Actually, no. I've published extensively on HIV/SIV evolution. I have never had an editor censor or otherwise limit use of the terms 'evolution' or 'evolve'. As others have pointed out, the priimary issue with using 'evolution' with a virus like HIV is that it implies, to most people, benefit. While viral variants are clearly selected for by outside pressure, the resulting viruses generally replicate less well than the parental viruses in the *absence* of the selector -- as evidenced by sequence reversion that often happens upon transmission of a drug-resistant/immune selected/cxcr4-tropic virus into a new host. So with HIV at least, 'evolutionary benefit' is in the eye of the beholder, or more accurately, in the context of its replication.
Though I'm not sure if it works well, check US Computer Retrieval of Information on Scientific Projects. There is an enormous amount of pressure on government funded research programs to generate scientific advances, despite what many of the comments in this thread imply. Most NIH institutes currently fund less than 20% of all proposals (citation here); unproductive scientists will find it almost impossible to secure funding at these levels.
The answer is, 'right now, not many'. But, and this is a huge but, generic drug manufacturers in places like India and Brazil have shown they can drive down the cost of 1st world med production time and time again. When generic HIV drugs were introduced in India in 2000, the cost was $778 per month. Now the drugs cost about $30 per month. If this approach works, there will be ways to reduce the cost and make it feasible for the populations that need it.
The evidence that AIDS drugs can prevent infections comes not only from exposed health care workers, but also monkey studies. If monkeys are given AIDS drugs up to 48 hours before exposure to SIV (the causitive agent of simian AIDS), they fail to become infected. That has been known since the late 90s. There is some data suggesting that the drugs can't always protect against multiple exposures to SIV, but those studies used only one drug at a time (not a cocktail of pills, like you would take if you had HIV).
As an HIV researcher myself, I realize that we are not going to have a highly effective, preventative vaccine for HIV any time in the near future. There are no clear 'winners' in the pipeline right now, and even if a vaccine looked effective right now, it would be years (and millions of new infections) before it clears human testing and it broadly available. Issues like viral resistance to the vaccine, incomplete protection from infection, potential side effects, and a false sense of security would plauge any vaccine that is developed -- and these are many of the same issues confronting the use of drugs as HIV preventatives.
One major hurdle to testing these drugs in populations highly affected by HIV is to convince them that this intervention is not a magic bullet. There will be problems, some of which we probably can't predict. There will be breakthrough infections in people taking the drugs. And the long-term health consequences aren't known. So far, these concerns have led to the abandonment of several trials of PrEP (using tenofovir in HIV-, high-risk populations) around the world. Hopefully the new data (using multiple drugs together works better than tenofovir alone) will encourage vulnerable populations that the potential benefits may outweigh the risks.
The reason is that sexually transmitted HIV (the most common kind) is not much of a choice for many of the people who get infected. In sub-Saharan African, women and girls make up almost 60% of those living with HIV (www.unaids.org). Adolescent women are particularly vulnerable because they lack the social status and resources to negotiate safe sex with their partners, and most interventions (such as condoms) are overt (requiring knowledge of both partners) and male-focused (yes, there are female condoms, but they are rarely used).
It makes perfect sense to me. I use ChronoSync to keep files synced beteen machines, occasionally booting one machine in target disk mode if I want to completely replace a large file (the hooking them together you mention). The ability to keep completely updated personal information that travels with me from desktop->laptop->mobile phone automatically is beyond the scope of what I reasonably expect a single machine's OS to do. It is an ongoing service that is provided by.mac and one that, in my mind, is well worth it. People who don't use.mac aren't deliberately restricted from syncing their address books, etc. via file sharing, so I don't know why you'd think the software is 'crippled'.
Your comparison is reasonable -- for you. While no one will dispute that alternatives to.mac services are available, I'd argue that few are as easy to use as the.mac implementations. The other night I wanted to post a short AVI video to my website. Opened iMovie, opened the movie, clicked 'share', and it was converted to a QT movie and uploaded to.mac. Took 3 minutes. Could I have done it manually? Of course. But that's not the point of.mac. It takes these services and makes them easy. I have 4 OSX machines with synchronized bookmarks, contacts, and calendars. Amount of effort required to keep them up-to-date: none. It just works. For me, $100 per year is worth it for the convenience...it might not be for others. But to suggest that the.mac services should be offered free (not in the parent post, but a key topic in the thread) because there are free alternatives neglects the fact that most of.mac's value is in the implementation.
