5 ms·

This is a cool idea for a possible cure of HIV, and it's great to see researchers trying it out. But from what I heard, CRISPR is quite ineffective: when you wa

by est31 3y ago

This is a cool idea for a possible cure of HIV, and it's great to see researchers trying it out. But from what I heard, CRISPR is quite ineffective: when you want to do gene edits with it, you often do it to cell cultures, then keep only those cells where it actually worked. CRISPR does the cutting only, and you rely on cell repair mechanisms to mend the parts together again: they can be mended in any way. Also, the reservoir that makes HIV so tricky is in immune cells that are in a sleep state and only wake up every now and then: can the viral vector reach those? Also important quote from the paper: > The study was not designed to test the effect on the intact viral reservoir as EBT-001 was given when the viral reservoir was not stable and there was still active viral replication. Additionally, as animals were maintained on ART, we did not test the ability of EBT-001 to extend time to viral rebound or eliminate viral reactivation after an analytical treatment interruption.

mycall 3y ago
Is it possible that all viruses can wake in immune cells every now and then? I'm wondering how common this phenomenon is.
- cyberax 3y ago
  Not many viruses can stay dormant. They need to be adapted for that. A classic example is the herpes virus, that has special proteins that regulate its expression. HIV is a retrovirus, it inserts itself into the hosts's genome, making dormancy easier.
whimsicalism 3y ago
> can the viral vector reach those? I think yes from the article? The whole point of this therapy is to eliminate latent HIV from dormant cells that traditional small molecule retroviral therapy can't access. > CRISPR does the cutting only, and you rely on cell repair mechanisms to mend the parts together again But in this case, all we need is the cutting right because we don't care if the HIV survives the interaction. Agreed on the quote
- j16sdiz 3y ago
  > But in this case, all we need is the cutting right because we don't care if the HIV survives the interaction. In the "what could possibly go wrong" scenario, if it survive this drives the virus for mutantion.
  - civilitty 3y ago
    That’s always a concern with HIV regardless of the treatment. Most therapies include several mechanisms to reduce the probability of adaptation significantly.
soligern 3y ago
Technically the virus should be able to reach all the cells, irrespective of whether they’re latent or not I would think but I’m just a lay person.
- anjel 3y ago
  Latent HIV infectious reservoir are especially stealthy, when viral titers are undetectable in the blood, its hiding behind the blood brain barrier. "The major reservoirs for HIV in the CNS are in the microglia, perivascular macrophages, and to a lesser extent, astrocytes" https://pubmed.ncbi.nlm.nih.gov/27873219/ https://pubmed.ncbi.nlm.nih.gov/27873219/
thebears5454 3y ago
Being able to cure people that are undetectable would be a miracle of modern science, even if it's not able to cure everyone that's positive
svsaraf 3y ago
You are out of date. CRISPR is extremely effective in live patients, usually packaged in a virus or lipid nano particle. While CRISPR is often used in cultured cells (eg for CAR T therapies) there are CRISPR therapeutics in live human patients today in phase 3 trials for sickle cell disease (among other indications).
- est31 3y ago
  The phase 3 trials you mention were probably for exa-cel, a therapy that involves removing the cells from the patient, editing them with CRISPR in the dish. Meanwhile you do myeloablation of the patient, aka destroy their bone marrow, then put in the repaired cells. The key here is: the application of CRISPR happens outside of the patient. https://doi.org/10.1056/nejmoa2031054 https://doi.org/10.1056/nejmoa2031054 > Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. Similar (not the same) things have already been done multiple times for HIV patients who had to have their bone marrow destroyed for other reasons, generally leukemia (Düsseldorf Patient, Geneva Patient, London Patient, etc). They received transplants from donors that had mutations in CCR5, which prevents HIV. But you can't cure 40 million people living with HIV that way. This therapy is extremely involved, expensive, and it also impacts the health of the patient (e.g. their entire immune memory is reset, they have to redo all their vaccinations). You don't destroy the bone marrow of someone due to no reason. Them requiring regular blood transfusions is a good reason, but them having to take antiretroviral drugs once per day is generally not seen as one. The paper of this thread is about a single injection that does these CRISPR edits while inside the patient, without involving destruction of the bone marrow.
- deleted 3y ago
  [deleted]

by est31 3y ago

mycall 3y ago

Is it possible that all viruses can wake in immune cells every now and then? I'm wondering how common this phenomenon is.

cyberax 3y ago
Not many viruses can stay dormant. They need to be adapted for that. A classic example is the herpes virus, that has special proteins that regulate its expression. HIV is a retrovirus, it inserts itself into the hosts's genome, making dormancy easier.

whimsicalism 3y ago

> can the viral vector reach those? I think yes from the article? The whole point of this therapy is to eliminate latent HIV from dormant cells that traditional small molecule retroviral therapy can't access. > CRISPR does the cutting only, and you rely on cell repair mechanisms to mend the parts together again But in this case, all we need is the cutting right because we don't care if the HIV survives the interaction. Agreed on the quote

j16sdiz 3y ago
> But in this case, all we need is the cutting right because we don't care if the HIV survives the interaction. In the "what could possibly go wrong" scenario, if it survive this drives the virus for mutantion.
- civilitty 3y ago
  That’s always a concern with HIV regardless of the treatment. Most therapies include several mechanisms to reduce the probability of adaptation significantly.

soligern 3y ago

Technically the virus should be able to reach all the cells, irrespective of whether they’re latent or not I would think but I’m just a lay person.

anjel 3y ago
Latent HIV infectious reservoir are especially stealthy, when viral titers are undetectable in the blood, its hiding behind the blood brain barrier. "The major reservoirs for HIV in the CNS are in the microglia, perivascular macrophages, and to a lesser extent, astrocytes" https://pubmed.ncbi.nlm.nih.gov/27873219/ https://pubmed.ncbi.nlm.nih.gov/27873219/

thebears5454 3y ago

Being able to cure people that are undetectable would be a miracle of modern science, even if it's not able to cure everyone that's positive

svsaraf 3y ago

You are out of date. CRISPR is extremely effective in live patients, usually packaged in a virus or lipid nano particle. While CRISPR is often used in cultured cells (eg for CAR T therapies) there are CRISPR therapeutics in live human patients today in phase 3 trials for sickle cell disease (among other indications).

est31 3y ago
The phase 3 trials you mention were probably for exa-cel, a therapy that involves removing the cells from the patient, editing them with CRISPR in the dish. Meanwhile you do myeloablation of the patient, aka destroy their bone marrow, then put in the repaired cells. The key here is: the application of CRISPR happens outside of the patient. https://doi.org/10.1056/nejmoa2031054 https://doi.org/10.1056/nejmoa2031054 > Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. Similar (not the same) things have already been done multiple times for HIV patients who had to have their bone marrow destroyed for other reasons, generally leukemia (Düsseldorf Patient, Geneva Patient, London Patient, etc). They received transplants from donors that had mutations in CCR5, which prevents HIV. But you can't cure 40 million people living with HIV that way. This therapy is extremely involved, expensive, and it also impacts the health of the patient (e.g. their entire immune memory is reset, they have to redo all their vaccinations). You don't destroy the bone marrow of someone due to no reason. Them requiring regular blood transfusions is a good reason, but them having to take antiretroviral drugs once per day is generally not seen as one. The paper of this thread is about a single injection that does these CRISPR edits while inside the patient, without involving destruction of the bone marrow.
deleted 3y ago
[deleted]