Therapeutic Interfering Particle

[BillTre]

Read about this in a Science mag news article.

More than 15 years ago, University of California San Francisco biophysicist Leor Weinberger proposed an audacious new strategy to beat the AIDS virus: giving already infected people an engineered version of HIV. The variant, stripped of nearly all its genes and designed not to cause disease, might outcompete and suppress the natural version, he thought. The therapeutic interfering particle (TIP)—his bland term for the defanged HIV—could even spread person to person, reducing AIDS prevalence globally.

The TIP works by competing for HIV capsid proteins in infected cells and can reduce monkey HIV counts by 10,000 for extended periods of time in monkeys.

He stripped or crippled HIV’s genes to create the TIP’s RNA genome but left sequences that help it replicate. To do so, this neutered HIV genome “parasitizes” the molecules made by the HIV already infecting the cell, including its capsid proteins, which form a shell around the TIP’s RNA. Because the TIP’s genome is simpler than HIV’s, the variant can copy itself more rapidly. “Most of the interference occurs because the TIP genomic RNAs are grabbing capsid better because there’s more of them,” Weinberger says.

Science article here. Probable paywall.

The TIP genome is smaller and therefore replicates faster.
It can also infect other people and possibly protect others also. Some live vaccines are also known to do this.

They want to try it out in humans now.

 

[berkeman]

Sorry, no comprendo. Cliff Notes summary please? Thanks.

 

[Vanadium 50]

could even spread person to person, reducing AIDS prevalence globally

What could possibly go wrong with that?

 

[BillTre]

Sorry, no comprendo. Cliff Notes summary please? Thanks.

The TIP is a simplified HIV virus. It is smaller and does not produce its own capsid protein.
The capsid protein is what makes the shell of the HIV virus particle. It is necessary for the virus's function.

The TIP has a smaller genome which replicates faster because it is smaller and has less sequence to duplicate.
The TIP genomes take the HIV capsid proteins (during the viral assembly process) to make their shell so the HIV virus can't use them to make their own shells.
HIV viruses without the outer capsid protein shells can't infect other cells.

What could possibly go wrong with that?

Inflammation is possible.
Cancers triggered by the virus inserting into the host cell genome are another possibility. However, this is considered a low likelihood event because it is not common with HIV viruses which the TIP is derivceed from.
Those are considered the likely problems.

 

[pinball1970]

What could possibly go wrong with that?

Quite a lot of attenuated viral vaccines. I agree though, people hear HIV and probably get a bit twitchy.
Jenner probably got similar twitchiness on his ideas.

 

[Laroxe]

I wonder, this appears to suggest that this would be a virus capable of reproduction, in which case it needs to infect cells. So the first issue is what does it do to these cells? usually this would mean it kills the cell or the immune system kills the cell. This would suggest the possibility of symptoms.
The HIV virus in the wild is basically a mutation ridden mess, so far it has proven to be impossible to isolate parts of the virus that can produce a broadly neutralising antibody, the best that they have come up with is actually a more complex hybrid that provides our immune system with a very wide range of targets. So far, this hasn't produced anything worth developing.
I simply don't understand how this TIP can work, if it doesn't produce a capsid how is it transmitted to other cells and what does the immune system target, it seems to be more like how a drug action might work.

 

[BillTre]

I simply don't understand how this TIP can work, if it doesn't produce a capsid how is it transmitted to other cells and what does the immune system target, it seems to be more like how a drug action might work.

Once in a cell, it can replicate its dumbed down genome (no capsid proteins).
If it is in a cell with with a functional HIV, it replicates its genome faster (because it is smaller) and then uses the capsid proteins produced by the HIV genome in the cell to escape the cell and enter another. It could infect other people if it escapes the first person's body.

Like HIV, TIPs could be transmitted to others, primarily via sex. Some see that as ethically problematic. To Weinberger it is a public health benefit that could help curb the HIV/ AIDS epidemic—akin to the way the weakened virus in oral polio vaccines spreads to unvaccinated people, boosting their immunity.

It out competes the HIV viruses by replicating faster and using the capsid proteins before the HIV viruses can.

“Most of the interference occurs because the TIP genomic RNAs are grabbing capsid better because there’s more of them,” Weinberger says.

The guy who came up with this has worked on it or about 15 years. Tests have been done in monkeys:

A single injection of TIPs into monkeys already infected with a simian version of HIV knocked down their virus levels 10,000-fold for prolonged periods, he and colleagues report today in Science.

The monkey study, done by a team led by Nancy Haigwood at Oregon Health & Science University, injected Weinberger’s TIPs into six infant macaques and 24 hours later infected them with a SHIV, a labmade virus that combines the simian immunodeficiency virus with the gene for HIV’s surface protein. After about 30 weeks, five of the six TIP-treated monkeys were healthy and their levels of SHIV had dropped from a peak of about 100,000,000 copies of virus per milliliter of blood to 10,000 copies per milliliter. Three of the four control animals, in contrast, got so sick from SHIV they had to be euthanized at 16 weeks.

“This is an exciting paper,” says Nobel laureate David Baltimore. He and his wife Alice Huang, both virologists at the California Institute of Technology, in the 1970s described similar disabled versions of poliovirus and vesicular stomatitis virus (which sickens livestock) that naturally emerge in cell cultures and interfere with the intact virus. “We never put in the effort to make it a reality,” says Baltimore, who is excited that now, “There is a chance that the therapeutic potential of defective interfering particles will be realized.”