Adding some information for those who are interested:
The advent of better genetic maps has allowed scientists to more accurately time the emergence of the delta32 CCR5 mutation. It now appears that this allele emerged earlier than previously thought and has not been strongly selected by plague. In other words, its frequency in Northern Europeans is explained by 'random', neutral selection and is not markedly different from other genes in the genome. (See here for more details)
Small molecule inhibitors that block the interaction between HIV and susceptible host cells show promise. Two huge concerns -- 1) HIV is not absolutely dependent on CCR5 usage. During chronic infection (presumably, when many CCR5+ cells have already been depleted), HIV can utilize an alternate coreceptor, CXCR4, to mediate entry into a cell. CXCR4-using viruses tend to be more aggressive than CCR5 viruses, and it is possible that CCR5 inhibitors would drive the more rapid emergence of these CXCR4-using strains. 2) Even though CCR5 inhibitors target a conserved, functionally essential target, HIV can still become resistant to these inhibitors.
Kidding aside, one of the saddest aspects of the entire crisis is the absolutely misguided reliance on faith. Before the storm hit, the cable stations kept interviewing people who weren't evacuating because of their 'faith in god.' Even tonight, in the midst of arguably the worst humanitarian and logistical crisis our country will face this decade (if not ever), a senator from either Missisip. or Louisiana appeared on MSNBC and was asked what the viewers could do to help. He responded with something like "pray for us. i firmly believe in the power of prayer." I've got nothing against religion or spirituality, but it seems like in this case it may be impeding progress.
Of course, its easy to Monday morning quarterback from a dry room in Wisconsin.
There is a huge amount of research into those individuals do not become infected after repeated HIV exposures or who appear only transiently infected. Some are resistant because of an unusual CCR5 mutation (the virus uses CCR5 to enter cells...esp. right after transmission), but we don't know why others are resistant. A tragic aside -- in the late 90's, there were several studies of prostitutes in Kenya who did not become HIV+ despite huge numbers of exposures. Some then took a break from prostitution, headed back to their rural homes, etc. but eventually wound up prostituting themselves again. After the break, several became HIV+, showing how tenuous "protection" can be (see here.
A much bigger story this week is the striking result of a clinical trial of male circumcision. Apparently circumcised men have a 70% lower risk of contracting HIV than uncircumcised men (see here). Though others have shown this anecdotally, proof in a large clinical trial could revolutionize HIV prevention -- particularly in sub-Saharan countries where HIV incidence is high and male circumcision is currently rare.
Don't be so sure and sanctimonious. I run Panther Server 10 client (purchased and licensed) quite happily on a headless mac mini (purchase price, about $500). I also run Retrospect for Workgroups on the same machine (again, purchased and licensed). It is all about meeting needs. For simply serving network homes to a workgroup of about 5 users and backing up all the client machines nightly, it is more than sufficient.
Perhaps, but I don't think altruism and wealth are mutually exclusive. As for the rationale for setting up the Gates Foundation, I think that it had a lot to do with Gates's belief that he could accomplish more and do it better than the existing institutions. I read an article a few years ago that described key differences between GF and other charities. It boiled down to accountability -- the GF competitively funds business plans and *requires* grantees to meet milestones to qualify for continued funding. This approach leads to increased accountability and reduced waste....and I think the preliminary evidence suggests that its working (www.gatesfoundation.org).
I don't think your analogy works. Gates didn't rob anyone. People elect to buy his products. Unfair competition? Perhaps, but he wouldn't have made his billions without the support of consumers.
This is a ridiculous statement. And one that is categorically wrong. The fact of the matter is that the Gates Foundation is doing an enormous amount of good work *and donating huge amounts of money in the process*. In the four years since it was established, the Gates Foundation has established a $27 Billion endowment. The 750m is only the most recent announcement. You could make a reasonable case that the Gates Foundation's impact on public health may eventually rival that of the World Health Organization's.
It is all well and good to say that "if I had that sort of money, I'd donate huge amounts of it too", but he is actually doing it. If you are an American (or Canadian, or Western European, or reading/. pretty much anywhere), then you likely *are* affluant consiering that a full half the world's population lives on less than $2 per day (http://www.globalissues.org/TradeRelated/Poverty. asp). And we (as affluant societies) could and should do more to help close this gap.
