Skip to comments.Scientists say crack HIV/AIDS puzzle for drugs
Posted on 01/31/2010 3:55:57 PM PST by neverdem
* Study solves puzzle that eluded scientists for 20 years
* Finding should help development of new HIV/AIDS medicines
* Allows scientists to see how Merck and Gilead drugs work
LONDON, Jan 31 (Reuters) - Scientists say they have solved a crucial puzzle about the AIDS virus after 20 years of research and that their findings could lead to better treatments for HIV.
British and U.S. researchers said they had grown a crystal that enabled them to see the structure of an enzyme called integrase, which is found in retroviruses like HIV and is a target for some of the newest HIV medicines.
"Despite initially painstakingly slow progress and very many failed attempts, we did not give up and our effort was finally rewarded," said Peter Cherepanov of Imperial College London, who conducted the research with scientists from Harvard University.
The Imperial and Harvard scientists said that having the integrase structure means researchers can begin fully to understand how integrase inhibitor drugs work, how they might be improved, and how to stop HIV developing resistance to them.
When the human immunodeficiency virus (HIV) infects someone, it uses the integrase enzyme to paste a copy of its genetic information into their DNA, Cherepanov explained in the study published in the Nature journal on Sunday.
Some new drugs for HIV -- like Isentress from Merck & Co and elvitegravir, an experimental drug from Gilead Sciences -- work by blocking integrase, but scientists are not clear exactly how they work or how to improve them.
The only way to find out was to obtain high-quality crystals -- a project that had defeated scientists for many years.
"When we started out, we knew that the project was very difficult, and that many tricks had already been tried and given up by others long ago,"...
(Excerpt) Read more at reuters.com ...
Congrats to all the scientists involved. While, based on this short article, I fully do not understand the science, the ramifications of this promise to be immense.
Congrats again to the Imperial and Harvard teams.
Could this integrase be of any use in pluri-potent stem cell research?Just wondering.
1983 AIDS had become big enough in the American and European press to pique the interest of the influential infectious disease establishment, particularly the cancer virus hunters.
At that time the virus hunters had been engaged for over a decade in president NixonÂs War on Cancer with unsuccessful attempts to find a human cancer virus (Duesberg 1996b; Fujimura 1996; de Harven 1999).
Now they were looking for new diseases that could be attributed to viruses (Duesberg 1987). Perhaps AIDS could at last yield clinically relevant lymphoma-, KaposiÂs sar- coma- or immunodeficiency-viruses (Duesberg 1996b). Indeed, virus hunters from the CDC were the first to alert the public that AIDS may be ÂtransmissibleÂ (Francis et al 1983).
A similar alert came from a French virus team, which had discovered a retrovirus in a homosexual man at risk for AIDS, which a year later became the accepted cause of AIDS (Barre-Sinoussi et al 1983).
News, that the cause of AIDS may be a virus, and thus transmissible to the general population, immediately set off a national panic that opened the doors for new surveillance programs by the CDC and predictably set off a race among virus hunters for the AIDS virus (Shilts 1987).
According to an international press conference called by the US Secretary of Health and Human Services in Washington DC on 23 April 1984, that race was won by government researchers from the NIH who had found in some AIDS patients antibodies against a new retrovirus closely related to a hypothetical human leukemia virus (Altman 1984).
The virus was introduced as fortunate fallout of the failed War on Cancer. The next day the new virus was already termed, the ÂAIDS virusÂ, by the New York Times (Altman 1984). Overnight nearly all AIDS researchers dropped the lifestyle-AIDS hypothesis to work on the new ÂAIDS virusÂ, which was already endorsed by the US government.
The CDCÂs director of the Task retrovirologists officially sealed the seemingly tight package of a new ÂAIDS virusÂ and the CDCÂs assumption that immunodeficiency was the common denominator of the 26 AIDS-defining diseases (table 1) by naming it, Human Immunodeficiency Virus (HIV) (Coffin et al 1986).
Even before the AIDS virus became the officially accep- ted cause of AIDS, the CDC had already made antibodies against the virus the only definitive criterion to diagnose any of the heterogeneous diseases as AIDS in 1985 (Cen- ters for Disease Control 1985, 1987, 1992).
