In essence, an antibody called N6 was extracted from an HIV patient. The patient is a long-term nonprogressor who has had HIV for 21 years, but an exceptionally low viral load of <1000/mL and normal CD4 T-cell count. This indicates that his immune system has kept the virus at bay for all these years with essentially no ill effect.
HIV viruses have a surface protein complex called Env, which binds to the CD4 surface protein to gain entry to T-cells (part of the immune system). HIV cannot transmit without this protein complex, and so certain parts of the complex are very well conserved across different HIV strains.
N6 binds to this part of Env, in some sense "simulating" CD4. However, because it's just an antibody and not a cell, once Env is bound it cannot infect anything. This is what makes N6 a neutralizing antibody.
The thing that makes N6 special (more potent and more broadly applicable) is that it is able to avoid the parts of Env that HIV doesn't need for replication. Imagine Env as a wrench. The head of the wrench is a specific hex shape to mate with CD4 and can't change. Antibodies can grab on to the wrench handle to prevent infection. But the handle can change, and HIV regularly mutates this part to avoid being caught - adding side branches, changing the shape, and so forth. N6 is cleverly arranged so that it can strongly bind to the wrench without grabbing the handle too strongly - in other words, it tightly binds the head of the wrench like a person wrapping a thumb and index finger around it (this hand analogy appears in the paper). The result is that HIV has a much harder time getting out from under the antibody, since mutating itself to alter the head shape would also affect infectivity.
Now that larger HIV screening trials are done, and the technology has advanced to better detect such super-antibodies, more of these clever antibodies may be discovered. We may yet have a good shot at defeating this tricky virus!
The scientists who discover these solutions are my heroes. They spend their lives tangled in these complexities and save actual lives with their work. That's admirable!
And may those scientists who devote their life to stuff like this, but who will never find a solution, be (y)our heroes as well!
It's a game of big numbers, much (very smart) trial and error I suppose, and never finding something meaningful may result in much frustration. Still this has to be done because you simply don't know which path will lead to the solution.
They're too are my heroes. Those who never find a solution still did the work, traversed the other paths - which is a necessary part of figuring out which path is the correct one - and quite often, what they saw on those paths may lead someone else to solve some other problem in the future!
This is why big time negative results that lead to closing a big path that may have wasted humanity huge research time should also get rewards and grants.
Now if you only do negative research you cannot publish and you if you don;t publish you die.
Just to check I understand this correctly, as a layman:
It stops HIV from progressing in the body, holding it at bay. Someone with HIV would need to take this medicine for the rest of their lives. It doesn't actually cure it. (not denying that holding it at bay is a significant step forward)
Obviously, curing HIV is an open research question, but also the way to go about curing this retroviral infection is still unknown. When there is sustained virologic response, we know that the virus will come back if drugs are withdrawn. Exactly which niche of cells have integrated HIV into their genome, and how to identify them, is an active area of research at least as of about a year ago when I last looked into it (hint: probably macrophages and T cells).
The Berlin patient shows that cure is possible via treatments that also eradicate the bone marrow, but these are not generalizable across populations due to the high morbidity and mortality.
For prevention, vaccination that can generate antibodies such as the one in the article would be highly valuable. Less valuable but still very beneficial would be a long-lasting monoclonal antibody injection that can be given once a month (or ideally less often) to reduce the likelihood that high-risk individuals become infected.
For cure, I suspect that an approach which pairs replication suppression with genome editing tools, such as CRISPR, may ultimately prove successful in curing individuals of HIV.
> The Berlin patient shows that cure is possible via treatments that also eradicate the bone marrow, but these are not generalizable across populations due to the high morbidity and mortality.
Correct me if I'm wrong but I thought that patient got HIV back a year or two after the bone marrow transplant?
We're actually both right: there are two patients referred to as "The Berlin patient." The first one is a man who was given an unusual ART regimen and has been able to stay off of it for an indefinite time, with low circulating levels of HIV. But this isn't the person that most physicians think of when we talk about the Berlin patient. Rather, we're thinking of the man who had a bone marrow transplant and has been truly cured.
It's an antibody, so in theory the human body can produce it itself. That's how vaccines work: they trick your body into producing antibodies against the real pathogens.
The question is whether all humans can produce this, or just some genotypes. If it's the latter, then yes, some people would have to take it as medicine and never stop.
> then yes, some people would have to take it as medicine and never stop.
Which is a problem since it would probably be a monoclonal antibody and those are the most expensive drugs to make. Like hundreds of thousands or even millions per year expensive (depending on what dose is needed).
If it really does cost millions per year the US couldn't afford it - it would cost over a trillion per year to treat everyone in the US, and more than 40 trillion to treat everyone (and that's just for the medicine).
(For comparison total healthcare spending in the US is 3 trillion.)
So better hope that either the price goes down, or that it only requires a limited course of treatment. Can you imagine a cure for HIV, and we can't afford it?
What are the reasons behind such prohibitive cost? Rare expertise, advanced factories, amount of time required, lack of economy-of-scale, monopoly, something else?
If the cure is proven, the society will likely be able to mobilize much more resources, particularly to scale up operations.
Special expertise can be trained to other biologists (the underemployment problem would be mitigated as well). More biologists could be trained. Likewise for factories, materials, etc. Monopolies can be broken.
What factors cannot be scaled up with such an approach? (Honest question. I do not know anything about antibody production.)
> What are the reasons behind such prohibitive cost? Rare expertise, advanced factories, amount of time required, lack of economy-of-scale, monopoly, something else?
The first 3. Monopoly doesn't help I'm sure, but this drug class in inherently very expensive to produce, there's a reason there is little outcry over the prices charged.
It's extremely labor intensive, and very hard to scale up. They are also inherently dangerous, so there is a need for extreme purity. (See: https://en.wikipedia.org/wiki/TGN1412 for what a monoclonal antibody can do, you would not want that to happen by accident.)
As of right now this drug class remains the most expensive of all drugs, I would assume if it were possible to make it cheaper they would have.
But we'll only really know once the first generics enter the market.