As someone who flies quite a bit, mostly on American, I'll at least speak to preferential treatment of gold+ AAdvantage members. In several airports (O'Hare and Logan, to name two) there are special security lines reserved for gold+ members. I have *never* been hassled in one of these lines. When flying through airports without these special lines, I've been stopped, had my bags searched, laptops screened, etc.
On the one hand, it is a nice convenience for those who fly a lot. On the other, it makes the dangerous assumption that anyone who flies more than 25K miles a year (or whatever the qualifying criteria is these days) is somehow less of a threat.
If you're on OSX, you may want to check out the combination of Mellel and Bookends. Mellel really is a nice replacement for MS Word, though it doesn't support some features like 'track changes' that are helpful in a collaborative setting.
Bookends (http://www.sonnysoftware.com/) integrates with both Mellel and MS Word, and they don't even force a paid upgrade for compatibility with new versions of Word (damn Endnote). The mechanism for adding refs to Mellel and Word docs from Bookends is similar to Endnote -- the only real problem with Bookends is that is uses an overly large, non-customizable (I think) display for the main reference window.
Also, the related Reference Miner app is terrific for extracting references from databases like Pubmed. Much, much faster than connecting to databases from within Endnote.
No affiliation with these products, except as a long-suffering Endnote / Word user who stumbled onto these excellent alternatives earlier this year.
All good points. Fuzeon is primarily a salvage drug (when all else fails, use Fuzeon -- very unpleasent, or so I hear) and the integrase inhibitors are preclinical (see Science. 2004 Jul 23;305(5683):528-32. Epub 2004 Jul 08 for the monkey study I referenced). Initially, I thought your post implied that pharma had given up completely on drug development because of the generics / developing world issues, and I just wanted to point out that this isn't true. As you rightly say, though, there haven't been many new 'front-line' drugs in the clinic in a while.
The MVA based vaccines have their own set of problems. The set of MVA vaccines already being tested in people fell short of expectations, and the International AIDS Vaccine Initiative plans on halting the studies completely next year (see http://www.iavi.org/viewfile.cfm?fid=565). Other formulations of MVA may make it further -- but they will need to be markedly different than those tested already.
As to the child post asking whether prolonging life will lead to more new infections, the prevailing answer is 'maybe'. If you have less virus in your blood, you are less likely to transmit. But, if having less virus means you live longer, then you may have a longer timeframe to transmit. Researchers who are much better than me in math modeled this recently and predict that interventions that reduce viral burden by 1.5 logs (95%) or more will slow the epidmic (see Lancet Infect Dis. 2004 Oct;4(10):636-9.); reductions in viral load of less than 1.5 logs may make the epidemic worse. In that context, the dendritic cells vaccine discussed in this thread might actually worsen the epidemic, even if it allowed individuals to survive longer.
dave
Re:Mixed feeling
on
HIV Vaccine
·
· Score: 3, Informative
Haven't red the WebMD blurb, wasn't at the Munich AIDS Day, but I did read the article in Nature Medicine and I am an HIV researcher. First, HIV clade B is NOT most common in Africa, it is most common in North America / Western Europe. Clade C predominates in Southern Africa, while clade A predomiantes in East Africa. Though frankly, it doesn't matter much in this context. For this vaccine to work, the scientists extract the patient's own HIV (clade probably won't matter), inactivate the virus chemically, and then pulsed purified dendritic cells with the inactivated virus. The level of suppression is impressive, though not stunning. Stunning would be a reduction of viral load to levels that are barely detectable (from 100,000 to 50, as is observed with combination antiviral therapy) -- not 100,000 to 10,000. It is promising, though, and a surprisingly positive result that definitely warrants more study.
A few other misconceptions in the parent post:
1) To my knowledge dendritic cells are not viable for 2 years at 50C. In the paper, the DCs were stored at -140C for no more than 4 weeks.
2) Even though virus in the blood decreased by 90% in some patients, CD4 counts still declined during the study. Unclear whether the reduction in virus burden really has a clinical benefit.
3) Fuzeon, the first drug in a new class of therapies termed entry inhibitors, was approved by the FDA in March 2003. Earlier this year, Merck published the results of a promising monkey trial of an HIV integrase inhibitor. Saying that there hasn't been anything new for 3 years in simply incorrect.
I don't understand why people are complaining about the NBC coverage (or purporting a lack thereof). While they are not showing every minute of every event, the coverage on the cable networks so far has been broad (many sports) and deep (entire events, rather than just excerpts or highlights). The prime time broadcast on NBC last night contained more fluff, but hey, that's what the Tivo is for. Record the events in the middle of the night/morning, and then watch the Netherlands vs. Russia in Volleyball later in the day.
