Non-neutralizing anti-HIV antibodies-- Is the 'chaff' more valuable than the wheat?

Its no secret that Im not a huge fan of the antibody hunter branch of the HIV-1 research world-- they search through thousands and thousands and thousands of B-cells looking for one or two that can perform a neat trick. They are brilliant people working really hard doing things that have limited application in the real world, and give us limited insight into the basics of HIV-1 virology, but boy howdy, theyve got a great PR department, and Science/Nature eat their publications up.

Identifying broadly neutralizing antibodies is 'neat', but those antibodies are of limited value. The people they find these antibodies in are dead, and were populated by viruses that had escaped this supposed 'super' antibody. To the virus, these 'super antibodies' are just one more selective pressure, and in isolation, it just dont give a rats ass. I think these researchers talents could be better used elsewhere, and I think other publications are more worthy of big PR slashes.

I am totally pumped about this paper in boring ol Journal of Virology:

Antibody-dependent cell-mediated viral inhibition emerges after SIVmac251 infection of rhesus monkeys coincident with gp140 binding antibodies and is effective against neutralization-resistant viruses

This paper is AWESOME!!! Its not sexah like 'Scientists identify antibody that neutralizes 95% of HIV-1 variants', but its implications are incredible! Basically-- Non-neutralizing anti-HIV-env antibodies (aka shitty antibodies) have a very important role in control of virus.

We cannot induce the production of those super awesome broadly neutralizing antibodies via vaccination.

We can get people to make non-neutralizing antibody via vaccination. We could get people to make a broad repertoire of non-neutralizing-anti-Env antibodies (Im working on how to do that right now, as a matter of fact). If people had a head start-- if they had a broad repertoire of non-neutralizing antibodies to recognize a broad repertoire of viruses-- they might actually have a chance in hell of clearing an HIV-1 infection before it gets a real foothold in their immune system.

Generally (very, very generally)-- When someone is infected with HIV-1, you get several different kinds of antibodies:

1. Junk Antibodies-- Yeah, Im saying it. Junk antibodies. Your body can make aaaaaaall the antibodies it wants to Gag or Pol, and it will have no effect on the virus. Those antibodies are responding to proteins released from dead cells or dead viruses, its not something that will have any effect on live-infected-cells or live-virus. They do nothing. Junk.
2. Non-Neutralizing antibodies-- These antibodies bind to Env, but not in such a way it interferes with that viruses ability to infect another cell. The B-cells that make these antibodies could mutate into cells that make #3.
3. Specific neutralizing antibodies-- These guys recognize Env, and they bind in a way that interferes with the viruses ability to infect cells. YAY! BUT, they are very specific to particular kinds of HIV-1, usually just the quasispecies that is in the actual patient. Just because someone is infected with a Subtype C virus, it doesnt mean that their neutralizing antibodies will neutralize ALL Subtype C viruses. The antibodies might just work on the particular Subtype C viruses in that patient. If you take viruses out of another Subtype C patient, these antibodies might still recognize that viruses Env, might neutralize it, but maybe not. It really wont work on all Subtype A/B/AG/etc viruses.
4. Broadly neutralizing antibodies-- These are like #3, except the antibodies have the ability to neutralize viruses from many many different patient and laboratory isolates, covering a spectrum of Subtypes.

The vast majority of B-cells make #1, #2, and #3. Vaccine designers have been trying to get people to make #3 and #4. Antibody hunters have been sifting through them all to find the vanishingly few cells that make #4. Nobody wants #1 or #2. But Asmal et al are saying 'Wait... #2s are not just 'potential-might-one-day-turn-into-a-neutralizing-antibody'... They might have a direct impact on disease progression... They might be able to help us with vaccines".

"WAIT!!" Some of you ERV readers might be thinking. "Antibodies neutralize viruses. Thats what we want in vaccines, thats why the antibody hunters get so excited-- What possible good could non-neutralizing antibodies do?"

Apparently, they can kill infected cells.

Well, its not just that the *can*-- They *do*. The problem is, anti-Env (neutralizing or not) antibodies dont develop until HIV-1 already has a foothold and youre screwed. But when they *do* develop, viral load plummets.

This works because infected cells have HIV-1 envelope all over their cell surface. Non-neutralizing anti-Env antibodies stick to those envelopes, coating the cells with antibodies with their hind ends (Fc regions) waving in the air. A Natural Killer cell cruises by and is like "WTF IS THIS SHIT! YOU DIE NOW!": Antibody-dependent cell-mediated cytotoxicity.

Kill the infected cells-->No more babby viruses.

No more babby viruses-->... Better prognosis/slower disease progression? (HIV without the AIDS)... Decreased ability to spread virus? (low viral load=harder to transmit) ...Cleared infection?

People infected with HIV-1 do have ADCC responses and they dont clear the infection, but that might be because the antibodies develop too late. This information might help with how we vaccinate people, though. We might not 'need' to generate neutralizing or broadly neutralizing antibodies via vaccination at all (the former is hard enough that we cannot do it yet, the latter is impossible short of gene therapy). We might just need *some* reaction to Env (it can be crappy, as long as it sees Env in some way) that is broad enough to recognize any kind of Env that someone might be exposed to.

We might not need to mine turds for gold. We might not have to teach everyone how to poop gold. Maybe crappy antibodies are good enough in their own right.

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This is more a question of assay choice then "good" vs "crappy" abs IMHO. The ADCVI assay includes not only traditional neutralization, but ADCC, and other methods of viral inhibition. Thus, it has more of a chance to find some activity than an assay that only looks at traditional neutralization.

Really in this case, "neutralization" is just word choice. Viral inhibition is more accurate and the ADCVI assay allows for multiple types of viral inhibition mechanisms.

By coweringomega (not verified) on 25 Apr 2011 #permalink

I heard you all were getting bought out by the publishers of Playboy or Penthouse or something.


By William Wallace (not verified) on 25 Apr 2011 #permalink

This could be the worst paper in the world to get excited about. Even without the tons of data from failed vaccine studies that included HOMOLOGOUS Envelope (i.e. best case scenario in the world for this hypothesis), the diamond-studded elephant playing the trombone is still break-dancing in the room:

How can you induce effective antibodies against against a protein as variable HIV Env? (Not even mentioning the glycoslyation...)

You're now reduced to trolling based on who owns someone?

[better off dead]
Truly a sight to behold. A man beaten. The once great champ, now, a study in moppishness. No longer the victory hungry stallion we've raced so many times before, but a pathetic, washed up, aged ex-champion.
[/better off dead]

"Champ"? He's had victories? Nah, more like a burnt-out old addict*. Once riding high on week-long coke binges**, now he scrounges through dumpsters for half-empty cans of scotchgard to huff.

* addicted to negative attention on the internet
** long threads where people actually tried to educate him

By minimalist (not verified) on 26 Apr 2011 #permalink