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Author Topic: scientists show why anti-HIV antibodies are ineffective at blocking infection  (Read 3714 times)

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Offline datdude

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Caltech scientists show why anti-HIV antibodies are ineffective at blocking infection
Findings provide possible explanation for failure of decades-long AIDS vaccine search
 
     
   
 IMAGE: This anti-HIV antibody has a typical Y-shaped architecture and a span of 15 nanometers.


Click here for more information.
   
     
 
PASADENA, Calif.--Some 25 years after the AIDS epidemic spawned a worldwide search for an effective vaccine against the human immunodeficiency virus (HIV), progress in the field seems to have effectively become stalled. The reason? According to new findings from a team of researchers from the California Institute of Technology (Caltech), it's at least partly due to the fact that our body's natural HIV antibodies simply don't have a long enough reach to effectively neutralize the viruses they are meant to target.

Their findings were published last week in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).

"This study helps to clarify the obstacles that antibodies face in blocking infection," says Pamela Bjorkman, the Max Delbrück Professor of Biology at Caltech and a Howard Hughes Medical Institute Investigator, "and will hopefully shed more light on why developing an effective vaccine for HIV has proven so elusive."

Y-shaped antibodies are best at neutralizing viruses--i.e., blocking their entry into cells and preventing infection--when both arms of the Y are able to reach out and bind to their target proteins at more or less the same time. In the case of HIV, antibodies that can block infection target the proteins that stud the surface of the virus, which stick out like spikes from the viral membrane. But an antibody can only bind to two spikes at the same time if those spikes fall within its span--the distance the antibody's structure allows it to stretch its two arms.

"When both arms of an antibody are able to bind to a virus at the same time," says Joshua Klein, a Caltech graduate student in biochemistry and molecular biophysics and the PNAS paper's first author, "there can be a hundred- to thousandfold increase in the strength of the interaction, which can sometimes translate into an equally dramatic increase in its ability to neutralize a virus. Having antibodies with two arms is nature's way of ensuring a strong binding interaction."

As it turns out, this sort of double-armed binding is easier said than done--at least in the case of HIV.

In their PNAS paper, Bjorkman and Klein looked at the neutralization capabilities of two different monoclonal antibodies isolated from HIV-infected individuals. One, called b12, binds a protein known as gp120, which forms the upper portion of an HIV's protein spike. The other, 4E10, binds to gp41, which is found on a lower portion of the spike known as the stalk.

The researchers broke each of the antibodies down into their component parts and compared their abilities to bind and neutralize the virus. They found, as expected, that one-armed versions of the b12 antibody were less effective at neutralizing HIV than two-armed versions. When they looked at the 4E10 antibody, by comparison, they found that having two arms conferred almost no advantage over having only one arm. In addition, they found that larger versions of 4E10 were less effective than smaller ones. These results highlight potential obstacles that vaccines designed to elicit antibodies similar to 4E10 might face.

But b12 has its own obstacles to overcome as well. In fact, when the researchers looked more closely at their data, they realized that the benefits of having two arms--even for b12--were much smaller than those seen for antibodies against viruses like influenza. In other words, the body's natural anti-HIV antibodies are much less effective at neutralizing HIV than they should be.

But why?

"The story really starts to get interesting when we think about what the human immunodeficiency virus actually looks like," says Klein. Whereas a single influenza virus's surface is studded with approximately 450 spikes, he explains, the similarly sized HIV may have fewer than 15 spikes.

With spikes so few and far between, finding two that both fall within the reach of a b12 or 4E10 antibody--the spans of which generally measure between 12 and 15 nanometers--becomes much more of a challenge.

"HIV may have evolved a way to escape one of the main strategies our immune system uses to defeat infections," says Klein. "Based on these data, it seems that the virus is circumventing the bivalent effect that is so key to the potency of antibodies."

