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Author Topic: HIV-1's high virulence might be an accident of evolution  (Read 2423 times)

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Offline MitchMiller

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HIV-1's high virulence might be an accident of evolution
« on: June 17, 2006, 01:47:43 AM »
The virulence characteristic of HIV-1--the virus predominantly responsible for human AIDS--might amount to an accident of evolution, new evidence reveals. A gene function lost during the course of viral evolution predisposed HIV-1 to spur the fatal immune system failures that are the hallmarks of AIDS, researchers report in the June 16, 2006 Cell.

AIDS has killed more than 25 million people since it was first recognized in 1981, according to The Joint United Nations Programme on HIV and AIDS. In 2005, an estimated 4.1 million were newly infected with the virus. While infection with related strains of "simian immunodeficiency virus" (SIV) is similarly rampant among many species of monkeys, naturally infected nonhuman primates usually don't suffer the symptoms associated with AIDS. The evidence now revealed by an international team of researchers is the first to offer an explanation for this striking difference.

The group found that a viral protein earlier shown to help the virus evade the immune system, thereby allowing the SIVs that infect monkeys to persist and multiply with high efficiency, also has a protective role in the host immune system. The viral Nef protein ratchets down the activation of critical agents of immunity called T cells following SIV infection, thereby limiting the detrimental effects otherwise caused by chronically strong immune activation.

The HIV-1 Nef protein, and those of its closest related simian viruses, however, lack this protective function, leaving those infected susceptible to the heightened immune activation associated with progression to full-blown AIDS, reports Frank Kirchhoff of the University of Ulm in Germany and his colleagues.

"Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system," the researchers said. "The findings suggest that the gene function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans."

"Heightened immune activation is the only clear cut difference between pathogenic and non-pathogenic infections with the immunodeficiency viruses," Kirchhoff added. "The observed difference in Nef function may provide--for the first time--a mechanism to explain why many monkey species naturally infected with SIV do not develop disease."

Study coauthor Beatrice Hahn of the University of Alabama has previously shown that the two forms of HIV that infect humans originated from related SIVs found in different species of African primates. HIV-1--most closely related to an SIV strain found in chimpanzees--is the more virulent of the two human strains and the source of the majority of HIV infections throughout the world. The less pathogenic HIV-2 evolved from a virus that infects long-tailed relatives of baboons called sooty mangabeys. While HIV and SIV strains all infect T cells that are critical for a functional immune response, SIV usually does so without causing serious damage in their natural primate hosts.

Of more than 30 SIVs that have been molecularly characterized, all encode a Nef gene. However, Kirchhoff noted, functional information about the gene's role had been almost exclusively derived from the HIV-1 version of Nef. To get a broader evolutionary perspective in the current study, Kirchhoff's group examined nef gene variants taken from a variety of divergent SIV lineages.

Nef variants from the great majority of primate SIVs, including the less virulent human strain HIV-2, suppress the expression of a receptor normally found on the surface of T cells, making the immune cells less responsive to activation, the researchers found. In contrast, they report, the nef gene of HIV-1 and a subset of closely related SIVs failed to limit T cell activation and death.

"Intriguingly, this loss of Nef-mediated suppression of T cell activation appears to have occurred twice, once in the ancestor of a group of viruses infecting Cercopithecus monkeys, and once in SIVcpz, the ancestor of HIV-1 which infects chimpanzees," noted study coauthor Paul Sharp, of the University of Nottingham, who is a leading expert in HIV and SIV evolution.

"What these viruses have in common is a vpu gene, not found in other SIVs, and so it's tempting to speculate that the presence of vpu is somehow causally related to the change in Nef function," Sharp added.

The findings expand on previous studies that found that nef-deficient SIV failed to cause symptoms in a monkey species normally susceptible to disease, Kirchhoff said. Rhesus macaques infected with the mutant virus had extremely low viral loads and "either no pathogenicity, or a markedly protracted disease course." Similarly, humans infected with nef-defective HIV-1 progress to disease symptoms slowly, if at all.

Several Nef functions were found to be likely contributors to the effect, including the gene's ability to get around the immune system.

"The gene was shown to be important for viral pathogenicity," Kirchhoff said. "It appeared that Nef was a 'bad guy' because it enhanced persistence and replication of the virus."

