...and this one actually looks respectable.
September 25, 2011 3:03 PM   Subscribe

Researchers have apparently found a way to prevent HIV from damaging the immune system. Johns Hopkins and Imperial reseachers have developed a chemical that breaks down the cholesterol membrane around HIV. This stops the virus intererfering with immune response, and may allow a vaccine that prevents infection.

For those that can get to it: Adriano Boasso, Caroline M. Royle, Spyridon Doumazos, Veronica N. Aquino, Mara Biasin, Luca Piacentini, Barbara Tavano, Dietmar Fuchs, Francesco Mazzotta, Sergio Lo Caputo, Gene M Shearer, Mario Clerici, David R. Graham. Over-activation of plasmacytoid dendritic cell inhibits anti-viral T-cell responses: a model for HIV immunopathogenesis. Blood, 2011 DOI: 10.1182/blood-2011-03-344218

I am curious what the MeFi hive mind thinks of this research; consider this a bat signal, people with expertise in the area.
posted by jaduncan (23 comments total) 20 users marked this as a favorite
Rly? That's stupendous. Rock on!
posted by that's candlepin at 3:12 PM on September 25, 2011

...and this one actually looks respectable.


This seems like the type of thing I'd stopped hoping for. Not holding my breath but certainly crossing my fingers.
posted by MCMikeNamara at 3:27 PM on September 25, 2011

It looks like this is the actual article.
posted by Blasdelb at 3:38 PM on September 25, 2011

Good news, VERY promising. And breaking down cholesterol sounds like it should always be a good thing. If this method can be expanded, we could end up with Bacon and Eggs without negative side effects.
posted by oneswellfoop at 3:47 PM on September 25, 2011 [1 favorite]

I haven't exactly read deeply into this, but from the Science Daily post it appears that they haven't actually developed a treatment that removes the cholesterol from HIV. They can do it in the lab when they have some HIV in a tube, but getting that to happen inside a person is a different problem.

It's still a great discovery, right, because now we have a new avenue of research open. But they haven't found a way to prevent HIV that people actually catch in real life from damaging the immune system.
posted by LogicalDash at 3:52 PM on September 25, 2011 [2 favorites]

Yes, it's lab work.
posted by jaduncan at 3:54 PM on September 25, 2011

The researchers are using one in a class of compounds called cyclodextrins to punch holes in the coating around HIV. This makes it difficult for HIV to bind on to and infect one of the immune system cells called CD4:

Partial withdrawal of cholesterol by treatment with the starch derivative 2-hydroxy-propyl β-cyclodextrin (βCD), destabilizes the envelope organization, depriving HIV of its ability to infect CD4+ cells in vitro26,27.

It's not perfect. From the paper:

The mechanism by which permeabilized HIV achieves partial pDC activation without stimulating IFN-α/β production is still obscure. It is possible that residual viral RNA present in the βCD120-HIV preparation is a sufficient stimulus for APC to upregulate only surface molecules with a lower activation threshold. An alternative possibility is that other viral components, such as host-derived proteins or unique oligosaccharides on viral proteins, may participate to APC activation independently of the TLR7/8-RNA interaction.

Even after poking holes in the HIV particle's cholesterol coat, it looks like a virus particle can still have the capability to trigger disease (suppressing the immune system, i.e., AIDS).

The researchers do not understand why, but there may be other factors present that coordinate pDC activation.

The researchers also note that the link between pDC activation and suppression of the immune system is not completely established:

Nevertheless, there is no direct demonstration that pDC activation is a specific mechanism adopted by HIV to escape adaptive immune responses.

Looks promising, but there are lots of questions, like how to administer this as a therapeutic drug without killing someone, or what other factors contribute to pathology. Perhaps this cyclodextrin would be best used in conjunction with other therapies that target those cofactors, for example.

Onwards and upwards...
posted by Blazecock Pileon at 3:54 PM on September 25, 2011 [3 favorites]

Despite the simplistic view of cholesterol that permeates public understanding of the compound, it would not be desirable, much less possible, to get rid of all of the cholesterol in a human system. This is a really neat paper, and it has a lot of promise for researchers trying to figure out how HIV does its thing but not much as a potential therapeutic target.

If anyone would like a copy of the paper for the purposes of this academic discussion, which we are currently having on this community weblog, MeFi-Mail me with an email address I can send a PDF to.
posted by Blasdelb at 4:03 PM on September 25, 2011 [1 favorite]

They can do it in the lab when they have some HIV in a tube

Yep, the key term is "in vitro". When the researchers have something ready in vivo, get the champagne ready.
posted by Blazecock Pileon at 4:10 PM on September 25, 2011 [3 favorites]

It sounds to me more like this would be more helpful in the quest to develop a vaccine rather than fighting the virus itself. If you can treat a sample of HIV such that it's not infectious, but still recognized by the immune system (as they are claiming to have done by disrupting the cholesterol in the HIV envelope), it would likely make for a good attenuated vaccine.
posted by greatgefilte at 4:48 PM on September 25, 2011 [1 favorite]

Here's a quick summary of the human immune system cells and how it works. It's incredibly complicated and a lot of the details on not well understood, but I hope that this help people understand why researchers having a hard time with HIV and what this research does.