Their unortho- dox decision to use antibodies against the virus (normally functioning as a vaccine), instead of the virus, for the diagnosis of AIDS was based on the flawed analogy with some bacterial pathogens. For example, syphilis bacteria can be pathogenic despite the presence of antibodies, e.g. the Wassermann test for syphilis (Brandt 1988).
But viruses are typically unable to enter cells in the presence of anti-viral antibodies Â the basis for the effectiveness of Jennerian vaccines. Because of the CDCÂs decision, AIDS is diagnosed worldwide if antibody against (!) HIV, rather than HIV, is detectable in a patient along with any of the CDCÂs 26 diseases.
Since 1992 even low T-cell counts are diagnosed as a condition, termed ÂHIV/AIDSÂ, which is treatable with anti-HIV drugs provided it occurs in the presence of antibodies against HIV (Centers for Disease Control 1992), (see table 1, and Â§ 4.2). 3.1 Discrepancies between the predictions of the virus-AIDS hypothesis and the facts.
Despite its spectacular birthday the HIV-AIDS hypothesis has remained entirely unproductive to this date: There is as yet no anti-HIV-AIDS vaccine, no effective prevention and not a single AIDS patient has ever been cured Â the hallmarks of a flawed hypothesis. Indeed the hypothesis was born with several serious birth defects and has developed further defects since; most of these should have given pause to HIV-AIDS researchers to rethink and reconsider.
However, in the race to claim a share of the new viral cause for AIDS and of virus-based AIDS treat- ments, ÂThe Trojan horse of emergencyÂ (Szasz 2001) was saddled so quickly that there was little time and no interest to address these defects, not even the most fundamental ones (Weiss and Jaffe 1990; Cohen 1994; OÂBrien 1997).
An analysis of the defects of the HIV-AIDS hypothesis based on its failure to predict AIDS facts is shown in table 4. Our analysis is based on the most recent and most authoritative case made for the HIV-AIDS hypothesis since 1984, namely the Durban Declaration that was published in Nature in 2000 and has been signed by Âover 5,000 people, including Nobel prizewinnersÂ (The Durban Declaration 2000). It can be seen in table 4 that the HIV-hypothesis fails to predict 17 specific facts of AIDS.
The most fundamental discrepancy between the HIV-AIDS hypothesis and the facts is the paradox, that a latent, non-cytopathic and immunologically neutralized retrovirus [a virus that is inherently not cytopathic (Duesberg 1987)], that is only present in less than 1 out of 500 susceptible T-cells and rarely expressed in a few of those, would cause a plethora of fatal diseases in sexually active, young men and women.
And, that the plethora of the diseases attributed to this virus would not show up for 5Â10 years after infection (table 4). As a result of the many discrepancies between the HIV hypothesis and the facts, we conclude that HIV is not sufficient for AIDS, and is most compatible with being a passenger virus. Surprisingly our conclusion is supported by a survey of AIDS researchers conducted by the New York Times, shortly after the publication of the Durban Declaration.
At the 20th anniversary of AIDS, on 30 January 2001, the New York Times interviewed a dozen leading AIDS researchers for an article that turned into a list of questions, ÂThe AIDS questions that lingerÂ (Altman 2001a), similar to those asked by us in table 4: ÂIn the 20 years since the first cases of AIDS were detected, scientists say they have learned more about this viral disease than any other, and few have dispu- ted the claim. Â Despite the gains Â experts say reviewing unanswered questions could prove useful as a measure of progress for AIDS and other diseases.
Such a list could fill a newspaper, and even then would create debate. (E.g.): How does H.I.V. subvert the immune system? . . . Why does AIDS predispose infec- ted persons to certain types of cancer and infections and not others? . . . Dr Anthony S Fauci, the director of the National Institute of Allergy and Infectious Diseases, said, ÂIt is the rare person who gets up and strips himself of his personal agenda and articulates what we really do not know because by saying that they would diminish the impact of their own work, which is their agendaÂ.
(Regarding anti-HIV medications:) . . . the new drugs do not completely eliminate H.I.V. from the body, so the medicines, which can have dangerous side effects, will have to be taken for a lifetime and perhaps changed to combat resistance.
The treatments are now so complicated that it is difficult, expensive and time-consuming to answer basic and practical questions. What combinations of drugs should be started first and when? Why do side effects like unusual accumulations of fat in the abdomen and neck develop? . . . Anti-H.I.V. drugs suppress replication of the virus, which should give the functioning parts of the immune system a chance to eliminate re- maining virus.