The new findings suggest the gene's role may be less black and white. "SIV Nef not only facilitates SIV persistence but may act as a 'rheostat,' allowing high enough levels of T cell activation to ensure sufficient viral replication and transmission, while at the same time preventing escalation of immune activation to levels that may be harmful to the host," the researchers said.

The results also raise the possibility that treatments that could carefully limit the immune system in infected humans--mimicking the tight balance maintained in the other primates--might offer a new approach to HIV therapy, Kirchhoff said.

"A strong immune response can be good in the short term, but if sustained for a long time as in those with HIV, it can exhaust the immune system," he said. "If you could somehow dampen the response, it might effectively convert the condition to the more chronic, asymptomatic infection seen in monkeys."

Further studies by the team will examine whether SIVs carrying Nef genes artificially made incapable of limiting T cell activation might become more pathogenic in their natural monkey hosts. The group will also examine whether Nef variation among HIV-2 strains might explain differences in the rate of progression to disease in infected humans.

###

The researchers include Michael Schindler, Jan Münch, and Frank Kirchhoff of the University of Ulm in Ulm, Germany; Olaf Kutsch, Hui Li, Mario L. Santiago, Frederic Bibollet-Ruche, and Beatrice H. Hahn of the University of Alabama at Birmingham in Birmingham, AL; Michaela C. Müller-Trutwin of Institut Pasteur in Paris, France; Francis J. Novembre of Emory University in Atlanta, GA; Martine Peeters and Valerie Courgnaud of University of Montpellier in Montpellier, France; Elizabeth Bailes and Paul M. Sharp of University of Nottingham, Queens Medical Centre in Nottingham, UK; Pierre Roques of CIRMF in Franceville, Gabon; Donald L. Sodora of University of Texas Southwestern Medical Center in Dallas, TX; Guido Silvestri of Emory University in Atlanta, GA and University of Pennsylvania in Philadelphia, PA.

This work was supported by grants from the National Institutes of Health (R12 AI 55380, RO1 AI 058718, RO1 AI 50529, R01 AI-052775, R01 AI-066998, N01 AI 85338, P30 AI 27767, P30 CA 13148, P51 RR-00165, UO1 AI-067854), the Bristol Myers Freedom to Discover Award, the Deutsche Forschungsgemeinschaft, and the Wilhelm-Sander-Stiftung.

Schindler et al.: "Nef-Mediated Suppression of T Cell Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1." Publishing in Cell 125, 1055–1067, June 16, 2006. www.cell.com

Preview by Foster et al.: "HIV Pathogenesis: Nef Loses Control."


Offline otherplaces

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #1 on: June 17, 2006, 02:57:28 AM »

Interesting article. As usual the article seems to just raise more questions for me.

Have there actually been any real trials using immuno-suppresive drugs? Seems like an oxymoron for people with HIV. But I guess makes some sense. As HIVworker has described HIV as a fire...I guess suppressing the fuel to the fire might make some sense.

Also, do LTNP'ers have a from of HIV that is easy for their body to control? I'm sure this has been studied. Anyone know the answer?

Offline MitchMiller

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #2 on: June 18, 2006, 09:17:24 PM »
There have been some clinical trials using immuno suppressive drugs, but don't think the results were conclusive.  In one case, an immuno suppressive drug was discounted in trials due to side effects, but has been thought to be beneficial when prescribed in smaller doses. There was a feature article in POZ quite a few months ago about it.  I can't remember the name of the drug, but that doc was upset there weren't more formal trials of his techniques.  The drug had been given a bad name and taken off drugs recommended for treating HIV due to side effects.

Here's one article where a patient has been using prednisone to suppress his immune response and preserve tcells:
http://www.poz.com/articles/265_2000.shtml

Here's a similar story on slowing down the immune response:
http://www.mc.vanderbilt.edu/reporter/index.html?ID=3387

Offline otherplaces

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #3 on: June 18, 2006, 10:53:59 PM »

Thanks for the info Mitch.

brian

Offline DCGuy511

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #4 on: June 18, 2006, 11:07:03 PM »
There was an article about two years ago about a Spanish physician who noticed the viral loads dropped in his patients when he had them on prednisone for an unrelated condition.  NIH in Bethesda was conducting a study on immuno-suppression drugs last year.  I was screened for it, but did not qualify due to my elevated liver functionality at the time.  Not sure how it turned out.
Steve
Infected/Diagnosed Fall 2003
"No Man Is An Island" - J Donne

Offline Cliff

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #5 on: June 18, 2006, 11:25:54 PM »
I agree with someone above.  It's great to find out these new discoveries, but they only seem to ask more questions and never really solve anything (at least not anything relevant to the here and now).

