In her new book, Living with the Fluid Genome, Mae-Wan Ho writes,
"The responsiveness of genes and genomes to the environment makes clear that the only way to keep genes and genomes constant and healthy is to have a balanced ecology... On the other hand, it is definitely futile to think that we can go on ruining our ecosystem and stay healthy so long as we have 'good' genes... Genes, unlike diamonds, are not forever."
This miniseries offers new insights into how major chronic diseases arise from the inability to take the fluid genome seriously, and how strategies to combat the diseases are similarly misguided and dangerous.
The US administration is offering AIDS-ravaged nations support for fighting AIDS tied to the purchase of GM products. The main anti-AIDS strategy is a class of vaccines that carries its own risks. Prominent AIDS researchers have called repeatedly for a moratorium as evidence of hazards accumulates. Dr. Mae-Wan Ho reports.
George Bush has taken Europe to the World Trade Organisation over Europe's de facto moratorium on GM imports. In the week of the G8 summit in Evian, France, Bush blasted Europe for perpetuating starvation in Africa by blocking US food aid with anti-GM policies, and announced his pledge of $15bn to combat AIDS globally, especially in Africa [1].
The UN Population Division reported earlier this year [2] that by 2050, the population of the hardest hit nations will have risen by 400 million less than previously estimated because of AIDS. "This estimate could be the first sign that HIV-1 will cause extinction of human beings in this millennium unless an effective AIDS vaccine is developed," said a commentary by Veljko Veljkovic and colleagues [3] in the Lancet, published in February.
The only AIDS vaccine to have progressed past phase 3 trial, made by VaxGen, took 5 years and involved 5108 gay men and 309 women [4]. Unfortunately, it proved ineffective, and may even be harmful.
In the 3003 white and Hispanic volunteers who received VaxGen's vaccine, a higher proportion suffered breakthrough infections than in the 1508 controls: 6% vs 5%. Although the difference is not significant, it could indicate a dangerous trend. But the company is not releasing further details on the trial results.
A few days after Bush announced the AIDS package, US Congress was denounced for tying support for anti-AIDS research programmes in 50 countries to their acceptance of GM products [5]. This accusation came from Julio Sanchez, representative of Mesoamerican Trade. Introducing GM food to hungry, malnourished nations ravaged by AIDS is bad enough in terms of health risks, but AIDS research programmes are heavily concentrated towards vaccine development with a strategy that introduces its own health hazards, as is becoming increasingly clear. During the past decade, a number of AIDS researchers, among whom Veljkovic and his team in Yugoslavia, have been studying the properties of the human immune deficiency virus, HIV-1, especially its envelop glycoprotein, gp120, which features in most of the AIDS candidate vaccines.
The gp120 protein is strongly immunogenic, which is why it is widely used in vaccines, in the hope that the body will produce antibodies against the protein and hence protect against the virus. But there have been many worrying signs that it may have just the opposite effect [6].
For although the body mounts a strong immune reaction against the protein, and produces antibodies against it, those antibodies fail to protect against the virus. One main reason is that the virus is very mutable, and can readily mutate to escape immune detection. In addition, the immune reaction mounted against the original gp120 undermines the effectiveness of the immune system by over-stimulating it, so that it is less effective to cope with new infections.
A recombinant gp120 vaccine tested in HIV-negative individuals in phaseI/II trails, was not effective in protecting against the disease [7, 8]. Not only that, participants in the trials had significant levels of circulating antibodies against the vaccine before they became infected, and came down with AIDS disease.
The vaccine could also be dangerous. A vaccine based on the gp120 from the strain SF2, actually suppressed the production of antibodies that could neutralise the later infecting virus, while boosting the production of useless antibodies that were specific for the vaccine strain, SF2 [9]. In other words, gp120 acts as a molecular decoy to disarm the body's antiviral response, leaving it more vulnerable, and increasing the likelihood of rapid disease progression in those vaccinated that later became infected. This phenomenon is called "deceptive imprinting" of the immune system [10].
Were those effects predictable in advance of the clinical trials? Veljkovic and his colleagues answer a definite yes [11].
First of all, the part of the gp120 molecule that plays the dominant role in provoking an immune response is the V3 loop. The V3 loop and flanking regions are similar in base sequence and structure to the antigen-binding region of the human immunoglobulin (Ig) (antibody protein). And it has been proposed since the early 1990s that this immunoglobulin-like domain in gp120 may interfere with the immune regulatory network [12]. This is strongly supported by later observations that the anti-V3 and anti-Ig antibodies of healthy individuals are similar in structure [13], and that antibodies reacting to V3 are present in sera that are HIV-negative [14].
In 1999, Howard Urnovitz and colleagues identified a mysterious case of AIDS in a French woman with no risk factors [15]. Analysis of the isolated HIV viral envelope showed that it had homology to sequences found on at least 14 different human chromosomes. This opened a whole new can of worms. Was this rare strain of HIV-1 the result of genetic recombination (reshuffling) in the human genome, similar to that found in veterans suffering from Gulf War syndrome (see "Dynamic genomics", this series)? Antibodies to human endogenous retroviruses were found in the urine of patients with clinical AIDS. Thus, vaccinating against HIV-1 may be tentamount to vaccinating people against their own genes (see "Endogenous retroviruses & chronic disease", this series). Does that mean genetic reshuffling and retroviral elements in the human genome may have a key role to play in AIDS disease?
Another piece of evidence implicating genetic recombination is that the V3 loop and its flanking regions are located between recombination signals similar to those found in human immunoglobulins, and also similar to the Chi recombination hotpots found in many viruses and bacteria [16]. Consequently, the immunologically dominant region of gp120 may be involved in recombining with human immunoglobulin genes resulting in autoimmune responses, and may also recombine with co-infecting viruses and bacteria to generate new pathogens. Evidence of such recombination has subsequently been found in the sera of AIDS patients [17, 18].
Many other observations have linked gp120 with auto-antibodies that react against the body's own cells and enhance the infectivity of HIV-1 (reviewed in ref. 9), and those researchers have also issued warnings against AIDS vaccines.
In fact, warnings against AIDS vaccines go back to Albert Sabin, one of the most prominent viral vaccine developers of the 20th century. "The available data provide no basis for testing any HIV vaccine in human beings either before or after infection," Sabin stated.
The current issue of Vaccine carries an article [19] evaluating the long-term safety of a range of AIDS vaccines involving 3189 HIV uninfected, healthy volunteers who were enrolled into 51 NIAID (NIH) - sponsored Phase I and II clinical trials. It concluded that there were no adverse effects. Veljkovic remarks, "This conclusion was based on analysis of many important parameters ….Unfortunately, the key information - comparison of the health status between breakthrough infected vaccinated volunteers and control subjects who participated in these trials - was not reported, just as it was not reported by VaxGen in the results of their Phase III clinical trial."
Unless this information is reported, says Veljkovic, the companies and institutions that organized these clinical trials are in danger of committing a scientific and ethical misconduct.
It is pertinent to point out that transgenic DNA in GM food and feed also carry recombination hotspots, such as the ones associated with the CaMV 35S promoter and the left and right borders of the Agrobacterium T-DNA used as vector to introduce transgenic DNA into the plant genome. These recombination hotspots enhance horizontal gene transfer and recombination. Furthermore, as Veljkovic remarked [20], the recombination hotspots in transgenic DNA may interact with the recombination signals flanking the V3 loop of the gp120 gene in AIDS vaccines to generate yet more exotic viruses.
Veljkovic and his colleagues have repeated their call for an immediate moratorium on the current clinical trials of HIV-1 gp120/160 vaccines.
Article first published 17/06/03
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