One interesting consequence of the poor ticket sales is the NBC response. In the prime time broadcast, they felt compelled to justify the empty seats in the gymnastics arena. Earlier in the day, during the US Women's soccer game, I'm pretty sure that they used a sports equivalent of a laugh track. For a few minutes during each half, the crowd noise suddenly doubled or tripled in volume and intensity suddenly, while the small number of people watching live seemed bored.
The first generation of vaccines to make it through clinical trials used purified HIV protein. The first large-scale clinical trial of this type of vaccine was a complete failure. A free news article describing this trial can be found at http://www.aegis.com/news/lt/2003/lt030219.html. The vaccine probably didn't work because it didn't elicit a strong enough immune response. The trick to making an effective vaccine is to 1) raise immune responses that mimic those that occur during a natural infection and 2) make the immune responses strong enough to be effective. This is a little oversimplified, but close enough.
Right now there is a big expensive controversy in the vaccine field regarding a planned large-scale clinical trial of a similar vaccine in Thailand. Earlier this year, 22 respected scientists published an opinion piece in Science (http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi? cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=147 26576) calling on the government to withdraw support for this trial. Since the trial will cost over 100 million dollars, the US government's support and money is pretty important. The controversy probably won't go away for a while -- especially since the biennial International AIDS Meeting will be hosted by Thailand in July.
Nature Medicine (subscription only) recently published an excellent review article discussing the problems with making HIV vaccines. The PubMed citation is http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=pubmed&dopt=Abstract&list_uids=1499 1035.
Just a minor correction to my own post. HIV packages two positive-strand RNA molecules (positive-strand diploid, as pointed out by someone else), not negative strand. That'll teach me to post quickly while heating up dinner.
HIV is a lentivirus, a subcategory of the retroviruses. HIV virions package two, negative strand RNA molecules. Within a cell, the HIV reverse transcriptase synthesizes cDNA that integrates into the host cell. The low replication fidelity of the reverse transcriptase is what accounts for HIV's incredible ability to rapidly escape from drug treatment and immune responses.
Unfortunately, the Wired article doesn't provide many scientific details. The idea is pretty creative, but there is a huge difference between simulating a cure (and even making one in a test tube) and finding a cure that works in animals. A few concerns off the top of my head:
1) Recombination between HIV and the treatment vector. Remember those two strands of RNA I talked about above? You can get mosaic viruses that resemble part of one virus and a second part of another. I'd be willing to bet that this is the 'it could make things worse' aspect mentioned at the botom of the article.
2) Any time you insert foreign DNA into the genomic DNA of cels (as would occur with this anti-HIV, if I understand it correctly), bad things can happen.
3) Attenuating (or weakening) HIV has been widely tested as a vaccine. And basically, it works, at least in monkeys. If you give monkeys an attenuated version of SIV (monkey AIDS virus), the monkeys are basically protected against full-blown SIV. So why isn't this a vaccine that is being used in people? Monkeys that have weakened immune systems, are young, are old, or just have plain bad luck eventually get sick and die...from the attenuated strain of the virus. In other words, the attenuated vaccine makes the monkeys sick. The 'anti-HIV' sounds like a different riff on the same theme, with the possible caveat that they are looking to use it on people who are already infected, unlike a vaccine which would be used on uninfected people to prevent infection.
Just my two cents. My cred: 8 years in HIV research, with a Ph.D. in it.
Might cause information overload? In almost every field I'm aware of (virology and immunology are mine), there are already too many journals, each publishing more information that any one person could ever hope to read. One example is the proliferation of Nature and Cell 'sub-journals' in the last few years. Material that used to be published in Nature (and eventually) and Nature Medicine is now spread across Nature, Nature Medicine, Nature Reviews Immunology, Nature Reviews Microbiology, Nature Reviews Cancer, Nature Genetics, and Nature Biotechnology. And these journals are all 'top-tier'. The morass of less prominent journals seem to exist primarily to be searched out for individual articles resulting from citation searches, not to be 'read' in the conventional sense (as one reads a magazine or newspaper).
