Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era

What Does the Research Say?

Roberto Patarca-Montero

• Publisher: Routledge
• Year: 2014
• eBook ISBN: 9781135416294
• Topic: Medicine
• Subtopic: Diseases & Allergies

Are viruses the key to understanding this mysterious, devastating disease?Chronic fatigue syndrome (CFS) causes great suffering, not least because its etiology is so poorly understood. Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era offers proof that viruses may be direct or indirect causes of the disease. Therefore the new antiviral agents, the first fruits of the expanding genomics revolution, may be of use in treating this disorder.In recent years, innovative hypotheses on disease have challenged conventional medical wisdom. New studies give powerful evidence that pathological processes as diverse as atherosclerosis and autoimmune disease may be of viral origin. Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era takes these ideas a step further and applies them to CFS, offering fresh possibilities for treating this debilitating disease.This breakthrough book presents the latest research on antiviral agents, including:

• the scientific rationale for their use in CFS
• the historical evolution of these drugs
• results of clinical trials
• new lines of research

It also offers updates on specific drugs and treatments, including:

• Acyclovir, Ampligen, Imunovir (Inosine Pranobex), and 2CVV
• vaccines against Epstein-Barr virus, influenza, staphylococcus, and stealth virus
• Interferon-Alpha
• ginseng and other herb-based antivirals . . . and many more!

Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era is an essential resource for physicians, researchers, virologists, and patient advocates, as well as for anyone who is trying to obtain the best possible treatment for CFS.

Chapter 1

The Antiviral Era

The dawn of this century is brightened by the growing frequency of use and discovery of antiviral agents, the first fruits of the expanding genomics revolution. This new antiviral era, which flourished from the knowledge provided by the molecular biological characterization of the genetic makeup of viruses, is engendering new chemical and biological agents that are able to treat and not just prevent viral diseases. Hypotheses have also been rekindled that challenge conventional wisdom to expand the realm of diseases of viral etiology to include pathological processes, such as atherosclerosis and autoimmune disease, that would not have been previously thought as secondary to infectious processes. Regardless of whether the latter hypotheses prove to be correct, the experience that is being garnered in this antiviral revolution also serves, in the light of the information now available on the genetic makeup of human beings, as an encouraging paradigm for the development of drugs to treat all kinds of human diseases.

One of the diseases of possible viral origin that started to receive close attention in the latter part of the twentieth century is chronic fatigue syndrome. Chronic fatigue syndrome (CFS) is characterized by debilitating fatigue that is not attributable to known clinical conditions, has lasted for more than six months, has reduced the activity level of a previously healthy person by more than 50 percent, and has been accompanied by flu-like symptoms (e.g., pharyngitis, adenopathy, low-grade fever, myalgia, arthralgia, headache), and neuropsychological manifestations (e.g., difficulty concentrating, exercise intolerance, and sleep disturbances).^25–31

Although syndromes are clusters of nonchance associations, and the components of a syndrome can be generally related to a common element, the cause of CFS still remains to be determined. CFS is frequently of a sudden onset. Possible precipitating factors include infections, psychiatric trauma, and exposure to toxins.^31–34 Even among those who favor a viral etiology for CFS, it is not yet clear whether CFS is a consequence of a chronic viral infection or an acute viral infection which resolves but whose sequel in the form of autoimmunity or other manifestations is responsible for the pathology seen. As detailed in Chapter 2, many families of viruses have been studied in association with CFS, including herpesviruses, enteroviruses, retroviruses, lentiviruses, adenoviruses, Borna disease virus, parvoviruses, and arboviruses. It has also been proposed that reactivation of certain viruses may play a role in the pathophysiology of CFS but may not be its primary cause.

Based on the postulates of viral and autoimmune etiologies of CFS, several interventions have been designed and tested and are covered in the following chapters. These interventions have become possible because of the growing armamentarium of antiviral agents in molecular medicine and their widespread use in clinical practice—changes which have, in turn, arisen thanks to a confluence of novel approaches and a fresh look at past clinical wisdom. It is therefore instructive to review the historical background of the current developments in antiviral therapy.