It's curious, because in the near future monoclonal antibodies, as produced by your own body, should be the very cheapest 'drugs' (sic; read 'therapy' or 'cure') to make. If your own body is the manufacturing plant, it's just the cost of delivering the blueprints, once (very cheap).
You design the monoclonal antibody, figure out its sequence, deliver the sequence back into your own body (via some HIV-like virus), and now your body has an unlimited continuous access to the therapeutic.
Production of the therapeutic-delivering virus could be done in such a way as to produce a global scale for a small amount of money that would never need to be administered again. For example, in lab I can produce enough (lab quality) purified protein for a single one-time dose for a few thousand dollars and a week's work. On the other hand, I could produce enough therapeutic virus for dozens of people to forever produce their own versions of that same protein for a few hundreds dollars and an afternoon's work. This is very unlike any other 'drug' of the 20th century.
> It's an antibody, so in theory the human body can produce it itself. That's how vaccines work: they trick your body into producing antibodies against the real pathogens.
Ahh, of course they do. Thanks for the clarification :)
What you've described is a similar concept to what immunologists call Vectored Immunoprophylaxis (VIP). VIP has been used effectively in vaccination and treatment of HIV in mouse models [1], and primate trials are ongoing. Essentially this approach entails delivering the gene encoding for an antibody (for example N6 from this paper) directly in a viral vector to cells in the body. This process completely bypasses the traditional physiological vaccination and antibody selection process which may fail to produce a useful antibody such as N6. Instead, the antibody is directly expressed, and secreted from cells that the viral vector infected. Because we know the delivered antibody is effective at targeting the pathogen, these antibodies enable the immune system to home in on the virus in a deterministic way.
This is very reasonable. Technically, today, it is a bit of a challenge to ensure it gets delivered in such a way as to not hurt more than it helps, and to ensure it remains active. But at this point that kind of auto-manufacturing of a therapeutic an 'engineering problem' rather than a 'scientific problem'.
as an aside: Curiously, in the lab at least, most of those therapies are delivered using a 'gutted' version of HIV (precisely because it is so good at delivering genetic payloads to humans). So there's a pretty good chance you'd be using an engineered version of HIV's own machinery to deliver a permanent anti-HIV payload to the patient's genome.
I think the ideal goal would be to create a vaccine that would induce a immune response producing this antibody immediately on contact with HIV. In that case I don't know that we know whether it would just keep it at bay or if it would be able to essentially prevent infection in the first place.
Reminds me of Shapely from William Gibson's Bridge Trilogy
"He was discovered by the AIDS industry when he had already been HIV-positive for twelve years. His strain of HIV was notpathogenic but was able to kill the lethal strain of HIV. By isolating his mutant strain of HIV it was possible to develop an AIDS vaccine."
Hmm, I wonder how well that would work. I believe HIV mutates a lot, and so if you infected yourself with a "nonpathogenic" version, I'm not sure it would remain so forever. (Though it says "develop", so perhaps they could find or introduce some other weaknesses in that strain, and let it kill all the existing HIV, then flood the patient's body with something that kills the new strain before it can mutate.)
The article indicates that this could be used to create a vaccine. How would that work? So far as I understand the medicine for vaccines, they are used to train your immune system to create new antibodies by exposing it to the virus. What process would be used to train the immune system from an existing antibody?
Did the study indicate if the long-term nonprogressor on any anti-viral drugs?
I think the most interesting nonprogressors to look at are the ones who refuse treatment. Many of them die within 5 ~ 10 years, but the ones who don't could potentially have a natural resistance to HIV.
Nice post, but there's an awful lot of anthropomorphizing there. As far as I know, viruses don't purposely mutate. Rather, their design has evolved to encourage beneficial (to them anyway) mutations.
Not my area of expertise but even if we can address 99% of strains, wouldn't that last 1% just take over and become the new 100% leaving us back where we started? Or is the promise here that we can combine this discovery with another that solves that remaining 1%? Or, do the mutations of that last 1% make HIV less virulent or harder to transmit?
That unaffected 1% will still be limited by the rate of transmission which has been falling globally for decades because of growing access to birth control and antivirals, anonymous needle exchanges, and education. HIV isn't like a bacteria that grows out of control because the probability of transmission is highly dependent on the viral load, which varies significantly over the different strains and patients' lifetimes as their immune systems battle the virus. Even if eliminating 99% of strains only cures 50% of patients, those cured would have to have sexual or blood contact with the remaining 50% in order to get reinfected with the resistant strains.
HIV is a very expensive disease to treat and since it's no longer a death sentence, a significant amount of resources go towards a lifetime supply of drug cocktails for long term HIV patients (which is all of them). Even a 10% reduction in the number of infections would free up a massive amount of resources at the NHS, CDC, and other agencies best suited to put them to use dealing with the remaining infections. Like with cancer and drug resistance, there is no single panacea but that doesn't mean we can't make big leaps that help a lot of people. Fighting a virus like HIV takes a lot of victories, big and small, that chip away at the problem until, like with smallpox or polio, there are so few cases left that each can be dealt with individually by the public health infrastructure.
> a significant amount of resources go towards a lifetime supply of drug cocktails for long term HIV patients (which is all of them)
With my tin foil hat on, I've always wondered that now there is a very profitable business (for the big Pharma companies) out of just providing HIV positive people with drugs for years, that there is little appetite (again, inside big pharma) to actually 'cure' the disease...?
If one company has expensive treatments for a disease, and another company has a cure for it (at any price), which company is going to make more money? The one who has the cure, I'd say.
Multiple companies could collude to keep a cure off the market. But such cooperation would require all the collaborators to be simultaneously honorable enough to keep the agreement, and dishonorable enough to keep life-saving drugs away from people who are dying. I find that unlikely.
Meanwhile it would only take one traitor to make the deal collapse. Such a traitor could be any person who is in on the secret and also has a family member affected by the disease in question. It takes dozens of scientists, project managers, lab assistants, and random extra staff to create a new drug. I don't believe that many people can keep any kind of secret for any amount of time, let alone a secret as hot as a cure for (in this case) HIV.
