Scientists document two separate reservoirs of latent HIV in patients | Hacker News Reader

Scientists document two separate reservoirs of latent HIV in patients

unc.edu

105 pointsgmays41 comments

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?

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.

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.

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

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.

TLDR edited down from https://hivinfo.nih.gov/understanding-hiv/fact-sheets/what-l... (I couldn't read TFA because uMatrix)

Finding ways to target and destroy latent reservoirs is a challenge facing HIV researchers

Some HIV-infected immune cells go into a resting or latent state. While in this resting state, the infected cells do not produce new virus. A latent HIV reservoir is a group of immune system cells in the body that are infected with HIV but are not actively producing new HIV.

HIV medicines prevent HIV from multiplying, which reduces the amount of the virus in the body (called the viral load). Because the HIV-infected cells in a latent reservoir are not producing new copies of the virus, HIV medicines have no effect on them.

People with HIV must take a daily combination of HIV medicines (called an HIV treatment regimen) to keep their viral loads low. If a person stops taking their HIV medicines, the infected cells of the latent reservoir can begin making HIV again and the person's viral load will increase. That is why it is important to continue taking HIV medicines every day as prescribed, even when viral load levels are low.

Finding ways to target and destroy latent reservoirs is a major challenge facing HIV researchers. Researchers are exploring different strategies for clearing out reservoirs, including:

Using gene therapy (manipulating genes to treat or prevent disease) to cut out certain HIV genes and inactivate the virus in HIV-infected immune cells.

Developing drugs or other methods to reactivate latent HIV so that the HIV can be destroyed by the immune system or new HIV therapies. This means of eliminating latent HIV reservoirs is sometimes known as the “shock and kill” or “kick and kill” strategy.

Hopefully this kind of research to go after "latent reservoirs" will bleed over into figuring out how to wipe out Herpes virii as well.

If you believe these people, ADCC (antibody-dependent cellular cytotoxicity) is sufficient to both prevent and clear HSV, and an appropriate vaccine can induce the appropriate antibodies to pull it off.

https://x-vax.com/

Of course, this seems to be suffering the usual fate of any vaccine technology other than spiffy mRNA vaccines against extremely urgent and well funded diseases: a neat proof of concept and some pre-clinical studies happen, followed by years of radio silence.

It's not like HIV is the easiest virus to test a vaccine against. A clinical trial against COVID is pretty ethically sound: provided the vaccine is harmless, the novel virus which most people still survive is survivable.

With HIV, if the vaccine is harmless, you're still left with the fact that failure means a bunch of people get an incurable, fatal disease.

HIV vaccine trials are costly and lengthy: you take a statistically at-risk population, vaccinate half, and then tell them to not assume the vaccine works, but a decent number of them are likely to (1) assume it does and (2) engage or be victimized by risky activity which leads to some of them getting HIV.

At the end of that, you then tally up your groups and see if you see a substantial difference in who is now HIV positive.

I can't imagine how much it sucks to be involved in the planning of those experiments. Someone, somewhere, talks to every single one of the people involved knowing full well what might happen.

> Someone, somewhere, talks to every single one of the people involved knowing full well what might happen.

I've known people who were involved in HIV vaccine studies, both as participants and as investigators. Everybody involved understands that side of the risk assessment ("this might not work, and you might get a placebo") from the very beginning, but the threat of HIV/AIDs is grave enough that people in the at-risk populations are happy to be involved.

It is not a fatal disease anymore though. I would rather have HIV than diabetes, all I have to do is take a pill every day. That’s much better than what diabetics go through.

While it's fatal if untreated, life expectancy for people who get HIV and are diagnosed early and put on a treatment regime is now believed to be similar to the general population (though they do tend to develop other health issues earlier), so while it's still problematic to accidentally induce risky behaviours, it's at least nowhere near as bad as it used to be.

My post and the GP were about HSV (herpes simplex virus), not HIV. HSV is extremely prevalent, so a simple randomized controlled trial in children should do the trick. (And there isn’t even any substantial ethical issue with participants potentially taking addition risks — kids don’t do anything to avoid HSV in the first place.)

But the specific discussion is about a potential cure. Finding a few hundred HSV patients who don’t take any antivirals when they don’t have any lesions should be very, very easy as trials go — something like half the population is seropositive, many of those have occasional symptoms, and very few of those are taking antivirals to prevent symptoms.

Hmmm, but it hasn't gotten past Phase I after almost 8 years? An HSV vaccine would be a real moneymaker so I find it hard to believe that there isn't enough money floating around for it.