Our cable company also recently announced a rate increase for expanded basic cable. As a former Dish subscriber (who left because local stations were not available in my subscription area at the time), I applaud their stance. This sort of channel creep has been occuring for the better part of the last decade -- I remember our cable company delisting VH1 in favor of the ever-popular Animal Planet in '97. Why? Because the terms of the contract forced the cable company to bundle niche channels having limited mainstream appeal with popular stations. As media distributors continue to consolidate, their 'pull' in these sorts of disputes will only increase. In the current dispute, a half-dozen channels are affected. In a few years, it could be a dozen or more. If cable/sat companies aren't willing to take a principled (albeit potentially unpopular stand), customers will eventually bear the burden of inflated channel pricing rates.
Just a counterpoint showing that mileage does vary.
I recently flew from LA to Melbourne, a brutal 14 hour flight. I turned on my 1st gen iPod immediately after we left LA, and, much to my surprise, it kept working until our approach in Australia. Yes, I didn't skip around very much, and I'm sure that helped battery life. But 14 hours of non-stop playback is 14-hours of playback.
So there are a few misconceptions in this thread that should be corrected:
1) Ebola is not a retrovirus. It does not have utilize RNA->DNA reverse transcription as part of its life cycle. It *is* however, an RNA virus, which means that it uses an RNA-dependent RNA polymerase to replicate.
2) Though a minute of cursory checking did not reveal the exact type of vaccine being tested in this study, it is, in all liklihood, an NIH formulation that uses a fragment of Ebola that is engineered into adenovirus. Preclinical trials of adenovirus-based Ebola vaccines have shown extraordinary promise(see: http://www.sciencemag.org/cgi/content/full/302/564 8/1141 (subscription required); http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=PubMed&list_uids=12904795&dopt=Abst ract).
What does this mean for safety? Well, the adenovirus is the only biologically active component of the vaccine, and many of the adenovirus strains being currently tested are replication-incompetent. That is, they infect a cell, produce viral proteins (which trigger an immune response), but do not assemble into new viral particles which can then escape the target cell and infect new cells. The Ebola component of the vaccine is just one or two genes, neither of which are responsible for the hemmoragic fever. In other words, you can't get Ebola from this type of vaccine -- the worst side effect might be a slight cold (as adenovirus infections cause cold symptoms).
One problem with this type of vaccine is that many people have already been exposed to adenoviruses naturally, and thus have preexisting immunity to the vaccine vector. This would prevent the Ebola gene fragments from being expressed and reduce the protective effect of the vaccine. Some more information about preexisting immunity to adenoviruses can be found in this article: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=PubMed&list_uids=12743287&dopt=Abst ract
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Actually, no. I've published extensively on HIV/SIV evolution. I have never had an editor censor or otherwise limit use of the terms 'evolution' or 'evolve'. As others have pointed out, the priimary issue with using 'evolution' with a virus like HIV is that it implies, to most people, benefit. While viral variants are clearly selected for by outside pressure, the resulting viruses generally replicate less well than the parental viruses in the *absence* of the selector -- as evidenced by sequence reversion that often happens upon transmission of a drug-resistant/immune selected/cxcr4-tropic virus into a new host. So with HIV at least, 'evolutionary benefit' is in the eye of the beholder, or more accurately, in the context of its replication.
Though I'm not sure if it works well, check US Computer Retrieval of Information on Scientific Projects. There is an enormous amount of pressure on government funded research programs to generate scientific advances, despite what many of the comments in this thread imply. Most NIH institutes currently fund less than 20% of all proposals (citation here); unproductive scientists will find it almost impossible to secure funding at these levels.
The answer is, 'right now, not many'. But, and this is a huge but, generic drug manufacturers in places like India and Brazil have shown they can drive down the cost of 1st world med production time and time again. When generic HIV drugs were introduced in India in 2000, the cost was $778 per month. Now the drugs cost about $30 per month. If this approach works, there will be ways to reduce the cost and make it feasible for the populations that need it.
As an HIV researcher myself, I realize that we are not going to have a highly effective, preventative vaccine for HIV any time in the near future. There are no clear 'winners' in the pipeline right now, and even if a vaccine looked effective right now, it would be years (and millions of new infections) before it clears human testing and it broadly available. Issues like viral resistance to the vaccine, incomplete protection from infection, potential side effects, and a false sense of security would plauge any vaccine that is developed -- and these are many of the same issues confronting the use of drugs as HIV preventatives.
One major hurdle to testing these drugs in populations highly affected by HIV is to convince them that this intervention is not a magic bullet. There will be problems, some of which we probably can't predict. There will be breakthrough infections in people taking the drugs. And the long-term health consequences aren't known. So far, these concerns have led to the abandonment of several trials of PrEP (using tenofovir in HIV-, high-risk populations) around the world. Hopefully the new data (using multiple drugs together works better than tenofovir alone) will encourage vulnerable populations that the potential benefits may outweigh the risks.