The current antiviral drug revolution can trace its first roots to the contributions of scientists such as Spallanzani, who compellingly challenged the theory of spontaneous generation supported by the Roman Catholic Church and revealed the existence of a biological microcosm invisible to the naked eye that could account for many occurrences that were until then shrouded by a cloud of mystical religious beliefs; from the growth of mold on a wet surface to the transmission of certain diseases. Although Girolamo Fracastoro taught, in 1530, that syphilis was a contagious disease spread by “seeds,” and in 1683 Antony van Leeuwenhoek observed bacteria by using a crude microscope, it was the nineteenth century, with the contributions of scientists such as Louis Pasteur and Robert Koch, that saw the consolidation of the germ theory of disease and the flourishing of microbiology thanks to the definitive isolation of infectious organisms and the demonstration of their association with disease.³⁵ Around that time, Dmitri Ivanowski and Martinus Beijerinck described viruses as small infectious agents that could pass through bacteria-stopping filters. Following the identification of infectious organisms, immunology was born as a discipline aimed at unraveling the mechanisms used by the body to control and defeat them. Shortly thereafter, modern infectious disease medicine was inaugurated with the discovery of antibiotics in the early part of the twentieth century, an accomplishment that was based on the observation that fungi produced substances that were able to kill bacteria. The isolation and medical use of penicillin and other naturally occurring antibiotics, as well as the development of their synthetic derivatives, has allowed to control the spread and severity of bacterial infections and to preclude the reemergence of vast bacterial epidemics, such as the bubonic plague caused by the bacteria Yersinia pestis that killed a large portion of the human population in the Middle Ages.

Unlike the case with bacteria, viruses have no known natural enemies from which to isolate antibiotic-like substances, and, until the mid-1980s, viral infections were thought to be inherently preventable in some cases but generally untreatable. Many viral epidemics, such as polio, yellow fever, whooping cough, AIDS, and viral hepatitis, have received worldwide attention in the past and during this century. There are also many historical accounts of diseases of presumed viral etiology that present similar to CFS, including George Reinhold Forster’s description of the Tapanui flu and the documentation of Akureyri or Iceland disease.^36,37 The first half of the twentieth century witnessed the first successful approach to control the spread of several viral infections: the development and worldwide use of vaccines. The concept of vaccination was originally developed by Jenner in eighteenth-century England based on the observation that milkmaids exposed to cows with cowpox were protected from smallpox. In this case, a subclinical infection with one virus was protective of an infection with a related one. The latter concept was also extended to the treatment of various infectious diseases by giving the patient even unrelated but more innocuous infectious diseases. Although in many cases the treatment was worse than the disease, the therapeutic approach was somehow useful with particular combinations of infectious agents.

Outstanding triumphs of worldwide vaccination programs have been the eradication of smallpox and predictably soon of poliomyelitis.³⁸ After smallpox was eliminated as an infectious disease in Great Britain in 1962, two outbreaks occurred, one in 1973 and one in 1978, when smallpox virus under study in laboratories infected susceptible individuals. In both incidents, deaths resulted.³⁸ With the eradication of poliomyelitis throughout the world soon to be accomplished, steps are being taken to prevent polioviruses that remain in laboratories from escaping into the community and causing disease. These examples stress the need for universal availability of vaccines to effectively eradicate the diseases they cause. Unfortunately, we do not have vaccines against all viruses; even in the cases for which we do have vaccines, the vaccine is not universally available. The dramatic success in immunizing children against childhood diseases stands in stark contrast to the much lower percentages of adults who are adequately immunized against common adult diseases. In the case of the flu vaccine, the influenza virus keeps changing, the vaccine has to be updated every year, and it is therefore not fully protective against all viral strains.

One alternative to vaccines has been the use of injections of immunoglobulins, the natural bullets that the body produces to kill foreign invaders. Not too long ago, physicians advocated the use of immunoglobulin injections as a way to “boost” the body’s immune defenses and heighten resistance against microbes. The latter reasoning was perhaps again reflective of the old wisdom of using one infection to protect against another with the added refinement of using the natural mediators of the body’s attack machinery against infections instead of the infectious agent itself.

