Posted February 27, 2008
August 2, 2007, over six months ago, I wrote an essay on the evolution of a cool new gene/protein in HIV-1 called 'Vpu'. To quickly summarize, Vpu first emerged in chimpanzees version of HIV, SIV. After chimpanzees transmitted SIV to humans, Vpu acquired new properties to deal with the environment of a new host. As time progressed, HIV-1 split into multiple subtypes, and the Vpus of different subtypes started to evolve different characteristics as well. Thus SIVcpz Vpu, HIVSubtype B Vpu, and HIVSubtype C Vpu are genetically and biochemically distinct proteins.
Quite the opposite of Behe's claims about HIV-1 in 'Edge of Evolution', "the story of Vpu is turning into a beautiful example of how evolution works in the real world, the continual evolutionary struggle between host and disease producing a novel function, formation of an active ion channel, from a simple protein. It also nicely illustrates and how scientists use evolution to explore our universe and produce improvements in medical practice." (to quote an email from Ian Musgrave)
This didn't happen a billion years ago. It didn't take a billion years to occur. This is real evolution happening in real time with real consequences.
While that was enough to put Behe's ridiculous claims about the evolution of HIV-1 to rest, there is still more to Vpus story. Six months ago, science only had a 'just so story' explanation for Vpu:
So theoretically, ion channel formation evolved in HIV-1 when it infected humans to overcome a species specific and cell specific host factor.
Why did Vpu evolve the way it did? Well, it had to overcome something in human cells. There was something about human cells that were different from chimpanzee cells that HIV-1 needed to evolve around. What's that something? Um... something. But that's what happened! That's why Vpu forms a viroporin!
It was one of those 'just so stories' that Creationists love to dismiss.
But that was six months ago. And, you see, scientists aren't like 'Creationist' scientists. They don't see a black box, declare a deity made the box, and take the rest of the week off. Scientists see problems and demand answers. Several weeks ago, a paper was published in Nature that turned Vpus 'just so story' into just another 'so?' story for evolution:
TETHERIN INHIBITS RETROVIRUS RELEASE AND IS ANTAGONIZED BY HIV-1 VPU
Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherins antiviral activity is a potential therapeutic strategy in HIV/AIDS.
These researchers used Vpus 'just so story' to discover a new component of the human innate immune system. When most people think of their immune system, they think of antibodies. But there are lots of ways your body can defend itself against viruses without the adaptive immune system. It can be something as simple as your skin (keeps em out!), or something really general like Toll-Like Receptor 3, or pH changes within a cell. So because there are a lot of ways the innate immune system can help get rid of viruses, and there is a very distinct pattern of need/no need for Vpu in different cell lines, these authors thought 'maybe' Vpu was countering one of those innate mechanisms. Here is their initial logic:
1. Some kinds of cells can't be infected well unless you use an HIV that has Vpu.
2. Other kinds of cells don't care if Vpu is there or not-- they produce lots of viruses.
3. What's different about the protein expression in these two cells?
They used a microarray to identify proteins that were upregulated in cell #1, and not expressed very much in cell #2. This gave them a list of putative proteins that could be interfering with HIV-1 particle release. Then they asked:
4. Vpu seems to act at the cell membrane, where viruses are budding off. That means that the putative protein should be either in the cell membrane, or secreted.
So they kicked everyone off the list that wasn't a membrane bound protein or secreted. This left them with one possibility-- 'CD317'. So then they asked:
5. The cells from #2 don't express CD317. If we make them express CD317, do they act like cells from #1?
6. The cells from #1 express CD317. If we knock down its expression with siRNA, do they act like cells from #2?
The answers to both of those questions is 'YES!!!'
They renamed CD317 'tetherin' and concluded that tetherin is a component of the innate immune system activated by interferon-alpha which interferes with the release of HIV-1 viruses in certain human cells, BUT this inhibition can be overcome by HIV-1 Vpu.
On top of Vpu down-regulating CD4.
On top of Vpu forming super sweet viroporins.Now it's important to note that tetherin is joining lot of other innate anti-viral systems like APOBEC3G (found using the HIV-1 protein Vif) and TRIM5alpha. It's also important to stress that like the APOBEC and TRIM, tetherin isn't a feature unique to humans-- lots of organisms have APOBEC proteins, lots of mammals have TRIM proteins. But, each species particular set of variants, each species restriction abilities, are unique. Comparing different species APOBECs and TRIMs has turned into a fruitful avenue of research.
The publishers at NATURE hope for the same with tetherin-- From a Nature News and Views on this paper:
Because the amino-acid sequence of tetherin differs considerably among mammals, some HIV-1-related animal viruses might find it difficult to overcome human tetherin, preventing them from becoming human viruses. Conversely, it is worth investigating whether tetherin contributes to the inability of HIV-1 to efficiently escape from most rodent cells, which has hampered efforts to develop small-animal models of HIV-1 infection. Even in human cells, Vpu might not always be able to overcome the powerful effect of tetherin, as the release of infectious Vpu-positive HIV-1 can be inhibited with high doses of interferon-alpha. Thus, an understanding of how tetherin works, and how Vpu fends it off, could lead to strategies to limit the spread of HIV-1 and other viruses that target humans.
In six months, evolution's 'just so story' led to new drug targets for new HIV/AIDS therapies, and a brand new avenue of research for immunologists and virologists all over the world (tetherins role in influenza, ebola, EBV, herpes, whoo!!!!).
... But what would have happened in Bizarro World? What would have happened if Intelligent Design Creationists were in charge of the NIH? What if someone like Michael Behe were controlling who got money for research?
Six months ago (well, four months, took him a while) Behe would have thrown everything known about HIV-1 Vpu into the garbage can. My original essay and all of the information it contained was 'pathetic', 'unimpressive', and 'meaningless.' Why would you continue to waste money studying the evolution of HIV-1, when it doesn't evolve in a 'meaningful way'?
This study, this study that discovered a brand new branch of innate immunity, this study that could potentially help us treat all kinds of viral infections, would have never happened in Bizarro World.
What has Behe been doing the past six months? How has he contributed to the HIV research community? The medical community? The scientific community? It's not fair to single Behe out in Bizarro World-- What about Dembski? Wells? West? Am I missing anyone? What have they done in the past six months to help stop AIDS, cancer, influenza, MSRA, anything??
Rather than being an icon for the failure of evolution, HIV-1 is an icon for the complete and utter failure of Creationism.