"I consider this a very important paper because it changes the focus of the discussion about why anti-HIV antibodies are so poor," adds virologist David Baltimore, the Robert Andrews Millikan Professor of Biology and a Nobel Prize winner. "It brings attention to a long-recognized but often forgotten aspect of antibody attack--that they attack with two heads. What this paper shows is that anti-HIV antibodies are restricted to using one head at a time and that makes them bind much less well. Responding to this newly recognized challenge will be difficult because it identifies an intrinsic limitation on the effectiveness of almost any natural anti-HIV antibodies."

In addition to Bjorkman and Klein, the authors on the PNAS paper, "Examination of the contributions of size and avidity to the neutralization mechanisms of the anti-HIV antibodies b12 and 4E10," are Caltech research technicians Priyanthi Gnanapragasam, Rachel Galimidi, and Christopher Foglesong, and senior research specialist Anthony West, Jr.

The work described in the paper was supported by a Bill and Melinda Gates Foundation Grant through the Grand Challenges in Global Health Initiative and the Collaboration for AIDS Vaccine Discovery.
http://www.eurekalert.org/pub_releases/2009-04/ciot-css042209.php

Offline Inchlingblue

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This is an interesting discovery and yet seems kind of obvious, I'm surprised it hasn't been discovered sooner.

These findings would seem to support even stronger the studies being done with elite controllers and LTNP since those individuals are able to produce broadly neutralizing antibodies.

Offline veritas

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4E10 and b12 are not potent enough. CHAVI came up with 11.31 which seems to  take care of the problem. This study is part of the anti-ps research. See entire link below:

http://www.investorvillage.com/smbd.asp?mb=1773&mn=705&pt=msg&mid=6497373

The above link compares the different mabs. Also, note that pgn632 is the same 11.31 mab.

v

Offline poz4afewyears

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Why Anti-HIV antibodies are ineffective at preventing HIV infection....
« Reply #3 on: April 23, 2009, 01:38:54 AM »
Contrary to all of the daily reports about how we are getting closer and closer to a vaccine every day, this article says that research has effectively been "stalled". Basically, this article says that the current approach is never going to work.

http://www.sciencedaily.com/releases/2009/04/090422151832.htm

That really seems to put a damper on the daily new threads here saying that an we are a step closer to a vaccine. This is why I don't donate to AIDS charities. Because they most are focused on a vaccine, while those of us on meds continue to suffer with the effects of HIV that HAART can't counteract and with it's side effects. They have wasted so much money on a vaccine that has never come to being. And it probably won't for a long, long time.

Offline John2038

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If this paper highlight that our body's natural HIV antibodies don't have a long enough reach to effectively neutralize the viruses they are meant to target, HIV antibodies are not the only answer to HIV.

So such paper do not compromise at all the others route to fight this infection.
Our problem is to purge the latent reservoir.

We might write as many papers as we want to explain why our body have beeen unable to defeat the rubella, polio, chickenpox, etc, the things is that we have a vaccine for them.

In more, the research is progressing using different approach DNA vaccination, T-cell receptor peptide vaccines, recombinant Vector, etc

Finally, there are elite controller, so even our bodies haven't just the antibodies as an answer to an infection.

Also, if we know why something doesn't work, we are progressing.

Offline poz4afewyears

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Also, if we know why something doesn't work, we are progressing.

You could look at it that way, but I don't. If I go on a tour around the world and visit every location and every city, which isn't possible, and then discover that I have lost something, when I find that it isn't in my luggage I am not going to feel like I am closer to finding it.
« Last Edit: April 23, 2009, 12:22:47 PM by poz4afewyears »

Offline Assurbanipal

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You could look at it that way, but I don't. If I go on a tour around the world and visit every location and every city, which isn't possible, and then discover that I have lost something, when I find that it isn't in my luggage I don't feel like I am closer to finding it.

As a physicist John was no doubt paraphrasing one of the fundamental tenets of the scientific method (showing a hypothesis to be false is an integral part of scientific inquiry.) 

One is free to look at things as one wishes, but that way of looking at things may not be scientific in accordance with the original thread title ("scientists show why...")
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Offline sensual1973

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hope they find a cure rather than exlpaining why this and whay that.
God grant me the serenity to accept the things i can not change.