The reason is that sexually transmitted HIV (the most common kind) is not much of a choice for many of the people who get infected. In sub-Saharan African, women and girls make up almost 60% of those living with HIV (www.unaids.org). Adolescent women are particularly vulnerable because they lack the social status and resources to negotiate safe sex with their partners, and most interventions (such as condoms) are overt (requiring knowledge of both partners) and male-focused (yes, there are female condoms, but they are rarely used).
It makes perfect sense to me. I use ChronoSync to keep files synced beteen machines, occasionally booting one machine in target disk mode if I want to completely replace a large file (the hooking them together you mention). The ability to keep completely updated personal information that travels with me from desktop->laptop->mobile phone automatically is beyond the scope of what I reasonably expect a single machine's OS to do. It is an ongoing service that is provided by .mac and one that, in my mind, is well worth it. People who don't use .mac aren't deliberately restricted from syncing their address books, etc. via file sharing, so I don't know why you'd think the software is 'crippled'.
Your comparison is reasonable -- for you. While no one will dispute that alternatives to .mac services are available, I'd argue that few are as easy to use as the .mac implementations. The other night I wanted to post a short AVI video to my website. Opened iMovie, opened the movie, clicked 'share', and it was converted to a QT movie and uploaded to .mac. Took 3 minutes. Could I have done it manually? Of course. But that's not the point of .mac. It takes these services and makes them easy. I have 4 OSX machines with synchronized bookmarks, contacts, and calendars. Amount of effort required to keep them up-to-date: none. It just works. For me, $100 per year is worth it for the convenience...it might not be for others. But to suggest that the .mac services should be offered free (not in the parent post, but a key topic in the thread) because there are free alternatives neglects the fact that most of .mac's value is in the implementation.
The advent of better genetic maps has allowed scientists to more accurately time the emergence of the delta32 CCR5 mutation. It now appears that this allele emerged earlier than previously thought and has not been strongly selected by plague. In other words, its frequency in Northern Europeans is explained by 'random', neutral selection and is not markedly different from other genes in the genome. (See here for more details)
Small molecule inhibitors that block the interaction between HIV and susceptible host cells show promise. Two huge concerns -- 1) HIV is not absolutely dependent on CCR5 usage. During chronic infection (presumably, when many CCR5+ cells have already been depleted), HIV can utilize an alternate coreceptor, CXCR4, to mediate entry into a cell. CXCR4-using viruses tend to be more aggressive than CCR5 viruses, and it is possible that CCR5 inhibitors would drive the more rapid emergence of these CXCR4-using strains. 2) Even though CCR5 inhibitors target a conserved, functionally essential target, HIV can still become resistant to these inhibitors.
Of course, its easy to Monday morning quarterback from a dry room in Wisconsin.
A much bigger story this week is the striking result of a clinical trial of male circumcision. Apparently circumcised men have a 70% lower risk of contracting HIV than uncircumcised men (see here). Though others have shown this anecdotally, proof in a large clinical trial could revolutionize HIV prevention -- particularly in sub-Saharan countries where HIV incidence is high and male circumcision is currently rare.
Don't be so sure and sanctimonious. I run Panther Server 10 client (purchased and licensed) quite happily on a headless mac mini (purchase price, about $500). I also run Retrospect for Workgroups on the same machine (again, purchased and licensed). It is all about meeting needs. For simply serving network homes to a workgroup of about 5 users and backing up all the client machines nightly, it is more than sufficient.
I don't think your analogy works. Gates didn't rob anyone. People elect to buy his products. Unfair competition? Perhaps, but he wouldn't have made his billions without the support of consumers.
It is all well and good to say that "if I had that sort of money, I'd donate huge amounts of it too", but he is actually doing it. If you are an American (or Canadian, or Western European, or reading /. pretty much anywhere), then you likely *are* affluant consiering that a full half the world's population lives on less than $2 per day (http://www.globalissues.org/TradeRelated/Poverty. asp). And we (as affluant societies) could and should do more to help close this gap.
On the one hand, it is a nice convenience for those who fly a lot. On the other, it makes the dangerous assumption that anyone who flies more than 25K miles a year (or whatever the qualifying criteria is these days) is somehow less of a threat.