A couple of mRNA HSV vaccines appear to be at the Phase I trial stage.

I'd pay a lot for one, even if it was out of my pocket. Not because of the annoyance of cold sores, but because I fear what these things trigger in the long term. As there is more and more research pinpointing HPV, HSV, Eppstein-Barr and Herpes Zoster, et al causing Alzheimers and auto-immune disorders down the road.

I personally find all this focus on mRNA to be disappointing. mRNA vaccines appear to be relatively easy to develop and produce, but I see no particular evidence that they’re good. With the efficacy numbers they seem to be currently showing against Covid, it’s not clear they would have made it through trials.

Your statement is completely contradicted by the actual vaccine development.

There were a LOT of Covid vaccines with different techniques and mechanisms in development simultaneously. Nobody knew a priori which vaccine would work so we funded the hell out of all of them.

mRNA came out on top relative to all the other options at 95% plus--it wasn't even close. Sinovac (inactivated virus) was at about 50% effectiveness. Novavax (protein subunit) was about 75% effectiveness and somewhat less in the Hispanic population (not understood why). Oxford/AZ/J&J/Gamelya were about 75% but had sufficient side effect to be troublesome.

And, to be fair, any of these vaccines would be in general use if we didn't have the others. The only reason why the viral vector vaccines (Oxford/AZ/J&J/Gamelaya) got pulled is because we had other options (effectively, they fail a Phase III trial since alternatives exist).

Finally, mRNA vaccines are NOT easy to produce. The fact that these things have to be held at -70C or -20C shows that they are quite complex. Contrast to the Sinovac vaccine which lasts forever with standard refrigeration.

The medical establishment would much rather use something like Sinovac; it's quite unfortunate that it just doesn't work that well. This is not surprising--there really wasn't any progress against other Coronavirii (common cold), either, until mRNA.

Here’s the paper the article discusses: “Rebound virus in the cerebrospinal fluid reveals a possible HIV-1 reservoir” in Nature Microbiology – https://doi.org/10.1038/s41564-022-01309-3

Which is a summary of the paper “Rebound HIV-1 in cerebrospinal fluid after antiviral therapy interruption is mainly clonally amplified R5 T cell-tropic virus” by Kincer, L.P., Joseph, S.B., Gilleece, M.M. et al. – https://doi.org/10.1038/s41564-022-01306-6

Latent reservoirs are super interesting. They've seen in experiments that they keep copies of all of the HIV strains that infected people go through (HIV is one of the viruses with the highest mutation rates). When people have gone off meds sometimes they've managed to sample their blood and seen how all of this viral strains activate around the same time.

To be clear, I imagine that it’s not that the reservoir is literally “intentionally” storing different strains but just that viruses are more accurately thought of as “quasispecies swarms”:

https://en.wikipedia.org/wiki/Viral_quasispecies

This is a naturally emergent phenomena.

(Just adding some further context to what you were saying)

I read this and I wonder why something like dialysis machines couldn't be adapted to filter the blood, recreating an artificial environment in which to attract infected CD4 cells.

I read a study from around the time of WW1 because blood banks didnt exists then, which is when MDMA aka Ecstasy was invented (for blood clotting purposes) one experiment drained all the blood from a dog, and replaced it with isotonic saline solution. 24hrs later about half the solution had been replaced with blood cells. There was no comment on what effect it had on other parts of the body, like the brain considering the oxygen carrying capacity of the blood.

They dont go into detail about which type of CD4+ T cells, there are different types of these cells. Sodium intake will increase Th17 cells which contributes to a class of diseases called autoimmune like arthritis.

Its a bit too vague for my liking, and as cells differentiate into different types of cells, the virus must be present somewhere else yet to be detected.

This virus sounds like bacteria going dormant in the body by forming biofilms until conditions are right in order to activate again, a risk with antibiotic use and no phage treatment.

In fact I wonder if phages have been used to target other virally infected cells, shall have to look that up. 1ml of seawater contains billions of phages.

Neutrophils are the only part of the innate immune system I know of which targets pathogens like bacterial biofilms, viruses & foreign objects.

Omega 3 EPA & DHA increase in the neutrophil membrane content to make it more effective at targeting pathogens, the higher content also increases the size of the neutrophil making it possible to target larger pathogens.

EPA (and possibly ETA a COX inhibitor) also down regulates the osteoclasts, helping to protect and seal the bones, which is where these bone marrow stem cell derived immune cells come from. Once your bones integrity starts to fail, other (adaptive) immune cells get in and start attacking the bone marrow causing the autoimmune diseases. I've seen studies using 8grams a day of Omega 3's ! Histidine/Carnosine would also compliment Omega-3 intake.

