Friday, October 2, 2009

Endogenous Viruses and Chronic Disease

Retroviruses are RNA viruses found in all vertebrates. The retrovirus reproduces by reverse transcribing (copying) its RNA into DNA that is then integrated into the host-cell genome to be transcribed into viruses. Many retroviral sequences have become permanently integrated into the human genome as human endogenous retroviruses, or HERVs. The human genome (indeed all genomes) also contains retrovirus-like retrotransposons, mobile elements that multiply by making RNA copies that are reverse transcribed into DNA and integrated into new sites in the genome. The main difference between a retrovirus and a retrotransposon is that the latter lacks an envelope.

Most HERVs and retrotransposons are defective, having lost one or more gene functions; but can nevertheless multiply and move with the help of other elements or infecting viruses.

Which came first, retrovirus or retrotransposon? As viruses depend on cells to reproduce, it seems reasonable to suppose that retroviruses are simply retrotransposons that have gained an envelop, which helps in entering other cells. That idea was first put forward by Howard Temin, who discovered reverse transcriptase, the enzyme that reverse transcribes, encoded by the retrovirus and retrotransposon.

Retrotransposons play an important role in turning genes on or off, and in rearranging and amplifying genes during development and cell differentiation. And evidence has been accumulating that they are the natural molecular genetic engineers of the fluid genome, which are necessary for the survival of the organism .

HERVs are flanked by ‘long terminal repeats’ that contain strong promoters for gene expression. Promoters are stretches of DNA with binding sites for transcription factors of the host cell that boosts transcription, effectively saying to the cell, "make many copies of the message following". HERVs and retrotransposons are regulated by the cell, and ultimately, by the organism as a whole, which stops most of them from being expressed; though they can be activated under a variety of conditions (see below).

Many endogenous viruses show xenotropism, i.e., they are not active in the host cell but can become infectious to cells of non-host species. Xenotropism is one of the major health hazards of xenotransplantation, the transplant of organs and tissues between species, as from pig to humans.

Defective or dormant HERVs, like defective retrotransposons, can become expressed when missing gene-functions are provided by a ‘helper’ virus that happens to infect the cell, and that includes ‘attenuated’ viruses in vaccines. Like retrotransposons, HERVs can also be induced: by X-rays or various chemical agents and drugs, such as inhibitors of protein synthesis, organophosphates and other pesticides, inflammatory cytokines (hormone-like factors that influence cells of the immune system) or steroid hormones, and retinoic acid.

In a comprehensive review published in 1996, virologists Howard Urnovitz and William Murphy raised the possibility that many chronic debilitating diseases may be linked to HERVs. These include leukaemia and other cancers, B-cell immunoglobulin diseases, inflammatory diseases of the nervous system, autoimmune rheumatic and connective tissue disease and chronic fatigue syndrome.

There are several mechanisms linking HERVs with chronic diseases, though it is not at all clear which mechanism comes into effect under different circumstances.

One way in which endogenous viruses can cause disease is for them to move and insert itself next to certain genes, that, when over-expressed, results in uncontrolled cell division, or cancer. This mechanism may be involved in mouse and human leukaemia, breast cancer and teratocarcinoma. This is also the mechanism that causes cancer in gene therapy, when viral vectors integrate next to these same genes.

Another possibility is for an HERV to recombine with an infecting virus to generate new viruses. One theory for the origin of the AIDS virus it that it may have come from early preparations of polioviruses used for vaccines that were propagated in rhesus and African green monkey kidney cells. At least 26 monkey viruses, including adenoviruses, cosackievirus, herpesvirus, echovirus, and possibly other groups of viruses were found as contaminants in such preparations. Current vaccines are presumably free of such contamination, though that does not necessarily make them safe (see below).

Urnovitz and Murphy suggested that human immunodeficiency virus type 1 (HIV-1) may be a chimera between one of the simian (monkey) viruses (simian immunodeficiency virus) and HERV sequences. Simian immunodeficiency virus capable of causing simian AIDS, appears to occur exclusively in African monkeys, particularly in the African green monkey. And DNA sequences related to the highly conserved domain of the HIV reverse transcriptase and glycoprotein gp41 (part of the gp160 polyprotein of the HIV that’s cleaved into gp120 and gp41) have been found in the human genome.

Another way in which disease may arise is when HERV encoded proteins are expressed. This provokes antibodies against the body’s own cells, giving rise to autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, Sj√∂gren’s syndrome, mixed connective tissue diseases and inflammatory neurologic disease. The inflammatory response could be the most important trigger for the development of autoimmune disease, as infecting viruses can strongly activate HERVs to express, resulting in production of HERV protein antigens.

In this context, vaccines came in for special criticism in Unovitz’ testimony to the United States House of Representatives in 1999.

In his view, "there appears to be a limit on how much foreign material to which the human body can be exposed before some level of genetic damage occurs and a chronic disease initiates". Gulf War I veterans (GWIVs) were given large numbers of vaccines (see "Gulf War Syndrome and vaccinations", this series), and vaccine overload is a significant factor in Gulf War Syndrome.

Urnovitz described a case of a woman who died from a mysterious case of AIDS. Over several years, laboratory tests failed to reveal HIV-1 antibodies in her blood. However, she was subsequently tested HIV-1 positive in her urine. The virus was eventually isolated and sequenced; and came to be known as HIV-1 Group O. Analyses of the viral genetic material suggest that the virus originated, in part, from genetic reshuffling of human chromosomal material.

Vaccination against HIV-1 is particularly dangerous, if as Urnovitz and Murphy have suggested, HIV arose from recombination between the simian aids virus and HERV sequences (see also "AIDS vaccines worse than useless?" this series).

"To put it simply, are we embarking on a course that will vaccinate people against their own genes?" Dr. Urnovitz asked.

A second example is the intensive effort directed to creating a vaccine for the hepatitis C virus. Unfortunately, there is no hard evidence in the scientific literature that hepatitis C virus exists. Urnovitz continued, "As a scientist I am compelled to ask, how can we vaccinate people against a disease-causing agent that has not been fully characterised?"

Finally, he drew attention to the contaminated polio vaccines that is now being increasingly implicated in cancer,

"Had my mother and father known that the poliovirus vaccines of the 1950s were heavily contaminated with more than 26 monkey viruses, including the cancer virus SV40, I can say with certainty that they would not have allowed their children and themselves to take those vaccines. Both of my parents might not have developed cancers suspected of being vaccine-related, and might even be alive today."

But even uncontaminated Polio vaccines are of doubtful efficacy in protecting against viral infections and chronic disease. Enteroviruses have been shown to be a major factor in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome by John Richardson who studied more than 4000 patients over a 50 year period. Vaccination against polio provides protection against only 3 strains of polio leaving no protection against the other 70 or so enteroviruses- coxsackie, echo and others. These viruses have a range of pathological effects on the central nervous system, the cardiovascular system, and endocrine and exocrine glands.


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