HIV-1 Vpu and Nef– ‘An unfortunate evolutionary coincidence’

Long-time readers of ERV know lots about HIV-1. You might think you dont, but you do. You know how ‘drug resistance’ works in a quasispecies. Most people dont. You know that AIDS is actually an exhausted hyperactive immune system, not a ‘weakened’ immune system. Most people dont. And you know some fun HIV-1 evolution facts, like where it came from, and what its doing now.

So I think you all will really like this Nature Reviews opinion piece about Vpu:

Is the high virulence of HIV-1 an unfortunate coincidence of primate lentiviral evolution?

Vpu is not a ‘core’ retroviral gene (gag, pol, env), its an accessory gene, as is nef. Nef has lots of regulatory functions– downregulate this receptor, upregulate that receptor, Kirchhoff calls it ‘master manipulator of cellular trafficking, signal transduction and gene expression’. Its kinda like an HIV-1 wedding planner. It makes sure the flowers are delivered on time and the host cell has enough cake for everyone. Seems like it might be a dispensable gene… but if HIV-1 doesnt have it, all hell breaks loose.

But nef is a gene all HIV/SIVs have. What does this have to do with Vpu?

Viruses that have Vpu have nef genes that cannot downregulate host cell CD3.
Viruses that do not have Vpu, have nef genes that can downregulate CD3.

CD3 is a host cell receptor that activates the T-cell. WAAAAY too active T-cells is what leads to immune system exhaustion–> AIDS. HIV-1 has Vpu!

As a consequence of the loss of Nef-mediated down-modulation of CD3, HIV-1-infected T cells respond strongly to TCR stimulation and show marked increases in transcription of the viral genome and various cellular genes, as well as in activation-induced cell death, whereas those infected with SIVSMM or SIVAGM maintain a resting phenotype.
…
… this might be because an effective virus release factor permits production of a sufficient number of progeny virions owing to increased activation of virally infected T cells, despite the shortened lifetime of these T cells, or because the ability of Vpu to counteract tetherin facilitates effective virus spread in an inflammatory environment.
…
The fact that vpu was specifically acquired in the primate lentiviral lineage that gave rise to HIV-1 and may have allowed the emergence of primate lentiviruses that cause higher levels of inflammation and immune damage supports the hypothesis that AIDS is, at least in part, the result of an unfortunate evolutionary coincidence.

‘An unfortunate evolutionary coincidence’– the gain of Vpu and a loss of function in Nef, helped HIV-1 kill people.

Lucky us!

Comments

#1 Sili
April 13, 2009

“And God saw that it was good.”

Seemed appropriate for some reason …
#2 Marc
April 13, 2009

Woah this is really interesting!
#3 Stephen Moore
April 13, 2009

Learning that AIDS is an exhausted hyperactive immune system was one of the biggest “Frack me!” things I learned from reading your blog, Abby. When I did learn that I had to write my own post to spread the word.
#4 cw
April 14, 2009

I am a HIV/AIDS researche.I want to discuss some problems with others.Would you please tell me which is the famous website for HIV/AIDS researcher? I’ll go back to read this page .Thank you!
#5 Magnus
April 14, 2009

Oh shit!
#6 Optimus Primate
April 14, 2009

Oh, come on! We can do better than five comments for such an interesting and informative post!

Let’s see…

[William Wallace]
Abbie,

You need to prove that “Abbie” is, in fact, short for Abigail, and not, as I may or may not be implying, simply a random assortment of letters that just happen to resemble a shortened version your full name by coincidence!

PWND, Evolander fanbois! LOLWTFBBQ!
[/William Wallace]
#7 Carl Magnuson
April 15, 2009

Dr. Smith,

Have you seen this documentary, House of Numbers, that critques the orthodox AIDS view:

http://www.houseofnumbers.com/

The local newspaper, The Tennessean has a review

http://www.tennessean.com/article/20090414/ENTERTAINMENT0403/90414019
#8 cprs
April 15, 2009

Carl, this idea ruined South Africa’s AIDS program – it’s like a 9/11 conspiracy.
HIV fulfills Koch’s postulates.
http://en.wikipedia.org/wiki/Koch%27s_postulates
#9 BAllanJ
April 15, 2009

Actually, cprs, I’m not overly concerned directly by the fact that it ruined the RSA AIDS programme…. I’m concerned by the number of South Africans that this conspiracy theory has actually killed and orphaned. I’m not usually an angry man, but people that promote crap like the one Carl is spreading here really get up my nose.
#10 Ben Netters
April 15, 2009

No, the people who challenge the retroviral cause of AIDS are not claiming conspiracy, you morons.

They are claiming that toxic drugs, particularly cancer chemo like AZT, make the problem worse.

There is no doubt that Nevirapine has awful side effects.
#11 jon
April 15, 2009

Obviously not worse than non-treatment Ben Netters, since life expectancy for AIDS patients has skyrocketed since the advent of HAART and new Antiviral drugs.

Side effects are to be expected, as drugs inevitably become more toxic to the host as the target and host become more similar.
#12 Dr. Duke
April 15, 2009

Actually, it’s not quite as simple as “all lentiviruses with Vpu cause disease, and all without Vpu are harmless”. It is clear, for example, that HIV-2 can and does cause AIDS in humans, and HIV-2 has Vpx rather than Vpu.

Also, the Feline Immunodeficiency Viruses (FIVs) are well known to cause immune deficiency in various species of cats, and they don’t have Vpu.

So, while it is clear that Vpu, CD3, and T-cell activation are indeed important components of the death and destruction that HIV-1 causes in humans, it is not clear that all viruses lacking Vpu are harmless.
#13 Eric Saveau
April 15, 2009

Ben Nutters,

Yes, chemo drugs have awful side effects. The next time a friend or relative of mine gets cancer, I’ll just tell them that they’re only making things worse by being treated for it, shall I? I’ll see if the cancer survivors I know wish to echo that sentiment…
#14 Ben Netters
April 15, 2009

Jon wrote:

Obviously not worse than non-treatment Ben Netters, since life expectancy for AIDS patients has skyrocketed since the advent of HAART and new Antiviral drugs.

Correlation does not mean causation. Do you have a double-blind placebo-controlled study to back up your flimsy claims?

Eric,

Cancer is a real disease, diagnosed by a biopsy. The choice between the cancer and the cancer chemo is a tough one.

You’re childish sarcasm proves the point — if HIV were as deadly as cancer, you’d be right. But, the anti-body test for HIV is so far removed from establishing infectious virus, that it is criminal to prescribe toxic drugs based thereon.
#15 Eric Saveau
April 15, 2009

Ben Nutters,

You are bad and wrong. The pathology of HIV, its effects on the immune system, and the disease and death that result from its effect are well-understood and well-documented. There is absolutely no excuse whatsoever for the insane droolings that you present here.