This is why I don't believe in the idea that drug companies intentionally keep cures off the market. If no cure is available, it's probably because it genuinely doesn't exist yet.
> If one company has expensive treatments for a disease, and another company has a cure for it (at any price), which company is going to make more money? The one who has the cure, I'd say.
That's not quite correct. The company with the cure will make more money going forward. But not necessarily overall, and the difference there is important.
Let's say you're a venture investor in biotech, and you're thinking about whether to fund the development of an HIV cure or a better HIV treatment. Both will completely replace the existing market in HIV drugs. When you do the net present value calculation for the treatment however, you'll see that you have some probability of people staying on it basically forever. That means that over time, you can extract more money from it, which means of course that you ought to be willing to invest more money in developing it.
It is through this completely rational, non-evil mechanism that treatments may receive more funding than cures. Nobody here is suppressing anything, it's just that one of them will receive more funding than the other because it has a greater potential ROI.
They definitely don't have equal value. The potential revenue stream for the treatment is much higher than the cure. You have to subtract the probability that someone else finds a cure from that revenue stream, amortized and discounted over its lifetime.
So, it may be that sometimes that causes it to make sense to search for a cure (if there is a particularly promising pathway that someone else is likely to explore, for instance), but all else being equal, it probably makes more sense to fund treatments.
The initial cost of developing any new drug is extremely high. We're talking hundreds of millions to billions. That's just to break even. That means if you have a cure for a disease that 100k people have, you have to charge them each $10k just to break even.
That is insane. The numbers of course scale directly with the number of patients, too. If only 10k people in the world have the disease, you need to charge them each 100k, just to break even (the average cost of developing a new drug is actually 2.5 billion, but for these purposes let's say you get lucky and it's 'only' 1 billion).
If you want to actually make a profit, you'll need to charge even more than that.
In that case, do charity organizations that collect money to cure specific diseases or cancers actually make a difference, since their donations are supposed to go to research for cures?
I'd say that they do make a difference relative to doing nothing. It's a way of funding cures that's independent of profit, same with government funding. As far as I can tell, the only solutions to this problem are government funding and private funding of cures.
A market based solution might be allowing pharma companies to charge extremely exorbitant prices for their cures, sufficient to recoup the foregone profits of treatment. But i'm not sure how well that would go down.
Maybe it wouldn't keep a cure, once discovered off the market, but perhaps it could reduce investment in trying to find a cure to begin with? I can imagine that this wouldn't require much collusion, and there's nothing illegal about not investing in finding a cure. Even from a moral standpoint, it's a tougher argument to make.
First of all, if a pharma company had an annual income of 2bn from HIV treatments, and that companies CEO went forward with a HIV cure that is only predicted to earch 3bn overall; that CEO could essentially be removed from his position, as that would not be in the best interest of the company and shareholders.
Also, there does not need to be an evil twist where someone deliberately holds back a developed cure. It is much easier to cut/steer the research in ways that favor treatment/management options, ensuring that a cure would only be found be accident.
> that CEO could essentially be removed from his position, as that would not be in the best interest of the company and shareholders.
No. Stuff like this gets posted to HN all the time but that is just not how things work. In a public corporation, management has broad latitude to make decisions about how to run the company and shareholders have essentially no say in it. They can sell the stock if they don't like it.
If you don't believe me, consider that Tim Cook, CEO of one of the most valuable public companies on Earth, said almost exactly the same thing in a shareholder meeting and nobody batted an eye.
It's a tempting conspiracy theory, but there are a few reasons that persuade me it's very unlikely.
1. Researchers build careers based on reputation. The reputational value of "cured cancer" (even for some small subset of cancer) is probably worth more than a lifetime of developing treatments.
2. Also, some motivated researchers have lost family or friends to the diseases they're working on.
3. Also, many researchers are simply not working at for-profit companies.
All of the above can be filed under "profit is not the only motive for curing diseases (even if it's a powerful one, it's not the exclusive one)." A different tack:
4. Many lines of research have unpredictable results. Studying a virus to develop a treatment may uncover a key weakness that results in a cure. Foundational research often is too early to prioritize a use, and breakthroughs happen in unpredictable ways.
5. There are a lot of players involved in research. A big mix of for-profit companies, NGOs, and governments might have to collude to avoid developing impending cures. So if there's an reasonable next step for global research, it'd be a bad gamble for a company to avoid it, hoping that no one else would pursue it either. ie, If you can get there, assume others can too, so just claim the credit.
EDIT: OTOH if you want to run with this line of thinking, there's a great classic comedy called "The Man in the White Suit" starring Alec Guinness. He invents an unstainable suit that never needs cleaned, and the garment industry sends people to stop him.
If nothing else, many academics are motivated by ego rather than money (I'd put myself in this category). Having successfully discovered a cure for HIV would do such spectacular things for my career that the level of money that would have to be involved is pretty substantial - and would have to be spread over a large number of people.
The market size for HIV/AIDS drugs is under $15 billion [1] so while it's not chump change, it is a tiny fraction of pharmaceutical revenue (over $900 billion I believe). Like the rest of pharma, there's a fast approaching patent cliff which will free a lot of the important IP and many nations have shown they're willing to spend billions to subsidize the development of cheaper generics so I'm not sure that this source of revenue is considered reliable by pharmaceutical companies. Cancer and HIV drugs are the most expensive to develop because they are all used in complex therapeutics and I wouldn't expect many more big blockbusters either. Note also that pharmaceutical companies acquire their IP through M&A of biotechnology startups about as often as through internal R&D and biotech VCs don't have the same incentives as the conglomerates.
Furthermore, the cost of HIV drugs isn't even the majority of the cost of HIV treatment because the constant monitoring and long term complications are extremely expensive. A single hospital visit for HIV-related pneumonia or another opportunistic infection can cost more than several years worth of the drug cocktails and the visits become more frequent and expensive with age as the weakening immune system contributes negatively to almost every other healthcare issue. The incentives for public health and universal healthcare agencies around the world is pretty cleanly aligned with curing HIV at any cost.