First first component of the immune system is the innate immune system. They have limited ability to recognize foreign extracelluar pathogens(stuff that floats between cells) like bacteria and basically eat them or destroy them with chemical attacks. For intracellular pathogens like viruses there are cells called natural killer cells that can recognize that a cell is distress and trigger cell death. This prevents the virus from replicating. When you get sick for the first time with a disease in the first 72 hours this is the system that is doing the most of the fighting by itself.

The second part of the immune system is the adaptive part of the immune system. This what helps prevents reoccurring infections by the same organism over and over again. There are two main parts, B cells and T-cells. The B-cell produce antibodies. Antibodies that are created float around in your blood and in your mucous secretion(intestines, respiratory tract, etc). While floating around they'll stick to foreign pathogens that are also floating around and signal the cells in the innate immune system to destroy the target. The main goal of modern vaccines is to create antibodies.

The catch is that they only get bacteria, viruses, and other pathogens that are floating around. The other part of the adaptive system the T-cells is much more suited to intracellular pathogens. However, the T-cells don't just help with intracellular pathogens they can also activate and regulate the other parts of the immune system. They can tell B-cells to produce more cells and antibodies against a particular pathogen or your innate system to ramp up its attack. If you lose(or never had them in the first place) your T-cell your immune system basically can't coordinate an effective response against disease. These are usually called Severe Combined Immune Deficiency Syndromes(SCIDS). This is similar to the end state of AIDS.

It is important to note that there is also two kinds of T-cells, CD8 and CD4. These are named after a protein on the surface of the cell. CD8 cells are designed to recognize when a cell has been infected by a certain intracellular pathogen(e.g. viruses like HIV) and destroy that cell and it's contents. CD4 cells are nicknamed helper cells, because they secrete the chemicals that coordinate the immune system response.

An important piece of puzzle to understanding the adaptive immune system is "how do T-cell know what to attack?". What happens is that cells in the innate immune system after they eat a pathogen or get infected themselves, they will go to to lymph nodes and say "Hey CD4 T-cell I've got something here that looks bad" and the T-cell will become active towards that particular object that is considered foreign. Once active it will get the immune system to look for that pathogen.

Onto HIV. HIV attacks CD4 cells, by actually binding to receptor they are named after. Overtime they gradually kill of these cell cause eventually death of the host by other diseases. The trademark of AIDS and SCIDS is the rate opportunistic infections by disease one would not normally get. Also, HIV can target other cells like Dendritic cells in the paper, but their primary target is CD4 cells.

I would classify this paper as more of basic mechanism research paper that is trying to figure out how HIV and immune system interact. Now to translate the abstract into layterms:

"A delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DC) and other antigen-presenting cells (APC) regulates the strength and efficacy of anti-viral T cell responses. "
-Dendritic cells and antigen presenting cells are cell in the innate immune system that say "Hey T-cell this looks bad. Target it for destruction". They also release signals important for telling T-cells to activate.-

"The human immunodeficiency virus (HIV) is a potent activator of plasmacytoid DC (pDC). Chronic pDC activation by HIV promotes the pathogenesis of the acquired human immunodeficiency syndrome (AIDS)."
-The HIV when infects a specific kind of Dendritic cell(plasmacyoid DC), it tells it to activate like crazy.This is important step to cause AIDS.-

Now the first question people should be thinking is why would a pathogen want to activate the immune system. Wouldn't this trigger the immune system to attack the pathogen? The important thing to note is that the Dendritic cell here hasn't recoginized HIV. It's tell the immune system to activate like crazy, but without giving it a specific target. So basically the immune system won't be able to discern HIV from the noise of the false alarms going off. This is one of the many ways, HIV systematically dismantle the ability of the immune system to respond to infection.

"Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDC."
-By removing cholesterol from HIV envelope we reduce it's ability to infect dendritic cells.-

It's important to know what an envelope is. An envelope is basically a section of patient's cell membrane that is taken by HIV to cover itself. This prevents the immune system from recognizing it because it looks like the patient's own cells. Basically a disguise. Cholesterol role in animal cells is to make sure that the cell membrane is stable. It prevents it from getting to rigid or too loose. By removing it this cholesterol from HIV it's disguise falls apart. It also prevents HIV from randomly activating dendrictic cells. This also means we can't use this experimental method to directly attack HIV. Since removing cholesterol from a solution(e.g. blood) would also destroy a person's cells. This is the main reason I consider this is a basic research paper.