The limitations of antibodies as antiviral therapeutic agents still leave us with having to treat viral infections and, unlike the case with bacteria, we do not know the natural enemies of viruses from which to isolate antibiotic-like substances. The Nobel laureate Paul Ehrlich preached in the early twentieth century about the usefulness of discovering chemical substances that would act as “magic bullets” against infectious agents with little or no untoward effects to humans. Although the “magic bullets” studied in Ehrlich’s days were too toxic, Ehrlich’s vision inspired the pharmaceutical industry’s search for therapeutic small molecules, a task that has now been rekindled with the help of modern biology.

Viruses were the first microorganisms whose complete genetic makeup was characterized. The information on viral genes and their protein products has allowed to develop a series of chemicals with targeted antiviral activity. The advent of the acquired immunodeficiency syndrome (AIDS) pandemic in the second half of the twentieth century became the largest challenge to infectious disease medicine of the modern era. The discovery and characterization of the first human pathogenic retrovirus, the human T-cell leukemia/lymphoma virus type I (HTLV-I),^39–42 facilitated the discovery of the etiological agent of AIDS, the human immunodeficiency virus type 1 (HIV-1). Determination of the primary structure of HIV-1, first known as HTLV-III or LAV (lymphadenopathy virus) and computerized analysis of the amino acid sequence of the gene products it encodes provided the targets and, at the same time, the reagents to develop rapid and sensitive assay systems for testing potential therapeutic agents with anti-HIV activity.^43–45 Therefore, anti-HIV therapeutic medicines were born from the marriage between molecular and cellular biology, traditional therapeutic small molecule screening, and the then-incipient discipline of bioinformatics,^46–62 a marriage that also fueled the vigorous resurgence of genomics research.

The first databases of nucleic acid and protein sequences were created in the late 1970s. The computerization of algorithms for primary structure comparisons and secondary structure predictions (hydrophilicity and folding structures) and their use to analyze the genetic makeup of the AIDS virus in the framework of the knowledge garnered over decades for other known viruses quickly provided the targets for the development of anti-HIV agents. It is therefore the case that, although nonprimate viruses were the first microorganisms whose complete genetic makeup was characterized, it was not until the complete sequence of the AIDS virus became available in an unprecedented record time thanks in part to the strong public pressure for basic and clinical research that the information on viral genes and their protein products triggered an exponential growth in the development of chemicals with targeted antiviral activity.

Before the AIDS epidemic, the only antiviral agent that had been widely introduced to clinical practice with modest acceptance was acyclovir. The drug acyclovir, which is used to treat infections by herpes simplex viruses, the causative agents of the most feared viral venereal disease before the AIDS era, inhibits the viral DNA polymerase, a protein that is needed for the virus to replicate. The drug, after chemical modification by the body, affects mainly the viral DNA polymerase because the latter is sufficiently different from its human cell counterpart. Similar in concept to acyclovir, the first medication introduced for AIDS and diseases related to HIV-1 infection was 3'-azido-2', 3'-dideoxy-thymidine (formerly known as azidothymidine [AZT] and currently known as zidovudine [ZDV]), a nucleoside analog that inhibits reverse transcriptase, a critical enzyme for the replication of HIV.^56–62 It is noteworthy that the discovery of reverse transcriptase several decades before the characterization of the AIDS virus had demolished the dogma in molecular biology that genetic information could flow only from DNA to RNA to protein by demonstrating that information could also flow from RNA to DNA, as was exemplified by the life cycle of retroviruses.

The initial success of AZT opened the door for the development of other antiretroviral agents, and no doubt exists today that antiretroviral chemotherapy can bring about reduction of viral load and clinical benefits to HIV-infected individuals. Besides AZT, a variety of 2',3'-dideoxynucleosides have been added to the anti-HIV armamentarium, among them ddI or didanosine, ddC or zalcitabine, d4T or stavudine, and 3TC or lamivudine. Many more are undergoing clinical or preclinical testing. Nonnucleoside reverse transcriptase inhibitors, including nevirapine and delavirdine, have also become available and more will emerge in the near future. The high mutation rate of HIV has allowed the selection of viral strains resistant to antiretrovirals, a feature that has fed a constant need for new viral therapeutic targets. As the first clinical application of what has been termed pharmacogenomics, the genomics era has also provided the intermediate- and high-throughput tools to genotype AIDS virus strains from patients to determine their drug resistance patterns. Changes in antiretroviral therapy choice based on the viral resistance patterns allow better control of viral load and disease progression.