There was a cure for Hepatitis C released last year. It's expensive, but priced below the average cost of a lifetime of treatment, so all the incentives align to get everyone to choose the cure.
This of course brings money and marketshare to the company that owns the cure over the company that owns the treatment patents, and it brings recognition to the scientists involved.
So you can take off that tinfoil hat, if someone would find a cure for HIV, they would absolutely not sit on it.
This doesn't make much sense, when very rich people (like Steve Jobs) get diseases and die. If there was a cure, at some point one of these ultra rich individuals would receive "the hidden cure" or have an overt relationship with a medical center leading to recovery. Being able to cure a disease, is generally more profitable for a generation (or more) as it's THE goto product and people are irresponsible enough that there's always new communication vectors.
This is often brought up but having had some experience in the field this does not happen. Not only would you hear a tremendous shout from the researchers themselves crying foul but the company that "cures AIDS" is going to make an assload of money and earn tremendous PR.
The real problem is not pharma trying to turn things chronic but rather people who have less common or less prominent diseases.
> This is often brought up but having had some experience in the field this does not happen.
That's not entirely true. When Hillary Clinton was running health policy in Washington, the white house threatened to impose trade sanctions on India and South Africa if they manufactured generic drugs to treat their citizens with HIV. This was before it had become an epidemic in those areas. And now that it is an epidemic, the pharma companies get tax writeoffs by working with the Clinton Foundation to provide treatment in those areas at 'reduced cost'.
When was Hillary Clinton ever running health policy? Apart from trying to implement 'Clintoncare' early in the Bill Clinton presidency I can not find any record of this.
I agree that insisting that third world countries who are already debtors to first world countries for aid pay huge sums for HIV drugs is problematic at best, but I am not sure why you add Clinton's name into this argument.
Bill controversially appointed her to be the chairperson for Task Force on National Health Care Reform, which was responsible for creating the healthcare policy for the white house. This task for is what created the Hillarycare bill.
A) That task force did not cover all health care policy, in fact it was insulated from current policymaking in order to give it freer rein to think innovatively about the future.
B) The issue you mention does not even fall under health care policy, it falls under IP and trade policy, because the point of objection is when foreign nations nullify or nationalize U.S. pharma patents. That is an ongoing fight to this day, BTW.
That's not what I was referring to. I was responding to the claim that pharmas are inclined to make treatments instead of cures in order to transform a terminal illness into a chronic one and thus make more money long term.
But with the case of HIV (and other infectious diseases), the treatment and the cure are the same drug. E.g. they could have treated people early to avoid the epidemic before it started. But instead the pharma companies lobbied the government to wait for the epidemic to take hold first, so that they could market the treatment later instead.
One could theoretically charge for a cure a little over the cost of the lifetime supply of drug cocktails, and it would still be slightly worth it for the buyer.
Of course, in practice, doing so would lead to severe media outrage, calls for regulation, state-sanctioned patent breaching all over the world, etc. So the practical price is capped. Investors know this.
wait..birth control doesn't affect STD transmission. Unless you mean people getting birth control tends to lead to mode education from the medical professionals who prescribe it to them?
It's all a statistics game. If you can vaccinate against 99% of current strains, you can severely stunt the spread of the virus with its current strain distribution. Combine this with adequate awareness about general prevention methods (safe sex practices) and you have a shot at severely reducing the incidence of the virus so that its numbers are small enough to control. New HIV infections are actually on the decline worldwide thanks to community awareness and ART meds that decrease the chances of spread.
We've been able to eradicate or nearly eradicate several viruses from the planet. It starts with getting them down to manageable numbers, then addressing every outbreak. (Granted, HIV is not quite an analagous in terms of spread to viruses like smallpox.)
The difficulty is that once you're a carrier, you're always a carrier. With modern ART these people can be expected to live long lives. ART decreases the odds of transmission, but not everyone is compliant with their medications. Reducing the spread is one piece of the puzzle. The only way we've managed to "cure" HIV is through a bone marrow transplantation from a donor that have a mutant CCR5 receptor (which the HIV virus needs infect T-cells).
I think that reducing the spread alone still could get us to a point where we "manage this out over the long term" as you say. Say you're a person with many sexual partners that has say a 1 out of 100 chance of sleeping with someone infected with HIV on a given day. Say there's a 1 in 10 chance that encounter will lead to transmission of the virus. (These aren't like factual numbers, just examples). That's still a 1 in 1,000 chance per encounter, so it adds up over time. After 1000 encounters chances are you've contracted HIV. But say you're vaccinated against 99% of the serotypes. That reduces your chance per encounter to 1 in 100,000. Even after 1000 encounters your chance of contracting HIV is 1 in 100. Not terrible.
Minor nitpick: the proportion of each serotype would determine the final reduction in your calculation above. If the serotypes in the 1% the vaccines don't work for are in 10% of the population of patients, then the final reduction would be to a 1:10,000 chance.
> Not my area of expertise but even if we can address 99% of strains, wouldn't that last 1% just take over and become the new 100% leaving us back where we started?
Not my area of expertise either, but as I understand it, it really depends on how many strains you are infected with. If it's just one, it'd reduce the infections in the next generation of patients by 99%. If the average patient had 10 strains, randomly distributed, it'd still reduce the infection rate by 90% (because there's a 10% chance of having that one resistant strain).
Only if all HIV patience had all strains (and I'm pretty sure that's not the case) would it bring us back to where we started.
You don't reduce the infection rate by 99% or by 90%, it's not even the correct term really.
The transmission rate of HIV is not really dependant on the strain but on the behaviour of the affected host.
Since HIV infection can be asymptomatic even for the natural life of a host the transmission rate is then dependant on the environment the social interaction of that host.
A host that has unprotected sex (or any other risky activity as far as blood transmitted diseases go) and does not get tested regularly will have a considerably higher transmission rate than a host that has only protected sex and gets tested when they switch partners.
Most HIV patients are infected with multiple strains, because at this point most new infections are multi-strain ones due to the lifestyle of the hosts and due to the fact that the virus can mutate in vitro.
I'm also not clear how does this press release counts "strains", since it's 16 it's more than just by major types HIV-1 and HIV-2, but then it's the question of what and how they count sub groups.