"We found that APC activation was dissociated from the induction of type I interferon (IFN-α/β) and indoleamine 2,3-dioxygenase-mediated immunosuppression in vitro."
-The dendritic cells we are studying no longer produce chemical signals like crazy when infected with the cholesterol removed from the virus envelope-

Interferons are chemicals signals released by cell to help fight viral infection . And that second chemical is something released by the special dendritic cell to suppress the immune system.

"Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T cell responses in HIV-exposed uninfected individuals."
-By removing the cholesterol the HIV and it's envelope are destabilized making it easier for the immune system to identify HIV as target and activate CD8 cell in people who have exposed, but not yet have an infection. (Also destabilizing the envelope caused the HIV to lose some of it's proteins and genetic material).-
Just some other facts to note:HIV is a RNA virus and stores it's gene as RNA versus DNA. Recall that CD8 cells are responsible for killing cell infected with viruses. Also, this is more of claim biased on their in vitro research on CD8 cells in a dish rather than in a person. The researchers did not expose people to the weakened virus(I hope).

"These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β."
I think this sentence is pretty straight forward. The improve immune response mention in the previous sentance was due to this cholesterol depleted envolped viruses they created with.

One other point I would like to make is that creating drugs against viruses is difficult. Things like bacteria have unique metabolic machinery that we can target by antibiotics. Viruses use your own cells to produce their proteins and genetic material. Virues also mutate relatively quickly. RNA viruses like HIV are very sloppy. This means they make a lot of duds, but they also make a lot of successful mutants that can evade the immune system(therefore vaccines) and drugs. The drugs we do have against AIDS mainly target the fact it is a RNA virus and needs special proteins so that it can use the host cell machinery to make copies. The only way viruses have been eradicated have been through vaccines. To date antivirals have only reduce the strength of an infection.

I only have slightly better understanding than a layman. So anyone with immunology experience feel free to point out any mistakes.
posted by roguewraith at 6:39 PM on September 25, 2011 [107 favorites]

I only have slightly better understanding than a layman.

posted by hippybear at 6:43 PM on September 25, 2011 [10 favorites]

When I first read read the paper this is what was going through my head. It took a bit of effort to understand what was actually happening.
posted by roguewraith at 7:10 PM on September 25, 2011 [1 favorite]

The proper way to link to a scientific paper is by DOI number: http:dx.doi.org/10.1182/blood-2011-03-344218

There is no such thing as bad, correct, information, so as long as this is correct it isn't a bad thing to know, even if we can't make drugs out of it.
posted by Canageek at 7:15 PM on September 25, 2011 [2 favorites]

Tag it with GFP, stick it in some cats, and then I'll get excited.

No, I'm being a smartass, this is exciting now, I just love those cats.
posted by maryr at 9:25 PM on September 25, 2011

I remember a few years back when everyone was so excited about pDCs. Not because of their potential (and still unclear) role in HIV, but from a more general anti-viral immunity point-of-view. pDCs make lots of IFN-alpha, which is an important cytokine in many viral infections (flu, HSV etc.). The fact that pDCs made lots of IFNa somehow morphed into this idea that pDCs were the most important source of pDCs. Then people started looking at viral infections in mice that lacked pDCs; the mice did fine. Because there are plenty of other cells in the body that make IFNa, more than enough to compensate for a population of cells that make about 0.3% of circulating white blood cells.

Yes, I am an immunologist and yes, I am underwhelmed by this paper.

What I do find interesting is that this research has managed to gain media traction while the last episode of Science featured two independent, in-depth (multi-discipline) reports on HIV-1 neutralizing antibodies.
posted by kisch mokusch at 5:02 AM on September 26, 2011 [1 favorite]

Apologies, the second Science paper was here. I mistakenly linked to the News and Analysis section of the same issue.
posted by kisch mokusch at 5:06 AM on September 26, 2011

roguewraith, what role does interferon play in immune response and HIV?
posted by infinitewindow at 2:18 PM on September 26, 2011

Wait, Kisch -- I'm confused.

Do I have this right?
Plasmacytoid dendritic cells (pDCs) are part of the non-specific innate immune response, specifically they release IFNα, activating the cytokine cascade which leads to, among other things, inflammation and fever. But IFNα is released by other innate immune cells, too. Mice pDC knockouts (?) have an unimpaired (?) immune response. So here we have some nice biological redundancy. Unless we know that HIV does *not* (?) stimulate IFNα release in the other cells (?) -- who cares?

"Muahaha! I have disabled this bus so you cannot get to the mall." Well, OK, but I can still get to the mall by walking (less efficient -- score one for the villain) or driving (more efficient) or...