Bookends (http://www.sonnysoftware.com/) integrates with both Mellel and MS Word, and they don't even force a paid upgrade for compatibility with new versions of Word (damn Endnote). The mechanism for adding refs to Mellel and Word docs from Bookends is similar to Endnote -- the only real problem with Bookends is that is uses an overly large, non-customizable (I think) display for the main reference window.
Also, the related Reference Miner app is terrific for extracting references from databases like Pubmed. Much, much faster than connecting to databases from within Endnote.
No affiliation with these products, except as a long-suffering Endnote / Word user who stumbled onto these excellent alternatives earlier this year.
The MVA based vaccines have their own set of problems. The set of MVA vaccines already being tested in people fell short of expectations, and the International AIDS Vaccine Initiative plans on halting the studies completely next year (see http://www.iavi.org/viewfile.cfm?fid=565). Other formulations of MVA may make it further -- but they will need to be markedly different than those tested already.
As to the child post asking whether prolonging life will lead to more new infections, the prevailing answer is 'maybe'. If you have less virus in your blood, you are less likely to transmit. But, if having less virus means you live longer, then you may have a longer timeframe to transmit. Researchers who are much better than me in math modeled this recently and predict that interventions that reduce viral burden by 1.5 logs (95%) or more will slow the epidmic (see Lancet Infect Dis. 2004 Oct;4(10):636-9.); reductions in viral load of less than 1.5 logs may make the epidemic worse. In that context, the dendritic cells vaccine discussed in this thread might actually worsen the epidemic, even if it allowed individuals to survive longer.
dave
A few other misconceptions in the parent post:
1) To my knowledge dendritic cells are not viable for 2 years at 50C. In the paper, the DCs were stored at -140C for no more than 4 weeks.
2) Even though virus in the blood decreased by 90% in some patients, CD4 counts still declined during the study. Unclear whether the reduction in virus burden really has a clinical benefit.
3) Fuzeon, the first drug in a new class of therapies termed entry inhibitors, was approved by the FDA in March 2003. Earlier this year, Merck published the results of a promising monkey trial of an HIV integrase inhibitor. Saying that there hasn't been anything new for 3 years in simply incorrect.
One interesting consequence of the poor ticket sales is the NBC response. In the prime time broadcast, they felt compelled to justify the empty seats in the gymnastics arena. Earlier in the day, during the US Women's soccer game, I'm pretty sure that they used a sports equivalent of a laugh track. For a few minutes during each half, the crowd noise suddenly doubled or tripled in volume and intensity suddenly, while the small number of people watching live seemed bored.
The first generation of vaccines to make it through clinical trials used purified HIV protein. The first large-scale clinical trial of this type of vaccine was a complete failure. A free news article describing this trial can be found at http://www.aegis.com/news/lt/2003/lt030219.html. The vaccine probably didn't work because it didn't elicit a strong enough immune response. The trick to making an effective vaccine is to 1) raise immune responses that mimic those that occur during a natural infection and 2) make the immune responses strong enough to be effective. This is a little oversimplified, but close enough.
Right now there is a big expensive controversy in the vaccine field regarding a planned large-scale clinical trial of a similar vaccine in Thailand. Earlier this year, 22 respected scientists published an opinion piece in Science (http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi? cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=147 26576) calling on the government to withdraw support for this trial. Since the trial will cost over 100 million dollars, the US government's support and money is pretty important. The controversy probably won't go away for a while -- especially since the biennial International AIDS Meeting will be hosted by Thailand in July.
Nature Medicine (subscription only) recently published an excellent review article discussing the problems with making HIV vaccines. The PubMed citation is http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=pubmed&dopt=Abstract&list_uids=1499 1035.
Hope this helps!
Just a minor correction to my own post. HIV packages two positive-strand RNA molecules (positive-strand diploid, as pointed out by someone else), not negative strand. That'll teach me to post quickly while heating up dinner.
Actually, no.
HIV is a lentivirus, a subcategory of the retroviruses. HIV virions package two, negative strand RNA molecules. Within a cell, the HIV reverse transcriptase synthesizes cDNA that integrates into the host cell. The low replication fidelity of the reverse transcriptase is what accounts for HIV's incredible ability to rapidly escape from drug treatment and immune responses.
