4 ms·

I recall way back reading about HSV that one of the reasons the virus is "incurable" is that it evolved a kind of staggered active reproduction/latent phase, su

I recall way back reading about HSV that one of the reasons the virus is "incurable" is that it evolved a kind of staggered active reproduction/latent phase, such that people would experience herpes outbreaks repeatedly, while enough of the viral load was undetectable to the immune system to repeat the cycle. Researchers hypothesized that a medication could be developed which would activate the entire reservoir for a singular, more severe outbreak which would give the immune system an opportunity definitively sweep up and eliminate most or all of the extant pathological cells and be rid of the infection for good. Not sure whatever came of that research, but could something similar be done with HIV?

Amorymeltzer 4y ago
There actually is this idea! I used to work on HIV, and there was was a paper (maybe around 2013?) that tried the idea and basically found that even when they did maximum reactivation there remained a huge pool of unactivated but replication-competent virus, so it was unlikely to be a fruitful avenue. Edit: Found the paper, yay zotero! https://pubmed.ncbi.nlm.nih.gov/24243014/ https://pubmed.ncbi.nlm.nih.gov/24243014/. You can check out the figures, but to quote from the abstract: > T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. and >The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated. I'm out the game, so can't comment on whether there's more recent work or if researchers have found a way around it.
mtlmtlmtlmtl 4y ago
Assuming you could, wouldn't the immune system lose that fight? It specifically attacks the immune system after all. deliberately increasing HIV viral load would probably be on the same level of danger as nuking someone's bone-marrow to prepare for a bone-marrow transplant. HIV is also a retrovirus which means it embeds its genetic code into host cell DNA. It can't be cured simply by getting rid of all present viruses.
- jljljl 4y ago
  Assuming it could be done, I think you'd activate the reservoir, then bombard the patient with anti-retrovirals until the virus was eradicated?
  - John23832 4y ago
    This is correct. You'd just get infected cells in the reservoir to express so that they can be identified and killed. That's what an outbreak is, viral expression. This is similar to how HSV outbreaks work. Your entire body isn't massively infected, the virus is just expressing. People often confuse an "outbreak" with "massive infection".
  - m0llusk 4y ago
    That is an approach being tried for a cure. So far it has not worked. It is not clear exactly why.
  - jjtheblunt 4y ago
    How would that excise the viral sequence from the already rewritten dna in cells previously infected, rather than just slow further new uninflected cells from being infected? The point is, in the presence of a retrovirus with its reverse transcriptase trickery, an organism is a chimera, populated by dna-distinct cells (for example, never infected cells vs cells previously infected and thereby holding modified dna, who would send out new virus during their own replication).
    - jljljl 4y ago
      The "assuming it could be done" in my comment referred to "finding a way to force latent cells to release their viral load rather than remaining latent". I'm not an immunologist, but if there was a mechanism, it would probably kill the rewritten cells. Then the released viruses would be eliminated with anti-retrovirals. If this same mechanism kept infected cells from remaining latent, eventually you would clear the virus. So I don't know the answer to your question, but my answer was assuming an answer existed :)
    - 4y ago
sjtgraham 4y ago
I read something last year where some researchers had found a mechanism to do exactly that and were looking for a therapeutic method to trigger it.
hummus_bae 4y ago
HHV6, the virus that causes roseola in children, does this. The daughter viruses have a longer latent period than the parent.

Amorymeltzer 4y ago

There actually is this idea! I used to work on HIV, and there was was a paper (maybe around 2013?) that tried the idea and basically found that even when they did maximum reactivation there remained a huge pool of unactivated but replication-competent virus, so it was unlikely to be a fruitful avenue. Edit: Found the paper, yay zotero! https://pubmed.ncbi.nlm.nih.gov/24243014/ https://pubmed.ncbi.nlm.nih.gov/24243014/. You can check out the figures, but to quote from the abstract: > T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. and >The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated. I'm out the game, so can't comment on whether there's more recent work or if researchers have found a way around it.

mtlmtlmtlmtl 4y ago

Assuming you could, wouldn't the immune system lose that fight? It specifically attacks the immune system after all. deliberately increasing HIV viral load would probably be on the same level of danger as nuking someone's bone-marrow to prepare for a bone-marrow transplant. HIV is also a retrovirus which means it embeds its genetic code into host cell DNA. It can't be cured simply by getting rid of all present viruses.

jljljl 4y ago
Assuming it could be done, I think you'd activate the reservoir, then bombard the patient with anti-retrovirals until the virus was eradicated?
- John23832 4y ago
  This is correct. You'd just get infected cells in the reservoir to express so that they can be identified and killed. That's what an outbreak is, viral expression. This is similar to how HSV outbreaks work. Your entire body isn't massively infected, the virus is just expressing. People often confuse an "outbreak" with "massive infection".
- m0llusk 4y ago
  That is an approach being tried for a cure. So far it has not worked. It is not clear exactly why.
- jjtheblunt 4y ago
  How would that excise the viral sequence from the already rewritten dna in cells previously infected, rather than just slow further new uninflected cells from being infected? The point is, in the presence of a retrovirus with its reverse transcriptase trickery, an organism is a chimera, populated by dna-distinct cells (for example, never infected cells vs cells previously infected and thereby holding modified dna, who would send out new virus during their own replication).
  - jljljl 4y ago
    The "assuming it could be done" in my comment referred to "finding a way to force latent cells to release their viral load rather than remaining latent". I'm not an immunologist, but if there was a mechanism, it would probably kill the rewritten cells. Then the released viruses would be eliminated with anti-retrovirals. If this same mechanism kept infected cells from remaining latent, eventually you would clear the virus. So I don't know the answer to your question, but my answer was assuming an answer existed :)
  - 4y ago

sjtgraham 4y ago

I read something last year where some researchers had found a mechanism to do exactly that and were looking for a therapeutic method to trigger it.

hummus_bae 4y ago

HHV6, the virus that causes roseola in children, does this. The daughter viruses have a longer latent period than the parent.