That does not happen. ÂSo something is bizarre about that, that we donÂt understandÂ, Dr Fauci said. Is a vaccine possible? . . . many unanswered questions exist about whether and when one can be developed.Â Thus HIV-AIDS researchers have not solved the discrepancies and paradoxes of the HIV-AIDS hypothesis, but still do not follow the scientific method of searching for alternative explanations (Costello 1995).
Since 19 years of HIV-AIDS research have failed to produce tangible benefits for AIDS patients and risk groups, and since there are no paradoxes in nature only flawed hypotheses, the scientific method calls for an alternative, testable hypothesis. Here we offer one such hypothesis.
Our hypothesis extends the early, and now abandoned ÂlifestyleÂ hypothesis (Â§ 2) and subsequent drug-AIDS hypotheses from us and others (Duesberg 1992; Duesberg and Rasnick 1998). ÂHistorically, the first step in determining the cause of any disease has always been to find out if there is anything, apart from the disease itself, that sufferers have in commonÂ (Cairns 1978).
However, the traditional search for the cause is only completed, if something that suf- ferers have in common can also be shown to cause the disease; in other words if KochÂs postulates can be ful- filled (Merriam-Webster 1965). This is true for viruses just as much as for drugs. Following this tradition, we try here to provide proof of principle for our drug and malnutrition hypothesis of AIDS Â alias chemical AIDS. 4.1
The chemical-AIDS hypothesis and its predictions The chemical-AIDS hypothesis proposes that the AIDS epidemics of the US and Europe are caused by recreational drugs, alias lifestyle, and anti-HIV drugs (Duesberg.
1. Since HIV is Âthe sole cause of AIDSÂ, it must be abundant in AIDS patients based on Âexactly the same criteria as for other viral diseases.Â But, only antibodies against HIV are found in most patients (1Â7)**. Therefore, ÂHIV infection is identified in blood by detecting antibodies, gene sequences, or viral isolation.Â
But, HIV can only be ÂisolatedÂ from rare, la- tently infected lymphocytes that have been cultured for weeks in vitro Â away from the antibodies of the human host (8). Thus HIV behaves like a latent passenger virus.
2. Since HIV is Âthe sole cause of AIDSÂ, there is no AIDS in HIV-free people.
But, the AIDS literature has described at least 4621 HIV- free AIDS cases according to one survey Â irrespective of, or in agreement with allowances made by the CDC for HIV-free AIDS cases (55).
3. The retrovirus HIV causes immunodeficiency by killing T-cells (1Â3).
But, retroviruses do not kill cells because they depend on viable cells for the replication of their RNA from viral DNA integrated into cellular DNA (4, 25). Thus, T-cells infected in vitro thrive, and those patented to mass-produce HIV for the detection of HIV antibodies and diag- nosis of AIDS are immortal (9Â15)!
4. Following Âexactly the same criteria as for other viral disea- sesÂ, HIV causes AIDS by killing more T-cells than the body can replace. Thus T-cells or ÂCD4 lymphocytes . . . become depleted in people with AIDSÂ. But, even in patients dying from AIDS less than 1 in 500 of the T-cells Âthat become depletedÂ are ever infected by HIV (16Â20, 54). This rate of infection is the hallmark of a latent passenger virus (21). 5. With an RNA of 9 kilobases, just like polio virus, HIV should be able to cause one specific disease, or no disease if it is a passenger (22).
But, HIV is said to be Âthe sole cause of AIDSÂ, or of 26 different immunodeficiency and non-immunodeficiency diseases, all of which also occur without HIV (table 2). Thus there is not one HIV-specific disease, which is the definition of a passenger virus!
6. All viruses are most pathogenic prior to anti-viral immunity. Therefore, preemptive immunization with Jennerian vaccines is used to protect against all viral diseases since 1798.
But, AIDS is observed Â by definition Â only after anti- HIV immunity is established, a positive HIV/AIDS test (23). Thus HIV cannot cause AIDS by Âthe same criteriaÂ as conventional viruses.