Unfortunately, the Wired article doesn't provide many scientific details. The idea is pretty creative, but there is a huge difference between simulating a cure (and even making one in a test tube) and finding a cure that works in animals. A few concerns off the top of my head:
1) Recombination between HIV and the treatment vector. Remember those two strands of RNA I talked about above? You can get mosaic viruses that resemble part of one virus and a second part of another. I'd be willing to bet that this is the 'it could make things worse' aspect mentioned at the botom of the article.
2) Any time you insert foreign DNA into the genomic DNA of cels (as would occur with this anti-HIV, if I understand it correctly), bad things can happen.
3) Attenuating (or weakening) HIV has been widely tested as a vaccine. And basically, it works, at least in monkeys. If you give monkeys an attenuated version of SIV (monkey AIDS virus), the monkeys are basically protected against full-blown SIV. So why isn't this a vaccine that is being used in people? Monkeys that have weakened immune systems, are young, are old, or just have plain bad luck eventually get sick and die...from the attenuated strain of the virus. In other words, the attenuated vaccine makes the monkeys sick. The 'anti-HIV' sounds like a different riff on the same theme, with the possible caveat that they are looking to use it on people who are already infected, unlike a vaccine which would be used on uninfected people to prevent infection.
Just my two cents. My cred: 8 years in HIV research, with a Ph.D. in it.
Might cause information overload? In almost every field I'm aware of (virology and immunology are mine), there are already too many journals, each publishing more information that any one person could ever hope to read. One example is the proliferation of Nature and Cell 'sub-journals' in the last few years. Material that used to be published in Nature (and eventually) and Nature Medicine is now spread across Nature, Nature Medicine, Nature Reviews Immunology, Nature Reviews Microbiology, Nature Reviews Cancer, Nature Genetics, and Nature Biotechnology. And these journals are all 'top-tier'. The morass of less prominent journals seem to exist primarily to be searched out for individual articles resulting from citation searches, not to be 'read' in the conventional sense (as one reads a magazine or newspaper).
Our cable company also recently announced a rate increase for expanded basic cable. As a former Dish subscriber (who left because local stations were not available in my subscription area at the time), I applaud their stance. This sort of channel creep has been occuring for the better part of the last decade -- I remember our cable company delisting VH1 in favor of the ever-popular Animal Planet in '97. Why? Because the terms of the contract forced the cable company to bundle niche channels having limited mainstream appeal with popular stations. As media distributors continue to consolidate, their 'pull' in these sorts of disputes will only increase. In the current dispute, a half-dozen channels are affected. In a few years, it could be a dozen or more. If cable/sat companies aren't willing to take a principled (albeit potentially unpopular stand), customers will eventually bear the burden of inflated channel pricing rates.
I recently flew from LA to Melbourne, a brutal 14 hour flight. I turned on my 1st gen iPod immediately after we left LA, and, much to my surprise, it kept working until our approach in Australia. Yes, I didn't skip around very much, and I'm sure that helped battery life. But 14 hours of non-stop playback is 14-hours of playback.
So there are a few misconceptions in this thread that should be corrected: 1) Ebola is not a retrovirus. It does not have utilize RNA->DNA reverse transcription as part of its life cycle. It *is* however, an RNA virus, which means that it uses an RNA-dependent RNA polymerase to replicate. 2) Though a minute of cursory checking did not reveal the exact type of vaccine being tested in this study, it is, in all liklihood, an NIH formulation that uses a fragment of Ebola that is engineered into adenovirus. Preclinical trials of adenovirus-based Ebola vaccines have shown extraordinary promise(see: http://www.sciencemag.org/cgi/content/full/302/564 8/1141 (subscription required); http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=PubMed&list_uids=12904795&dopt=Abst ract).
What does this mean for safety? Well, the adenovirus is the only biologically active component of the vaccine, and many of the adenovirus strains being currently tested are replication-incompetent. That is, they infect a cell, produce viral proteins (which trigger an immune response), but do not assemble into new viral particles which can then escape the target cell and infect new cells. The Ebola component of the vaccine is just one or two genes, neither of which are responsible for the hemmoragic fever. In other words, you can't get Ebola from this type of vaccine -- the worst side effect might be a slight cold (as adenovirus infections cause cold symptoms).
One problem with this type of vaccine is that many people have already been exposed to adenoviruses naturally, and thus have preexisting immunity to the vaccine vector. This would prevent the Ebola gene fragments from being expressed and reduce the protective effect of the vaccine. Some more information about preexisting immunity to adenoviruses can be found in this article: http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?c md=Retrieve&db=PubMed&list_uids=12743287&dopt=Abst ract