Most people in the west will get infected by HIV-1 Group M type B, type B itself can have several variations, and there are also host specific mutations, and if you are coinfected with another subtype you can have multiple variations of both and also recombinant (a new form made out of several types of the virus due to coinfection of a single cell) variations that may or may not be unique to each host.
That said effective post infection and pre AIDS outbreak treatments can drastically reduce of new hosts that end up as transmission vectors and carriers, if HIV becomes a considerably more manageable disease that would allow most infected people to carry on with a normal lifestyle (safely have sex with a partner, and have children) once treated more people are more likely to be tested regularly.
If you can also contain the disease to specific subtypes which are regionally locked as sad as it sounds you still doing quite a bit of good since now you can focus your resources on education and containment as well as further research since the transmission rates between say interveinal drug users in Berlin are considerably higher than between a sex worker in nairobi and the same drug users.
> Not my area of expertise but even if we can address 99% of strains, wouldn't that last 1% just take over and become the new 100% leaving us back where we started?
Yes, this is something to worry about and is exactly the reason why it is so hard to find a cure for AIDS. HIV mutates inside the body into thousands of different configurations and no matter what treatment you throw at it there will generally be at least a couple of strains that will survive and take over.
> Or is the promise here that we can combine this discovery with another that solves that remaining 1%?
That would be hard. There is always a chance that the additional treatment will only treat 99% of that 1% and even a single surviving virus might be enough to restart an infection with resistant strains.
> Or, do the mutations of that last 1% make HIV less virulent or harder to transmit?
One of the other comments here, from someone that read the paper, says that the antibody found in this study binds very specifically to a part of HIV that is crucial for infection so the 1% of strains that resist the antibody (due to mutations in the binding site) are less virulent. The antibody also binds only to parts of HIV that mutate very slowly so it might mean that it would take longer for virulent resistant strains to evolve.
It would seem to me that this concept of the strongest strain taking over only would happen if there were some sort of competition for resources. If you have one strain of HIV it seems weird to think that it would stop you from getting another strain and then passing both on. But "not my area of expertise" either.
First, it seems very difficult (for a virus) to transmit HIV via vaginal intercourse[1]. Second, most infections appear to start from a single virus,[2] despite the huge genetic diversity of intrapatient HIV that supposedly makes it hard to treat[3]. That means most of the strains found within one person never get transmitted. How do you manage to transmit HIV contaminated fluids but only one infection occurs in the receiving person? Very strange.
Another strange thing, it does not seem all that difficult (relatively) for interspecies transmission to occur:
"Scientists have now documented that the SIV virus has jumped from monkeys or apes into humans at least 13 separate times!"[4]
Perhaps those transmissions are due to self-injury while cutting infected meat, etc. The vagina is tissue that expects the presence of foreign human cells, and so has defenses against them. Anal sex, injections, etc are a different story. To me it sounds like an entire cell gets transmitted.
EDIT:
Another possibility is that the vast majority of these variants found floating free in the blood are non-functional and serve as chaff to confuse the immune system.
The concept is known as "vaccine escape" and is present in some viral diseases but not others. I confess I don't know how between-strain viral dynamics of HIV work, but it was definitely a concern for HPV, though it does not appear to be happening.
Most of the different variations of HIV found inside an infected person evolved inside that person from one or two initial strains they were infected with.
The various HIV strains inside the body compete with each other over infected cells. Once you kill some of the strains with a treatment it opens up space for the other strains to to fill.
Is this NIH scientist funded by tax money, and if so, what does that mean for a future vaccine or drug? Will it still be patented, and if so, who will hold the patent?
There are 35 authors, some of whom are funded by the NIH. Here's the full funding acknowledgment statement:
Support for this work was provided by the Intramural Research Program and the Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science under contract number W-31-109-Eng-38.
Are you sure about that? Bayh-Dole covers inventions arising from extramural funding (i.e., the NIH provides a grant to people who are employed elsewhere).
I'm not sure how it applies here, where ~80% of the authors appear to be directly employed by some of the NIH's Institutes.
Not my area of scientific knowledge, but this is a really exciting field!
One of the current challenges being worked on is how to train individuals to make these complex antibodies. We've isolated these from people with long-term exposures to HIV, showing that the body can generate these broadly neutralizing antibodies.
Some current work is focusing on developing a series of peptides that can coax HIV negative individuals to make these complex antibodies.
Interesting, I hadn't heard about that theory of HIV transmission. Do you think that having appropriate IgA secretions in the female genital tract might decrease initial infections?
1) I think what is understood about the immune system is really, really over-exaggerated. One specific thing is that a lot of studies regarding antibodies may be messed up by the presence of natively unfolded proteins (which will react with any antibody raised towards beta-sheets and give inaccurate mass estimates on western blot). Every anti-body is promiscuous, it just matters how much.
2) Notice I have no quantification or numbers associated with these ideas. As far as I know, no one has ever spent the time to work this out into a real model that can make precise predictions. Accordingly, consider them wild speculations.
3) According to this sketch of an idea, anything that contributes to identifying and lysing non-self cells should reduce transmission in a given tissue.
Your immune system can and does fight the HIV virus, it does loses that fight because HIV attacks the immune system, can hide for years, and has a cell to cell infection vector.
The immune system is also limited to what it can do, and when viruses can spread cell to cell there isn't much it can do since there is little to no attack surface available for the immune system to work with in that case.
Antibody and therapeutic vaccines can be used as post exposure treatments and combined with other regiments to help slow down or even control the progress of HIV and AIDS in already afflicted patients.
A therapeutic vaccine with a regiment of reverse-transcriptase inhibitors and a treatment to control cell suicide upon infection can probably be developed for HIV and for other retroviruses, well excluding the antibodies it is what we already are doing today mostly.
I am an absolute noob in science, but still want to ask out of curiosity. If a biological virus can have a cell to cell infection vector, can't an anti-body or immunogen also have a cell-to-cell "replenishing" factor?
Like mentioned already by another poster antibodies are an extracellular mechanism, they do not function within the cell.
