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Comment by lr4444lr | Hacker News Reader

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?

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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/. 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.

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.

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.

Assuming it could be done, I think you'd activate the reservoir, then bombard the patient with anti-retrovirals until the virus was eradicated?

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).

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 :)

Several things come to mind. First, you don’t need to remove viral DNA from cells. Just make them over-express HIV and trigger cytotoxic lymphocytes or antibody-mediated killing. You end up wiping all the infected cells. But then, of course, patient is left with compromised immunity. To solve this, you could make a stem cell transplant from a compatible donor. Alternatively, harvest healthy cells before the treatment and transplant them back after.

This is from the top of my had, I’m not an expert in the field.

Your body would eventually replace the Helper T-Cells lost, but yes, we'd probably want to do some mitigation for safety.

> Your body would eventually replace the Helper T-Cells lost

With thymus involution?

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".

That is an approach being tried for a cure. So far it has not worked. It is not clear exactly why.

> 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 kills in the long term. The human body fights very well against HIV, it just exhausts its resources.

One massive "outbreak" (I have no idea what that would look like), would be essentially laying out all of the HIV to the immune system saying "Here. Now do something about all of this."

> 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.

T-Cells remove infected cells. That would be the mechanism of removal from the body.

Since HIV infects T-cells, ramping up the T-cells to kill the T-cells will result in a higher viral load leading to an out-of-control spiral, and certain death. That's how HIV kills in the first place.

I’m not an expert on HIV, but that's not correct.

HIV infects your helper T cells. Helper T cells activate your B cells which create antibodies that alert for intrusions. Those antibodies then cause your Killer T cells to act (actually kill and remove intruders).

HIV basically causes your Helper T-Cells to die (quicker than they are naturally replaced by the body) causing an under-reaction (and eventually no reaction) by your B cells (which then means there are no antibodies for your Killers to act on). Essentially your immune system is turned off. This allows for opportunistic infections which are what actually kills you.

That’s the resource exhaustion that I was referencing. This is also why there is a focus on keeping CD4+ (Helper) T-cell levels high. You want your immune system to keep responding to outside threats.

An HIV outbreak would not mean that all of your Helper T-Cells are infected. It means that HIV in the viral reservoirs are active. Actively producing Helper T-Cells are cells that your body could then target. Killers would kill the affected Helpers, but your body would reproduce Helpers. The goal would be to allow your body to "be able to see" all of the infected Helpers.

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

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