Offline freaky_dream

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hope they find a cure rather than exlpaining why this and whay that.

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I swear some of you would make terrible scientists.
« Last Edit: April 23, 2009, 07:53:06 PM by freaky_dream »

Offline hahaha

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I am puzzeled with this conclusion.
The thesis only use influenza as an example. But they did not use SIV as an example.
SIV will not harm human being, Just like HIV will not harm certain Rhesus.
They are all very small , right?
If SIV is as small as HIV, and the antibody can fight SIV, WHY can't antibody fight HIV?
I think there must have other reason as well.
Anyway, I am still glad to hear the theory, at least, one error found is one step to the correct answer (cure).
Cross my finger and cross.  Hope that the cure can be my 50th birthday present.  (I am 43 now). 
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Offline Ann

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    • Num is sum qui mentiar tibi?
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I swear some of you would make terrible scientists.

;D :D I concur! :D ;D

Thanks for the giggle, Freaky. Much appreciated.

PS - do my eyes deceive me, or is that Jean-Luc?
« Last Edit: April 24, 2009, 06:53:18 AM by Ann »
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Offline georgep77

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I swear some of you would make terrible scientists.
Lol freaky....I agreed with you   :D
Come on Sangamo,  Geovax,  Bionor immuno, ...Make us happy !!!
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Offline veritas

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More info as to why anti-ps gets around the short problem " It's not the virus, it's the exposed PS":

http://1.bp.blogspot.com/_ekJ44PA8pQc/SfG06j17ocI/AAAAAAAAAQw/tNqtG2PvfB4/s1600-h/hiv+virion+cartoon+labeled.JPG


"With the Caltech discovery in mind, it's important to note the fundamental difference of a lipid-targeting approach to virus neutralization. Until quite recently, all attempts by scientists to develop powerful neutralizing antibodies against viruses were aiming at the virus, which of course seems logical. Rather than targeting the traditional common-sense target of the virus spikes poking up through the ocean of host-cell lipid goop, anti-lipid antibodies do not aim for the viral spikes or anything directly to do with viral proteins at all. Anti-lipid antibodies target the goop. There's no need for antibody stretches. That "goop" is made up of lipids from our own cell membranes which get stuck to the virus as it exits one of our cells. It was traditionally considered a waste of time, or possibly worse, to deliberately target lipids with antibodies. That opinion is quickly changing. It turns out that the host-cell lipids exposed on viruses may play a powerful role in inhibiting a successful immune response, as well as an active role in viral entry into cells."


v

Offline Inchlingblue

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I am puzzeled with this conclusion.
The thesis only use influenza as an example.
If SIV is as small as HIV, and the antibody can fight SIV, WHY can't antibody fight HIV?
I think there must have other reason as well. 

The comparison between Influenza and HIV here doesn't have to do with the size of the viruses but rather with how many "spikes" are on the surface of each. HIV has fewer than 15 spikes and Influenza has more than 450. The fact that HIV has so few makes it harder for these Y shaped antibodies to attach to it. If you do a Google image search for HIV and for Influenza you can see what they are talking about.

The reason I mentioned above in another post that this seems "obvious" is because for many years it's been known that the defense mounted by the body against HIV is not enough so that in itself is not new information. This research helps explain why it's not enough and that's important.

There are several other approaches being explored for neutralizing HIV with antibodies (as well as other approaches for eradicating HIV in other ways). As Veritas has brought up, there are other antibodies that are able to neutralize HIV and certainly elite controllers elicit an antibody response that neutralizes it.

This research is good news, the more knowledge the better.


Offline freaky_dream

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;D :D I concur! :D ;D

Thanks for the giggle, Freaky. Much appreciated.

PS - do my eyes deceive me, or is that Jean-Luc?

Most definitely is Jean-Luc Picard Ann. It's an ascii facepalm internet meme that's been making the rounds. Glad you got a good laugh.

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