Cell to call transfer and communication happens all the time, cells share nutrients and many other things, some viruses take advantage of that mechanism allowing them to basically cross cellular and tissue boundaries.
Some can exploit this to the extreme by actually replicating only parts of themselves in each cell and using the cell to cell transfer highway to be finally assembled in another cell, this is often used to prevent cell suicide since one of the intracellular defense mechanism is basically the cell invoking cell death upon detecting an infection.
If you want an analogy from the technology world think about it as staged payloads that some malware use, each payload on it's own is undetectable and even non-functional but when everything reaches the final target all the payloads are assembled into the final piece of malware that takes over the targeted host ;)
There are quite a few other sources on Google, overall viruses are pretty sneaky, some of them even ask the cell politely to establish new cell to cell contacts to facilitate cell to cell infection.
You might also like to look up virus assembly and budding, since it's also a pretty interesting topic, you might have viruses that do cell to cell infection of their naked forms then the final polymerization of their shells happens in another cell and they might even do the final budding in another.
Expect nightmares tho ;)
P.S.
Cell to cell transfers might also be called exocytosis (sometimes also called reversed endocytosis) (exit) and endocytosis (entry) so if you are googling and can't find what you need might need to use the scientific terms.
Antibodies are secreted extracellularly so they won't be any use unless the HIV antigens are expressing on the outside of the cell. There are defense mechanisms for dealing with intracellular viruses but these do not involve antibodies.
A virus hijacks the resources of a host cell to create copies of itself. These copies can then then move into nearby cells and hijack those too, setting off a biological chain reaction.
An antibody is just a protein molecule with no ability to create copies of itself. It might move from one cell to another, but that does create a new synthesizer of the antibody at the new location, and so does not trigger a spread of the antibody throughout the tissue or organism.
There are long-term controllers. Some of these people are able to suppress HIV for 10-30 years before eventually developing AIDS. Others have yet to develop AIDS and seem to suppress HIV permanently. That shouldn't be a surprise - some primates species do the same with SIV, basically controlling it permanently.
I see the comments about cell-to-cell infection; I don't know what it is about these controllers but it doesn't seem to be a problem for them.
Patents are to incentivise inventions. If an HIV patient could patent their antibodies, that would limit their usefulness while also giving no incentive to anyone to invent better ones, since you can't invent them - just wait and hope if they appear. So I certainly hope they can't do that.
Rather, it's the researchers who went looking for them who should be granted any patent rights. They're the ones who could work harder to produce better results and can have their performance improved with more rewards like a patent's monopoly.
I'm not an expert in vaccine development but I believe this could lead to a preventative treatment. Unfortunately, the treatment would probably be very dangerous because unlike smallpox or polio, the human body can't effectively fight HIV and an acute infection almost always turns into a chronic one. If a patient's immune system fails to attack a weakened smallpox strain (the vaccine) and it turns into an acute infection, the risk of life altering side effects is minuscule and more often than not, your immune system will fight off the infection. HIV is different because its only real effect on the body is the destruction of T-cells, which the virus uses to reproduce, and there is no stopping that process only slowing it down. If you take an HIV vaccine developed with this antibody and your immune system fails to learn it (or the strain mutates before it has a chance to, which is a remote but very real possibility with retroviruses), you will eventually develop AIDS or spend a lifetime taking expensive drug cocktails with a long list of serious side effects.
There are tricks to developing vaccines without using the pathogen directly, like constructing a decoy with the relevant surface proteins, but they're unlikely to work with HIV because it's so simple. When an antibody finds its antigen, it signals the immune system to consume the pathogen and learn about it if it hasn't seen the invader before. Since antibodies share a chemical structure (like DNA and RNA, except more complex), cells in the immune system can memorize the antibody and produce it even if it isn't present in our genetic code. This process is one of the most amazing adaptations in the animal kingdom, allowing complex organisms to compete with the microscopic in the evolutionary arms race, but the immune system needs to see the antibody and pathogen in order create mature B-cells, which adapt to bind to the same pathogen as the antibody. HIV is small, simple, and doesn't have many unique features on the viral package (which contains the RNA) so it'll likely be very hard to produce a decoy for the antibody to latch on to.
It's a possibility. Given the lack of details, it's too early to say but the article mentions "prevention" which kinda leads to believe that if this works as we all hope, a cure might be possible.
there's a lot of genetic variation in HIV due to natural selection. in the process of replicating they make many different strains -- mostly very similar to one another.
Yes, but that would require an effort by an organisation like WHO of a scale never seen before. I would be very proud of the human species if we could pull this off.
I think, as a species, we'll master time-travel before consensus...
What isn't true? Once in our history doesn't mean once as in a single host.
There are four major groups of HIV, HIV1 (likely to have originated in a strain of SIV commonly infecting chimpanzees and gorillas) O and M and HIV2 (likely to have originated in a strain of SIV commonly infecting mangabeys) A and B, it's not cleared how many times it independently jumped, what is clear that this was more or less a single temporal event in modern history (cavemen didn't had to worry about HIV or aids, neither did the Romans, and even the bushmen in africa only have been recently infected) and the jump happened between the late 19th and early to mid 20th centuries.
SIV doesn't jump species all the time, there are plenty of SIV strains that haven't done so even tho humans were and are in contact with primates that are infected by those strains all the time.
Other immuno suppressing viruses also haven't made the jump from other species to humans.
If you eradicate HIV today with a push of a button there is no guarantee that SIV will make a jump again and turn into HIV, and there is little to no evidence that HIV jumped back to primates or has yet to infect another species.
There is also no conclusive evidence that the four groups of HIV happened to jump species on 4 distinct occasions, could have been 4, could have been 2 could have been 1 could have been 400.
Heck if HIV1C somehow originated in South America and then was introduced to the human population in Africa half of our models can be thrown down the toilet.
What we do know is that this happened 80-140 years ago, why did a virus that infected primates for 50,000 to 2000000 years suddenly jumped species all of a sudden despite the fact that there was just as much if not more cross species interaction during human history is a better question, in fact if it indeed jumped multiple times all within a pretty small time window that would only raise more questions than give any answer.