7. HIV needs Â5Â10 yearsÂ from establishing antiviral immu- nity to cause AIDS.
But, HIV replicates in 1 day, generating over 100 new HIVs per cell (24, 25). Accordingly, HIV is immunogenic, i.e. biochemically most active, within weeks after infection (26, 27). Thus, based on conventional criteria Âfor other viral disea- sesÂ, HIV should also cause AIDS within weeks Â if it could.
8. ÂMost people with HIV infection show signs of AIDS within 5Â10 yearsÂ Â the justification for prophylaxis of AIDS with the DNA chain terminator AZT (Â§ 4).
But, of Â34â 3 million . . . with HIV worldwideÂ only 1â 4% [= 471,457 (obtained by substracting the WHOÂs cumulative total of 1999 from that of 2000)] developed AIDS in 2000, and similarly low percentages prevailed in all previous years (28). Likewise, in 1985, only 1â 2% of the 1 million US citizens with HIV developed AIDS (29, 30). Since an annual incidence of 1â 2Â1â 4% of all 26 AIDS defining diseases combined is no more than the normal mortality in the US and Europe (life expectancy of 75 years), HIV must be a passenger virus.
9. A vaccine against HIV should (Âis hopedÂ to) prevent AIDS Â the reason why AIDS researchers try to develop an AIDS vaccine since 1984 (31).
But, despite enormous efforts there is no such vaccine to this day (31). Moreover, since AIDS occurs by definition only in the presence of natural antibodies against HIV (Â§ 3), and since natural antibodies are so effective that no HIV is detectable in AIDS patients (see No. 1), even the hopes for a vaccine are irrational.
10. HIV, like other viruses, survives by transmission from host to host, which is said to be mediated Âthrough sexual con- tactÂ.
But, only 1 in 1000 unprotected sexual contacts transmits HIV (32Â34), and only 1 of 275 US citizens is HIV-infec- ted (29, 30), (figure 1b). Therefore, an average un-infected US citizen needs 275,000 random Âsexual contactsÂ to get infected and spread HIV Â an unlikely basis for an epidemic!
11. ÂAIDS spreads by infectionÂ of HIV.
But, contrary to the spread of AIDS, there is no ÂspreadÂ of HIV in the US. In the US HIV infections have remained constant at 1 million from 1985 (29) until now (30), (see also The Durban Declaration and figure 1b). By contrast, AIDS has increased from 1981 until 1992 and has decli- ned ever since (figure 1a).
12. Many of the 3 million people who annually receive blood trans- fusions in the US for life-threatening diseases (51), should have developed AIDS from HIV-infected blood donors prior to the elimination of HIV from the blood supply in 1985.
But there was no increase in AIDS-defining diseases in HIV-positive transfusion recipients in the AIDS era (52), and no AIDS-defining KaposiÂs sarcoma has ever been observed in millions of transfusion recipients (53).
13. Doctors are at high risk to contract AIDS from patients, HIV researchers from virus preparations, wives of HIV-positive hemophiliacs from husbands, and prostitutes from clients Â particularly since there is no HIV vaccine.
But, in the peer-reviewed literature there is not one doctor or nurse who has ever contracted AIDS (not just HIV) from the over 816,000 AIDS patients recorded in the US in 22 years (30). Not one of over ten thousand HIV researchers has con- tracted AIDS. Wives of hemophiliacs do not get AIDS (35). And there is no AIDS-epidemic in prostitutes (36Â38). Thus AIDS is not contagious (39, 40).
14. Viral AIDS Â like all viral/microbial epidemics in the past (41Â43) Â should spread randomly in a population.
But, in the US and Europe AIDS is restricted since 1981 to two main risk groups, intravenous drug users and male homosexual drug users (Â§ 1 and 4).
15. A viral AIDS epidemic should form a classical, bell-shaped chronological curve (41Â43), rising exponentially via virus spread and declining exponentially via natural immunity, within months (see figure 3a).
But, AIDS has been increasing slowly since 1981 for 12 years and is now declining since 1993 (figure 1a), just like a lifestyle epidemic, as for example lung cancer from smoking (figure 3b).
16. AIDS should be a pediatric epidemic now, because HIV is transmitted Âfrom mother to infantÂ at rates of 25Â50% (44Â 49), and because Â34â 3 million people worldwideÂ were already infected in 2000. To reduce the high maternal trans- mission rate HIV-antibody-positive pregnant mothers are treated with AZT for up to 6 months prior to birth (Â§ 4).