A virus that has approximately 15 genes, such as HIV, presents a much more limited drug target repertoire than bacteria such as the gut-dwelling bacterium Escherichia coli with approximately 1,500 different proteins. The latter limitation in target variety has rendered the traditional random drug screening efforts for anti-HIV agents disappointing for the most part, a hurdle that has been the inspiration for the introduction of different drug development approaches. Approximately one decade after the introduction of AZT, the inhibitors of another viral enzyme, protease, were hailed on their way into clinics as the long-awaited panacea for AIDS. The viral protease is needed to cleave the original synthesis products of the virus to generate building blocks required for assembly of new viral particles. The successful development of HIV protease inhibitors is arguably the greatest achievement to date for the relatively new method of structure-based drug design.^63–67 The latter design is possible when the structure of the molecular target has been determined by X-ray crystallography, nuclear magnetic resonance (NMR), or remodeling. Unbeknown to many clinicians, the presence in the viral genome and the start point for the generation of the protease gene had been originally predicted in the early 1980s with accuracy down to one amino acid in the first round of analysis of the HIV sequence. But it was not until the structure of this enzyme was determined that the first design studies with HIV-1 began with HIV protease in the early 1990s. Many protease inhibitors are currently available on the market; saquinavir, ritonavir, indinavir, and nelfinavir, and another large group is in clinical and preclinical development.

The initial experience with anti-HIV therapy has evinced the greater efficacy, as compared to monotherapy, of appropriately combining multiple classes of antiviral agents in patients with HIV infection. As structure-based drug design methods improve, new therapeutic agents will be effectively developed against novel antiviral targets for HIV-1 therapy. The X-ray crystallography and NMR structures of several HIV-1-encoded proteins have been determined, including the reverse transcriptase, RNase H, integrase, matrix, capsid, nucleocapsid, Tat protein, and a domain of gp41. In addition, the structures of the cell surface proteins with which the envelope proteins of HIV interact have also been characterized; i.e., the envelope binding domains of CD4 and that of certain chemokine receptors, such as CCR5. The need to continue to search for and develop drugs against novel antiviral targets for HIV therapy should not be underestimated, because the prevalence of new drug-resistant variants of HIV that are insensitive to even the best current regimens of triple and quadruple combination therapy is rising at an alarming rate, especially in the context of patient nonadherence secondary to the complexity or financial burden of combined regimens.

The discovery of protease inhibitors also illustrates another important strength of the genomics approach to drug discovery. The characterization of the genetic makeup of HIV allowed to develop target-based screens to identify novel lead compounds for specific targets that would otherwise have gone unidentified in cell culture-based assays. In this respect, high-throughput protease assays were responsible for identifying nonpeptidic lead compounds that were subsequently developed into potent protease inhibitors with anti-HIV activity, even though the initial lead compounds had no measurable antiviral activity in tissue culture assays. Conversely, compounds that exhibit antiviral activity in a cell culture-based screen can now be subjected to a battery of mechanism-based tests to profile their mode of action.

The characterization of the genetic makeup of the AIDS virus is also helping to fine tune the development of AIDS vaccines aimed not only at triggering, as most conventional viral vaccines do, the production of antibodies, the natural bullets that cells of the body’s immunological defense system produce to kill foreign invading agents, but also at stimulating the so-called cellular immunity, i.e., bringing into action other cells of the body’s defense system that can directly kill the virus or the virus-infected cells. Again, in this ...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• Chapter 1. The Antiviral Era
• Chapter 2. Viruses As Potential Direct or Indirect Etiological Agents for CFS
• Chapter 3. Viral-Specific and Immune-Based Nonspecific Antiviral Therapies for CFS
• Chapter 4. Concluding Remarks
• Notes
• Index