>"What we do know is that this happened 80-140 years ago, why did a virus that infected primates for 50,000 to 2000000 years suddenly jumped species all of a sudden despite the fact that there was just as much if not more cross species interaction during human history is a better question"
Simian AIDS was discovered after human AIDS though:
"Examination of the species-specific annual mortality rates of macaques at the center during the previous 4 yr showed a significant increase in deaths in 1980 and 1981" http://www.ncbi.nlm.nih.gov/pmc/articles/PMC393899/
I don't see how people really know whether the problem originated in humans and spread to apes or vice versa. If anything you would expect such issues to be detected in highly monitored animals kept in well controlled research facilities first...
Human HIV was discovered probably 5 decades if not more after it jumped.
We know it didn't originate in humans, because we can estimate how old SIV and HIV are based on their genetic material and other factors.
And we also know how old SIV at least is because we've tested primates on isolated islands and found that they are also infected, so if you find SIV infected primates on an island that was isolated from mainland Africa 30,000 years ago and it's preset within 100% of the primate population you know it's at least that old.
Another thing you can do is look at the DNA of the host and see if any viral DNA has been embedded within it, depending on where it is you can also estimate a timeline based on known processes and mutation rates.
There is very little to no doubt that HIV originated from SIV, the question is why now.
And yes we've discovered SIV later because AIDS happened then we found that it's a virus and not because they are gay, so people started looking at it's source and discovered SIV, FIV, EIAV and others.
You also need to understand that viruses are very hard to find, it's not like you just look at blood samples and see them, there are also not that many generic tests that can simply detect if a virus is present or not, it takes years to decades to isolate, classify and then develop methods to identify a virus and it's not like in the 1980's you could just order a full genome to be sequenced at will.
>"And yes we've discovered SIV later because AIDS happened then we found that it's a virus and not because they are gay, so people started looking at it's source and discovered SIV, FIV, EIAV and others."
This doesn't really fit with the narrative in the paper I linked. They give this reason: "It was the impression of workers at the New England Regional Primate Research Center that there had been an increase in the number of deaths in its macaque colony."
The paper you linked is from 1983 before any genetic and even epidemiological studies were conducted, AIDS was clinically observed in the US in 1980 or 1981, it wasn't even called AIDS until 1982, and HIV was only identified in 1983.
So what's exactly the surprise in the fact that an article from 35 years ago that was written at the dawn of HIV and AIDS research doesn't exactly fit with our modern understandings of the disease?
Given that the research animals are much more heavily monitored it is surprising that the simian analogue only showed up in that environment after the human version became a big deal.
As quoted earlier, they say the study was initiated because they noticed the animals dying more often than usual. You don't need genetic/epidemiological data to notice something like that. I do not understand what relevance that should have.
In 1983 AIDS wasn't still a big deal, no all primates have SIV strains, some primates never develop AIDS, we know some species for primates can effectively suppress SIV permanently, while some do develop immunodeficiency syndromes, heck it's even possible that the species or sub group of primates in the research was introduce to SIV from another species because of humans (mostly because the research does states that they have had 14 different species locked in their research center), it is however not possible for HIV to be the origin of the virus since we now have genetic models of the disease.
When that research was conducted we didn't even knew what was causing AIDS as neither SIV nor HIV have been identified yet.
Also research animals die all the time in great numbers, if it's a research laboratory then they'll probably die or be put to death way before they'll develop AIDS, if it's a conservation then they die to natural causes all the time, it's more likely that no one bothered to think why primates die to various infectious diseases more frequently than they should beforehand and then when AIDS research began to be published some one made a connection and looked into it.
It's not like in 1983 or prior to that we commonly had 100's of primates locked in for a multi decade research in a state of the art habitat which was constantly monitored, they were either lab rats that lived a very short life or at best simply tracked for conservation purposes on a reservation.
In fact after reading the research fully, it looks to me like they've unintentionally introduced SIV to Asian Macaca Cyclopis from an African species M. Mulatta (commonly known as a rhesus monkey) since SIV is not commonly present in Asia it's no real wonder why an Asian primate species would be considerably more affected as African species would be more or completely immune to AIDS while being SIV carriers.
If anything this paper proves that African primates coexisted with SIV for a long enough time to develop an immunity or high tolerance to the virus while species from other regions that did not have SIV strains did not.
And you can chuck this again to the fact that in 1983 no one knew that AIDS was caused by HIV, SIV, FIV and other similar viruses.
>"Also research animals die all the time in great numbers, if it's a research laboratory then they'll probably die or be put to death way before they'll develop AIDS"
Yes, yet (relatively) soon after human AIDs is discovered people start noticing an increase in macaque deaths in their labs. This was later attributed to a similar cause. I think that is an important aspect of the timeline to keep in mind, that is all on that point. The rest hinges on other evidence which we are discussing in parallel here.
In a species that was never exposed to SIV before, what is actually surprising here?
I really don't understand why you are even attempting to quite wrongly interpret the results of a study before HIV or SIV were even discovered that actually disproves your assertion.
>"we've tested primates on isolated islands and found that they are also infected, so if you find SIV infected primates on an island that was isolated from mainland Africa 30,000 years ago and it's preset within 100% of the primate population you know it's at least that old."
This sounds familiar, do you remember the ref? From what I remember the degree of "isolation" was questionable.
It's important to note that even if the location is not isolated it doesn't matter, and we do have proof that it is, what we look at is the molecular clock of the virus basically it's molecular structure based on the mutation rate of each virus.
When you calculate the drift between different strains you can estimate the age, more isolated populations help since they tend to have less types of infections, while it's not common to find a primate with multiple strains on the mainland primates in the deep jungles of south america and on isolated islands off the coast of africa usually only have a single strain due to their relative isolation from other primate populations.
Not much more time for me to read into this today but I see that the molecular clock estimate is based on the "isolation" estimate. So these are not independent measures:
"Crucially, he knew from geological records that the island separated from continental Africa around 12,000 years ago. Assuming that the strains had had at least 12,000 years to evolve apart, he determined that the mutation rate of SIV is much slower than originally thought."