But, less than 1% of AIDS in the US and Europe is pediatric (30, 50). Thus HIV must be a passenger virus in new- borns.
17. ÂHIV recognizes no social, political or geographic bordersÂ Â just like all other viruses.
But, the presumably HIV-caused AIDS epidemics of Africa and of the US and Europe differ both clinically and epidemiologically (Â§ 1, table 2). The US/European epidemic is highly nonrandom, 80% male and restricted to abnormal risk groups, whereas the African epidemic is random.
What a dreadful headline. At first, my brain was connecting crack cocaine with the HIV/AIDs concept. (Of course, I suppose those who use crack eventually wind up with HIV/AIDS.)
I bet the scientists involved had to listen to something like this:
"You've done 35,000 trials and what do you have to show for it? Absolutely nothing! This is just a huge waste of time and money!"
Besides the use of the word “crack” when discussing this dread disease (the jokes write themselves), let’s hope this is a real breakthrough.
I'm thinking more along the lines of gene therapy to avoid viral vectors, but cellular reprogramming for induced pluripotent stem cells might be doable too.
They used a cell-penetrating peptide in that article.
Once I click on the Table of Contents, it opens and the window becomes completely dead including the toolbar and everything else. I have to close the window.
Could someone check Nature's Table of Contents and see if the same thing happens to them? If you find the citation, could you link the abstract? I would appreciate it.
FReepmail me if you want on or off my health and science ping list.
Do you mean this?
The page is labeled "Journal home > Advance online publication > Table of contents."
Yes, TChad. Thank you. All I need is the author's surname, and voila, I can link the abstract.
I never heard of a intasome before. It wasn't in Dorlands Medical dictionary.
And when I got to the Table of Contents page the window died again. Earlier, the Nature selection on my Favorites vanished. Maybe my registration needs to be renewed.
You also might try a different browser or clearing your browser cache.
I think I'm stuck with Internet Explorer 6 for Microsoft Windows ME. How do I clear its browser cache?
One easy way to do it is to use CCleaner. It's a great, free program. CCleaner should work with IE6 on WinME.
If you have never cleared your Temporary Internet Files folder, there will be a lot to clean. CCleaner also empties your Recycle Bin and deletes other temporary files. You should make sure that it will not delete something important to you before running it. The program provides a list of the types of files it will delete.
If you delete cookies, you might have to reenter passwords for Internet sites.
You also might try a different browser or clearing your browser cache.*** I think I'm stuck with Internet Explorer 6 for Microsoft Windows ME. How do I clear its browser cache? ***
'scuse me for butin' in...
you're not stuck with IE6. I've used Firefox 'forever' and with 'ME", and on the Mozilla/Firefox page you can still download early versions like (example) Firefox 2.0 that'll work fine with ME (just turn off auto update).
BUT as Chad says in #16: Be. Very. Careful. when emptying any Temp Folders. Many programs store required files in there (Bill Gates is evil). A couple weeks back I was downloading a new program/application and the 'Instruction' said to 'delete EVERYTHING' in my Temp Folder. Well I looked in it first and its a good thing I didn't "delete everything". Plus some 'Temp Folders' may be hidden and you won't see them unless you go into My Computer thru Explorer and uncheck two boxes.
There is an easy way to 'clear your cache' though. Just Click Tools, Internet Options and check 'clear browsing history' under 'General Tab'. But that will delete your cookies so make sure you have all your website passwords & IDs written down.
Hope this helps and makes sense (still haven't had enough caffeine)
Thanks for your help. I appreciate it. I never had any formal training in operating systems.
And 'help' is what FReepers do for one another, but you know that :-)
My 'formal training' came from owning a DELL. I had both Hardware and Software problems with it. My Service Folder was at least an inch thick.
Ping... (Thanks, neverdem!)
Thanks for the ping!
I'll second that opinion. I downloaded a "trial" of Roxio Creator 9. The trial ran out. When I accessed it again, it asked if I wanted to purchase. I said yes. I was charged immediately and the software worked immediately. I cleaned my cache and temp areas a few days later. Now Roxio is looking for the "MSI" install file in a "temp" directory. I suspect my purchased copy is dead meat. It is most upsetting to deal with companies that are this brain dead.