 

[Vanadium 50]

I think that releasing an active, reproducing virus, even one that is believed to have beneficial effects, in the hope that it spreads to people who didn't sign up for it, is something that needs to be considered very, very carefully.

 

[BillTre]

It was basically done a long time ago.

The smallpox vaccine protects people from smallpox by helping their bodies develop immunity to smallpox. The vaccine is made from a virus called vaccinia, which is a poxvirus similar to smallpox, but less harmful. The smallpox vaccine contains live vaccinia virus, not a killed or weakened virus like many other vaccines. For that reason, people who are vaccinated must take precautions when caring for the place on their arm where they were vaccinated, so they can prevent the vaccinia virus from spreading.

from: https://www.cdc.gov/smallpox/vaccine-basics/index.html

 

[Vanadium 50]

I do not believe smallpox vaccine can spread beyond those vaccinated.

 

[BillTre]

from: https://www.health.ny.gov/publications/7004/

Is it possible for people to get smallpox from the vaccination?​

No. The smallpox vaccine does not contain smallpox virus and cannot spread or cause smallpox. However, the vaccine does contain another virus called vaccinia which is live in the vaccine. Because the virus is alive, it can spread to other parts of the body or to other people from the vaccine site. For that reason, the vaccine site must be carefully monitored.

Is it possible to get vaccinia, the virus in the vaccine, from someone who has recently been vaccinated?​

Yes. Vaccinia is spread by touching a vaccination site before it has healed or by touching bandages or clothing that have become contaminated with live virus from the vaccination site. Vaccinia is not spread through airborne contagion. The vaccinia virus may cause rash, fever, and head and body aches.

 

[Vanadium 50]

You said re: smallpox "Vaccinia is not spread through airborne contagion". But the airborne spread of this vaccine - or rather, engineered virus - is held up as a good thing.

Maybe the position to the public should be "We're smart, you're not, so you're just going to have to do it our way." But this seems sort of antidemocratic. And it's not like "we're smart so we thought of everything" has turned out to be wrong.

 

[BillTre]

I'm not saying the public should not be informed. I would like that.
However, I don't think all your beliefs are valid.
Biology is more complex than you think.

 

[Vanadium 50]

Biology is more complex than you think.

Which is exactly why I am advocating a go slow approach.

 

[Laroxe]

Well, it is interesting, so I decided to do a bit more reading, a decision I regret to this day. However, I have to admit to being even more confused about this.

My first concern is with the name, why TIP for gods’ sake, this automatically seems to link it to other RNA interfering mechanisms which control gene expression, when in fact this appears to describe an engineered virus capable of reproduction. Really, you can't just strip the virus of its RNA instruction set and live in hope and even if you are lucky enough to make it non pathogenic, there are a mass of other issues. All of our cells have multiple strategies for the recognition of viral proteins and acting against all the stages of cell infection, all usually controlled by interfering RNA molecules, with some 250 cellular proteins being identified as necessary for HIV infection. Many of these have other roles in cellular metabolism which are essential to the host but in some cases act as a hallmark of some RNA virus infections, the silencing of some of these miRNA's is an important cellular defence. It's also one that the HIV virus exploits, it promotes mutations in the double RNA's of the viral genome to escape the antiviral defences. Lentiviruses, also commonly stop reproducing in cells, the HIV virus often requiring the infected immune cells to be activated by other infections, these cells still appear to produce chemical warning signals that promote cell death in surrounding structures.

Now it seems that this TIP induces an active infection it would still require a capsid regardless of whether the HIV was active or not, this would still lead to cell death and inflammation, with the accompanying antibody responses which would clear the TIP. The only way that it could survive is if it could mimic the long periods of dormancy, early evidence is that the TIP reproduces more rapidly in monkeys. It would also need to share the same capacity for mutation, in which case the emergence of a pathogenic strain becomes an issue (as in with polio).

Its very difficult to make much sense out of what we do know about cellular processes in viral infections and HIV is a particular special case, the huge problems in vaccine development illustrate the many problems. I also wonder about the claim that HIV infection is not associated with cancer and so that shouldn't be a problem with TIP, I presume that we are expected to ignore the specific risks from Kaposi sarcoma, non-Hodgkin lymphoma, and some cervical cancers. In addition to the increased incidence of cancer's of the skin, anus, lung, and liver.

Brass LA, Dykxhoorn DM,Benita Y, et al.
Identification of hostprotein required for HIV infection through a functional genomic screen.
Science 2008 ; 319 : 921 -6

 

[Rive]

an active, reproducing virus

If I take it right, without the presence of a HIV infection, it cannot reproduce.
In presence of a HIV infection, it does reproduce and do spread (but the spreading stops at the first non-HIV-infected person).

The problem I see is that actually it cannot reduce the HIV presence in blood to zero (undetectable, as they say for the suppressive medications) so HIV likely remains infectious too, just at a reduced level: but so far we know nothing about the resulting infectiousness of HIV with TIP but without care and medication. But it already feels like a prefect excuse for carelessness and test-avoidance...

Also feels likely that to 100% prevent the spread of HIV the usual medication and care still needed to be applied: but that would kill the TIP too, I think.

I would expect some lot more testing in 'live' environment. Livestock, maybe? Or there are some nasty diseases wreaking havoc amongst stray cats, for example...

Ps.: also feels likely that a HIV+TIP infection would be able to stay undetected for very long.... I don't think it would be a good thing.