I find it difficult to believe that for 10k years a plausible scenario is that nothing happened like eg:
A) someone was hunting monkeys from more populated areas and traveled to "isolated" islands/regions to get more.
B) monkey on a branch gets thrown out to sea and floats to the island.
The molecular clock isn't dependant only on the isolation estimate, it comes from in vitro studies of a given virus and each of it's offshoots combined with our understanding of it's replication rates in a host.
Again it doesn't need to have a perfect isolation, and the fact that the island is home to completely different strains which are unique to that island and can be genetically studied for drift and mutation rates does show that there was sufficient isolation to prevent transmission between the mainland and the islands.
All isolation is relative, N. Korea is isolated it doesn't mean that nothing gets in or out, same thing here a monkey on a branch might be thrown out to the ocean but it doesn't mean it will become a transmission vector.
Strain X exists only on Island Y while strain M N and O exist only on Mainland Z but not vice versa is enough proof for isolation for the studies to be valid.
>"The molecular clock isn't dependant only on the isolation estimate"
Sure, not only, but according to your source it is dependent on the assumption the island was "isolated" for 10k years. We would have to look at the model to tell what effects relaxing this assumption and definition may have.
The molecular clock doesn't care when the island was isolated or for how long, it's used as a benchmark tool to differentiate the relative time period between 2 genetic sequences which share a common ancestor, it never gives you a date it can tell you that it took 4 times the time to arrive to state X from state Z than it took from state Y.
We know that the island is isolated sufficiently because of the unique SIV strains, we also know that the populations of the animals were isolated because there are no signs of cross-breeding.
There have also been countless studies to determine the age and the source of the tMRCA between HIV and SIV, and SIV is the source for every genetic study, even those that do not rely on using molecular phylogenetics to ascertain the time scale.
SIV and other primate lentiviruses are old, they are asymptomatic in the vast majority of their natural hosts which suggest coevolution which resulted effectively in cohabitation.
Most of the current work is done in regards to tMRC identification to build an accurate timeframe to understand why did HIV1 jumped from chimps to humans and HIV2 jumped from mangabeys.
We are also studying the divergence of different strains of SIV between different species of primates to better understand the virus, all of these studies find completely different time scale than what you are proposing, in fact other than conspiracy theories that were already disproven no science actually backs up any of your assertions.
Overall even if we take the studies that point to a completely different pathology and estimate the age of SIV at 100's or a few 1000's of years old, the divergence of the different strains still means it came first, spread across the primate population of africa, and then jumped to humans.
>"The molecular clock doesn't care when the island was isolated or for how long"
The rest of what you wrote is interesting (or will be once I get some sources for your claims), but you start out with this one that blatantly disagrees with what was written in your own source. In your source it says that molecular clock depends on the assumption the island was isolated for 12,000 years.
It would be great if you could:
1) Focus on that one point to clear up why you disagree with your own source, do this without writing about anything else. I am stuck on that issue right now.
2) Bring some links when referring to evidence, so I can tell what has made you believe the things you say. I am getting the sense you are well informed but not quite skeptical enough (perhaps current grad student?). The devil is in the details, as I have seen with the "isolated" island and molecular clock interdependence.
I've been hearing about "this looks like a cure for AIDS!" at least once a year since the 90s. It always just needs to go through FDA testing and approval and then evaporates. What we've gotten instead is incremental improvements in the treatment of the disease. Maybe if you tell me there is a new treatment that completely cures some 1% of those treated I'll buy it. But this, this is preliminary research.
I feel like the frequency of the "scientific breakthrough" headlines that led to nothing has muted my enthusiasm for remarkable findings like this.
There is a huge difference between the NIH announcing a finding and the sensationalist science journalism that is typically inaccurate. I wonder if this divergence erodes the public trust in science.
An earlier antibody in the same family, VRC01, is in Stage IIb clinical trials for the treatment of HIV. Medical science is slow and extremely methodical, but it can produce practical results. You just have to have patience.
I think the problem is that in popular news you often just get the impression that a "breakthrough" happened but it isn't super clear what the scientist actually did, what are the limitations of their work and what you should expect from future research.
So instead of seeing news that say specific things like "this might lead to a monoclonal antiboody treatment in 10 years" or "this could help vaccine research" you end up with a bunch of headlines that sound as if AIDS is going to be cured tomorrow.
Since the discovery of the virus 32 years ago there have been a large number of treatments successful in animals or the test tube, only to fail in humans
In essence, an antibody called N6 was extracted from an HIV patient. The patient is a long-term nonprogressor who has had HIV for 21 years, but an exceptionally low viral load of <1000/mL and normal CD4 T-cell count. This indicates that his immune system has kept the virus at bay for all these years with essentially no ill effect.
HIV viruses have a surface protein complex called Env, which binds to the CD4 surface protein to gain entry to T-cells (part of the immune system). HIV cannot transmit without this protein complex, and so certain parts of the complex are very well conserved across different HIV strains.
N6 binds to this part of Env, in some sense "simulating" CD4. However, because it's just an antibody and not a cell, once Env is bound it cannot infect anything. This is what makes N6 a neutralizing antibody.
The thing that makes N6 special (more potent and more broadly applicable) is that it is able to avoid the parts of Env that HIV doesn't need for replication. Imagine Env as a wrench. The head of the wrench is a specific hex shape to mate with CD4 and can't change. Antibodies can grab on to the wrench handle to prevent infection. But the handle can change, and HIV regularly mutates this part to avoid being caught - adding side branches, changing the shape, and so forth. N6 is cleverly arranged so that it can strongly bind to the wrench without grabbing the handle too strongly - in other words, it tightly binds the head of the wrench like a person wrapping a thumb and index finger around it (this hand analogy appears in the paper). The result is that HIV has a much harder time getting out from under the antibody, since mutating itself to alter the head shape would also affect infectivity.
Now that larger HIV screening trials are done, and the technology has advanced to better detect such super-antibodies, more of these clever antibodies may be discovered. We may yet have a good shot at defeating this tricky virus!