Now its always been my understanding there are parts of the body CD4 T helper cells cant go, like brain, eyes (eg causing blindness within seconds), testes and ovaries, so to see it mentioned that CD4+ cells are found in the spinal fluid, makes me wonder if there is some sort of blood brain barrier integrity breakdown occurred or is this a Nucleic Acid Amplification Test error, like the type seen with the Covid PCR testing?

The CSF is very slow to change as well, it takes weeks and months to get nutrients into CSF compared to other parts of the body.

Still interesting none the less.

How do CD4 T cells cause blindness in seconds if they get into the eye? Here's a study that shows that they could cause inflammation and dryness of the eye, but blindness in seconds?

https://pubmed.ncbi.nlm.nih.gov/19339740/

That's the surface of the eye not inside the eye.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948372/ "The eye attempts to limit local immune and inflammatory responses to preserve vision. This phenomenon, known as ocular immune privilege, is mediated by a combination of local and systemic mechanisms. While immune privilege is believed to protect the eye from day-to-day inflammatory insults, it is not absolute and its mechanisms are still incompletely understood."

Very interesting, thanks.

> I wonder why something like dialysis machines couldn't be adapted to filter the blood

I had a similar thought when I was younger. My idea was to just cool the below the temperature that HIV can survive at. When one considers the ways you can contract the disease though (semen, breast milk, blood), it's clear that it's permeated throughout more than just the blood. So just clearing it from the blood would be insufficient to remove the virus from our system.

True, but it could be an alternative to the ART treatment. The ART treatment also gives away intelligence, namely a theory, which appears to be that reducing viral load to dormancy levels is a valid attack vectory. Likewise the side effects are considered acceptable in much the way someone might consider office rental costs as a cost of business.

Such a machine could be an alternative way to reduce those side effect costs, plus there may also be additional benefits from this approach, like rejuvenating the blood or cleaning it. If someone with HIV or any other virus, lived in a sterile environment, so their complete immune system isnt having to tackle other issues, how much would the viral load go down by?

Sterile conditions must be important because of the changes COVID has forced on the medical profession, much like HIV also forced surgeons to start wearing latex gloves to reduce infections.

I've noticed over the last 4-5 years, AI cancer cell recognition increasingly being adapted for other uses, like counting bacterial biofilms in tissue samples.

Would it be possible to visually recognise virally infected cells using AI, by using some sort of adapted dialysis machine? Has anyone even attempted to visually compare good cells against virally infected cells?

Such a device could drastically increase some blood cell tests as such a machine could be seen as a realtime blood test lab on wheels, so the cost of setting up and running lab to carryout a variety of blood tests could become something miniturised and mobile.

I'm sure the US military and others would invest substantially in that in order to get closer to their super soldier dreams. Even Nasa might be interested in such an idea for the international space station, when thinking of the radiation risks.

I've see Breast Cancer detecting AI's get so good now, they can differentiate between a cancer lump and a calcium lump. To the end user, they just a detect a lump which might then trigger a clinical visit, plenty of worry but the clinicians ignore diet which should start showing up statistically along with other meta data obtained from devices like smart watches, supermarket loyalty cards etc etc.

These conditions dont happen on their own in isolation, other events have to occur besides the obvious act, like some illicit drug use.

what do you think about the Heisenberg uncertainty principle in this instance?

I recall hearing something about selective targeting with CRISPR gene editing packages to target latent cells containing the viral sequence. This might be it:

https://www.nature.com/articles/s41598-019-40222-4

> (2016) Kaushik et al. "Magnetically guided non-invasive CRISPR-Cas9/gRNA delivery across blood-brain barrier to eradicate latent HIV-1 infection"

> "In this research, for the first time, we demonstrated magnetically guided non-invasive delivery of a nano-formulation (NF), composed of Cas9/gRNA bound with magneto-electric nanoparticles (MENPs), across the blood-brain barrier (BBB) to inhibit latent HIV-1 infection in microglial (hμglia)/HIV (HC69) cells. An optimized ac-magnetic field of 60 Oe was applied on NF to release Cas9/gRNA from MENPs surface and to facilitate NF cell uptake resulting in intracellular release and inhibition of HIV."

Seems promising, I suppose complete clearance might still be difficult.

In this case the latent reservoir was in the central nervous system, cerebral spinal fluid specifically

Reading these stories it always helps me to remind myself that the human body contains an estimated 37 trillion cells. The human body is so complex that frankly it's amazing that medical science is making any progress at all curing all this stuff.

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