Plus I don't get the article...aren't all viruses, (and bacteria), well I guess all life itself, accidents of evolution?

Offline MitchMiller

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #6 on: June 19, 2006, 09:29:19 PM »
What they mean by "accident" is that the loss of the gene is contrary to the survival of the virus.  If the host dies, the virus dies.  Therefore, it seems that evolution should have favored the less lethal form of the virus... that which survives in the host without overwhelming the host.... like herpes.  The host would have lived much longer and therefore been able to spread infection for a longer period of time.  However, it seems that somehow the strain of HIV that cross over to humans had lost the gene used to strike a balance with the human immune system so as not to overwhelm it, resulting in death of the host.  It opens up the possibility that humans can live with HIV if meds can recreate this delicate balancing act between the virus and the immune system... much as has been observed in macque monkeys.
The article does seem to pay credence to docs that are currently using immuno suppressive drugs on their HIV patients. 
I like to follow the basic science articles so I have a feeling what therapeutic vaccines seem to have the most support in the literature... because someday I hope to participate in a trial and you typically only get one chance with a vaccine trial.  Past participation in one usually disqualifies you for other future trials.
« Last Edit: June 19, 2006, 09:34:51 PM by MitchMiller »

Offline HIVworker

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  • HIV researcher
Re: HIV-1's high virulence might be an accident of evolution
« Reply #7 on: June 19, 2006, 11:04:27 PM »
I think when it comes to HIV, it doesn't matter to it what it ultimately does to the host, the fact that the infection is persistent enough to last years without immediate pathological consequence allows it to be transmitted prior to AIDS. This separates it from other pathogenic viruses like EBOLA that have clear acute infection when they make the jump into humans with immediate fatal consequences to the host. This allows HIV to spread quicker through the population. I also don't like the term 'accident' as it implies some process of logical thought - which the virus has none. It exists because it is and it is widespread because of the non-lethal effect of initial infection.

While it is an interesting idea to immediately suppress the immune system to lower the height of the flames, in chronically infected people it is not the answer in my opinion. However, the idea that somehow you can give the immune system something to stop the HIV-activating elements that it uses to fuel it's fire is certainly an interesting prospect. Both Nef and Vpu have been assigned many functions by research, only a few of which are likely to be correct. However, the reason SIV is not pathogenic and HIV is in certain hosts has been a question that many have tried to answer. This might represent finally the reason why and assign to reason to Nef and Vpu. While it is not of use right now, it will at least open the door for something new to think about and try. It would be fantastic to use one of HIV's brother's tricks against it to suppress the fire. At least it would be a new therapy that hasn't been tried and it might further slow HIV's burn through the immune system enough for it to recover and fight off OI's.....and stopping AIDS.

Finally, I do understand that science can be viewed to move slowly and not make discoveries of immediate impact. However, everything new about HIV is something more that we know. While it might not be possible to come up with a Nef or Vpu treatment in less than 5 years, it is possible to use information such as this to redirect the efforts of current treatments to make them more effective. Anything we learn from nature is good. Mother nature knows how to fend off SIV, we just have to learn how....and we might have just found out. We might not have to replicate the exact Nef-like activity, but at least know what is important to stop. For instance, stopping cells being so active against HIV. Anti-Nef treatment isn't the only thing to try....

R
« Last Edit: June 19, 2006, 11:08:43 PM by HIVworker »
NB. Any advice about HIV is given in addition to your own medical advice and not intended to replace it. You should never make clinical decisions based on what anyone says on the internet but rather check with your ID doctor first. Discussions from the internet are just that - Discussions. They may give you food for thought, but they should not direct you to do anything but fuel discussion.

Offline whizzer

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Re: HIV-1's high virulence might be an accident of evolution
« Reply #8 on: June 19, 2006, 11:20:59 PM »
Regarding immunosuppresive drugs and HIV.  I was combing through the NIH clinical trials website and there is study recruiting to look at using Enbrel (enteracept) as salvage therapy in those with multiple failed regimens.

Enbrel suppresses tumor necrosis factor.  HIV stimulates tumor necrosis factor to increase the number of active CD4s, or something like that.  I'm not remembering my TNF biology too well, but the two are somehow related.

Anyhow, this is being looked at.

 


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