However, tourists could be seen resolutely ignoring these warnings and partying near river banks and water bodies.

As devastation unfolds, the death toll due to monsoon induced calamities has reached nearly 200, while damages to property were assessed to be in hundreds of crores. Over 350 roads, including Manali-Leh, Pathankot-Chamba, and Shimla-Kalka, were blocked due to landslides.  Half a dozen bridges, as many as 30 houses and several vehicles were destroyed. Hundreds of tourists were reportedly struck in Lahaul.

lahaul-spiti cloudburst

After a flash flood in Dharamshala, a massive landslide in Shahpur constituency, and a horrid rockslide in Kinnaur district that killed nine tourists and injured four people, a cloudburst triggered a flash flood in Lahaul-Spiti district on Tuesday that washed away over a dozen of people, who were said to be labourers.  

cloudburst in lahaul-spiti

According to the Director of the State Disaster Management, Sudesh Kumar, at the time of writing this report, seven bodies had been recovered while four others were missing. The cloudburst occurred over Tonzin nallah in the Lahaul region of the tribal district. Rescue operations were in progress to trace missing persons.

A team of the National Disaster Response Force, which was on its way to Lahaul-Spiti through road, remained stuck in Mandi for several hours.  

On Wednesday morning, cloudburst was reported in Kullu district resulting in deluging of Bhramhaganga – a tributary of Parvati river. A  tourist, a 25-year-old mother along with her 4-year-old son, and a hydropower official came in its spate and were yet to be traced. Beas river was also in spate and people living in shanties on its bank were evacuated. 

Beas in spate

Rackham area in Kinnaur district also reported heavy losses due to a cloudburst on Wednesday morning.

While a rockslide killed one person in Chamba’s Saluni, a helper tagged with a JCB deployed for clearing Bharmaur-Pathankot National Highway was swept away by gushing waters of a nullah on Tuesday night. His body was recovered on Wednesday.

In Shimla, a landslide between Vikasnagar and Panthaghati crushed a vehicle and caused damaged to some others. Gumma khud in Chirgaon was also in spate and reportedly swept away a bridge and about four vehicles. 

landslide in shimla crushed car

Dharamsala received the highest 122 mm of rain, followed by Una 119 mm. In Solan district, Kasauli and Nalagarh also received over 105 mm rain. 

This widespread destruction has worried climatologists and environmentalists who are linking increased instances of landslides and cloudburst to environmental degradation and destabilization of hills due to developmental projects, including cutting of hills for widening of roads, construction of four lanes, hydropower projects etc. 

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Kinnaur: Massive Landslide Caught on Camera, Kills 9 Tourists, Injures 4, Destroys Bailey Bridge

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kinnaur landslide in batseri

Kinnaur: A massive landslide in Batseri on Sangla-Chitkul road in the Kinnaur district of Himachal Pradesh on Sunday killed nine persons and injured at least four others. Huge boulders rolled down the mountain following the landslide and destroyed an iron Bailey bridge and many vehicles parked along the road within a few seconds.

A tourist vehicle, which was reportedly carrying about 11 tourists from Delhi NCR, Rajasthan, Maharashtra, and Chattisgarh, was hit by boulders near Gunsa, killing nine tourists. A couple of videos of this heart-wrenching incident went viral on social media. In the video, some people can be heard whistling and shouting to warn others.

“Nine people died, and three were injured after boulders rolled downhill due to a landslide in Kinnaur district. Batseri bridge collapsed in the incident. A rescue team is present at the spot,” Superintendent of Police (SP), Kinnaur, Saju Ram Rana said.

The intensity with which boulders hit could be assessed from the fact that the iron bailey bridge on the Baspa river collapsed instantly. 

Video of landlside in himachal pradesh

On receiving the information, teams of district police and Indo-Tibetan Border Police rushed to the spot and initiated a rescue operation. The district administration was also assessing the situation. As per reports, rocks sliding down from the hilltop made the rescue operation difficult for the teams.

sangla valley landslide

As per initial reports, a request was made to make a helicopter available to aid rescue work, which was yet to be fulfilled.

landslide in himachal pradesh

Chief Minister Jairam Thakur also expressed grief over the incident. An ex-gratia of Rs 2 lakh was announced for the deceased while injured would be given Rs. 50 thousand.

The exact cause behind the landslide was yet to be ascertained.

The deceased were identified as:

  1. Pratiksha Sunil Patil (27) from Sadhbhawna Nagar, Nagpur, Maharashtra
  2. Deepa Sharma (34) from Jaipur
  3. Amoghi Bapat (27) from Korba Darri in Chhatisgarh
  4. Umrab Singh (42) of Tagore Garden West Delhi
  5. Kumar Ulhas vedpathak (37)
  6. Anurag Biyani (31) from Sikar in Rajasthan, his mother Maya Devi Biyani (55) and his sister Richa Biyani (25)
  7. Satish Katakbar (34) from Chhatisgarh.

Those injured have been identified as Shiril Obroy (39) from West Delhi, Naveen Bhardwaj (37) from Kaharar in Mohali and Ranjeet Singh (45) from Batseri in Sangla.

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