So my question is this: Do we know whether pDCs are the preferential, primary, or only cells in which HIV stimulates IFNα release?
posted by pH Indicating Socks at 2:59 PM on September 26, 2011

Plasmacytoid dendritic cells (pDCs) are part of the non-specific innate immune response,
Yes. Although there are a few believers out there that believe pDCs present antigen to T cells (thereby making them part of the adaptive response). They can do it in vitro, but I'm not sure that too many people believe they're doing that in vivo. Not absolutely demonstrated, but the evidence to date suggests that they don't. At least, not for naive T cells

specifically they release IFNα, activating the cytokine cascade which leads to, among other things, inflammation and fever.

Well, there are a lot of cytokines involved in inflammation, and IFNa isn't essential to get, say, TNFa or IL-6 production. So I wouldn't look at IFNa as being at the top of the cascade.IFNa is certainly involved in fever. The really important role for IFNa is in activating a number of anti-viral processes within host cells, thereby making them more resistant to infection. In chronic infections, continual production of pro-inflammatory cytokines can do more harm than good.

But IFNα is released by other innate immune cells, too. Mice pDC knockouts (?) have an unimpaired (?) immune response.
Mice which happen to have missing pDCs, or were specifically generated such that pDCs could be depleted, and mice which have had pDCs depleted by antibody have only mild immune impairment. We're talking about some small delays in the kinetics of some immune cell subsets to the site of infection and other pretty minor effects which don't significantly impact on the outcome of infection.

So here we have some nice biological redundancy.

Yes. I think it's fair to say there is a great deal of redundancy when it comes to IFNa. Lots of different cell types can be induced to secrete it.

Unless we know that HIV does *not* (?) stimulate IFNα release in the other cells (?) -- who cares?

Well, the response of pDCs to viruses is still kinda interesting, at the mechanistic level. And they don't respond to HIV in the same way that myeloid/conventional DCs do. It's not my specialty, but as I understand it, pDCs don't fall for some of HIV's tricks the same way that the other DCs do. Understanding that could be quite useful down the line. That's kind of where this paper comes in. Understanding the the determinants of HIV infection with a long-term view to using the results to interfere with HIV function in the clinic. Important, but there is a lot of work like this being done all of the time. And it's a long way away from any therapeutic application.

So my question is this: Do we know whether pDCs are the preferential, primary, or only cells in which HIV stimulates IFNα release?

I think the jury's still out, but my personal feeling is that lots of things would be making IFNa in HIV-infected people besides pDCs. That is certainly the case in other viral infections, I don't see why HIV should be so different. I know that pDC numbers do change during HIV infection, but hell, a lot of things change. So it's not really clear how much pDCs influence the situation. I'm not aware of any people that have been found who lack pDCs, let alone what their response is to HIV. And I don't know of any therapy that has been tested in people in which pDC numbers have been actively manipulated (i.e. depletion antibodies). So how pDCs function in the actual real word in people with HIV has yet to be properly determined. Most of the work with pDCs and HIV is performed in vitro.
posted by kisch mokusch at 10:44 PM on September 26, 2011 [1 favorite]

Thank you. This is fascinating.

Of course I did not mean "Who cares?" Advancing science is tremendous. I meant, "Why would people who don't care about basic research care about this, if it is as far from therapeutic application as it looks?" And from what you've said, I guess the answer is that, if some believe pDCs are essential to HIV's suppression of the immune response, then those people are cracking open the bubbly -- and the rest of us see HIV researchers cracking open bubbly, which they don't do as often as we'd like, and get excited.
posted by pH Indicating Socks at 11:26 PM on September 26, 2011

Yes, I would think think that people who work on pDCs and HIV would be very interested in this paper. The rest of us perhaps not so much.
posted by kisch mokusch at 2:32 AM on September 27, 2011

Infinite window, kisch mokush answered it in his replies, but I also just realized he was using shorthand, which I've gotten used to as well.
IFN => interferon so IFNa is interferon alpha.
IL => interleukin
TNF => Tumor Necrosis Factor
These are all cytokines, chemical signals used by the immune system to coordinate.
I've linked to wikipedia because the articles are almost as good as intro to immuno college text book in terms of detail, but not really that useful for a high level overview. In relation to this article and for general understanding, inteferons are antiviral signals by the immune system. Pretty much every single virus(or pathogen) does something different to muck with the immune system and avoid detection and HIV from my understanding is one of the most tricky.
If I say anymore I'm speaking beyond my understanding. Anyone feel free to MeFi mail me, if there is some big picture thing that doesn't make to much sense. Yes, this is very confusing. The immune system has a ton of moving parts.
posted by roguewraith at 3:09 AM on September 27, 2011

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