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Introduction

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War in the Body

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Abstract

In 1984, two groups of investigators—Luc A. Montagnier’s at the Pasteur Institute in Paris and Robert C. Gallo’s at the National Institutes of Health in Bethesda, Maryland—announced the discovery of the human immunodeficiency virus (HIV in this book, although H.I.V. in the New York Times). The clinical manifestations of a new disease, acquired immunodeficiency syndrome (AIDS), had been observed 3 years earlier, in a population of men who have sex with men, in several cities of the United States. At this writing, HIV has established a global pandemic, among the worst in recorded history; 33 million people are currently infected worldwide, with 2.5 million new infections each year. At least 25 million have died of AIDS. The primary modes of transmission at this time are unprotected sexual activity and intravenous drug users sharing syringes. Although the government’s top-ranking doctor, Edward Brandt Jr., said shortly after the virus was discovered that he was optimistic that a vaccine would be available by 1987, 20 years later no vaccine against HIV/AIDS has been licensed.

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Notes

  1. 1.

    The 2008 Nobel Prize in Medicine was awarded to Montagnier and Françoise Barré-Sinoussi for the discovery of the human immunodeficiency virus and Harald zur Hausen for discover of the human papilloma virus, which causes cervical cancer. The Karolinska Institute’s opinion about the discoverers of HIV is controversial, coming after a long and acrimonious dispute between the French and American camps.

  2. 2.

    A brief account of a cluster of cases in Los Angeles of combined pneumocystis pneumonia and Kaposi’s sarcoma appeared in the Morbidity and Mortality Weekly, published by the Centers for Disease Control (CDC), in June, 1981. The combination of a rare form of pneumonia with a rare skin cancer alerted epidemiologists that a new infectious disease may have appeared.

  3. 3.

    These are revised estimates by UNAIDS, released on November 20, 2007. The current estimate of 33.2 (confidence interval, [30.6,36.1]) million infected replaced an earlier estimate of 39.5 ([34.1,47.1]); the UN agency’s revisions reflects lowered estimates primarily of the epidemic in India.

  4. 4.

    “Virus” is Latin for poison or slime; these disease-causing agents—originally called “filterable viruses” because they passed through the finest sieves in the laboratory—were discovered around 1915.

  5. 5.

    Pan troglodytes troglodytes; the “greater” chimpanzee.

  6. 6.

    Cercocebus atys.

  7. 7.

    There is also a reported route for virions to pass directly between cells by hijacking the immunological synapse formed between APCs and T-cells or creating a “virological synapse” between two CD4+ T-cells. Although this mechanism for cell-to-cell spread had been demonstrated in vitro, its importance in vivo is unknown.

  8. 8.

    The eclipse period was incorrectly estimated in 1996, from data about declining viremia after HAART, to be 1.1 day [237], a figure which made it into many models including some of my own. For discussion of this issue, see the Notes to Section 1.7.

  9. 9.

    It is sometimes asserted that only non-synonymous mutations can confer an advantage, but there are situations—involving RNA secondary structure or codon usage—where synonymous changes also affect fitness. Nevertheless, geneticists often use the ratio of synonymous to non-synonymous variation as a measure of the relative importance of neutral “drift” and selection.

  10. 10.

    A rationally-designed drug is one that was developed on the basis of hypotheses about disease mechanisms at the molecular level, perhaps including detailed X-ray photographs revealing the structure of targeted proteins. By contrast, most drugs in clinical use, even today, were discovered in screening programs and the mechanism of action is often unknown. The earlier anti-viral drugs licensed were acyclovir, amantadine, vidarabine, and ribavirin, active against herpes, flu, and hepatitis. The hurdle in discovering anti-viral drugs is that viruses hijack cellular enzymes to facilitate reproduction, so drugs acting against them are often toxic for the host. Bacteria bring along their own enzymatic machinery and thus are easier to target.

  11. 11.

    The assertion was made at the time that 36 months of drug treatment would amount to a cure. This prediction failure was probably due to neglecting the possibility of latency at the cellular level (see Chapters 2 and 10) rather than escape by mutation.

  12. 12.

    In 1957, Macfarlane Burnet had proposed the “clonal selection theory” to explain antibody diversity; a few years before, Niels Kaj Jerne, who also coined the term “epitope”, had expressed similar ideas. When, around 1962, Jacques Miller and collaborators demonstrated T-cell education by the thymus, it fully realized Jerne’s and Burnet’s conceptions. Random generation and selection replaced older concepts such as “instruction”, meaning that antigen had to be present at antibody or TCR creation; it has been called the Kuhnian revolution, aka “paradigm shift”, in immunology.

  13. 13.

    Some immunologists believe that some CD4s are cytotoxic, while some CD8s are not; this is typical of the field.

  14. 14.

    The collection of genes that encode these molecules is called the major-histocompatibility-complex (MHC); it is divided into three HLA regions. HLA class I are the molecules that display antigen to CD8 T-cells, and HLA class II display to CD4 T-cells.

  15. 15.

    HLA restriction of T-cell epitopes was discovered by Rolf M. Zinkernagel and collaborators in 1974.

  16. 16.

    For instance, there are three subvarieties of HLA class-I molecules, called A, B, and C; each of us has two of each type, one from each parent. The number of known variants (called “alleles”) are, A: 85; B: 185; and C: 42.

  17. 17.

    Proving an inequality. A wiseacre once defined a mathematical physicist as a person who knows that 2 + 2 lies between 3. 99 and 4. 01.

  18. 18.

    CD8+ T lymphocytes also secrete various cytokines that may have anti-viral effects.

  19. 19.

    In most of the medical literature a “model” means a disease in a laboratory animal that mimics the human affliction; i.e., in vivo rather than in silico.

  20. 20.

    The earliest proposal of “interspecific” rivalry, e.g., between parasite and host, as opposed to Darwin’s (and population geneticists’) intraspecific competition, may have been due to the 19th century Russian immunologist, Ilya Metchnikoff, a collaborator of Louis Pasteur.

  21. 21.

    Eigen and Schuster were revolutionaries, but not so much because they believed in a high mutation rate (which simply sets the pace of evolution), but rather because they left Fisher-type competition out of their models!

  22. 22.

    It was the precursor of the branch of analytical philosophy that later came to be called “logical positivism.”

  23. 23.

    The analogy to Austrian physicist Ludwig Boltzmann’s H Theorem, which proves that entropy in a dilute gas always increases, at a rate proportional to the deviance from a Gaussian law, is obvious. Fisher himself remarked, referring to the second law of thermodynamics, “It is not a little instructive that so similar a law should hold the supreme position among the biological sciences”. Boltzmann’s atomism was much derided by the arch-positivist, Ernst Mach, and therefore Fisher the geneticist was not an adherent to positivism.

  24. 24.

    Fisher noted the objection, remarking in a lecture in 1953, “Of course, for any particular species, it does not follow that it is gaining on its competitors and enemies…”

  25. 25.

    Etch-a-Sketch is a mechanical drawing toy invented by French inventor Andre Cassagnes and subsequently manufactured by the Ohio Art Company.

  26. 26.

    The “ordinary” bit apparently refers to a single independent variable, namely time, as opposed to “partial differential equations”, PDEs, which have more independent variables. Unfortunately, this peculiar usage—no one We know of can produce even an historical defense of “ordinary” or “partial”—resists being driven out by some more evocative phrase, e.g., “deterministic rate equations”.

  27. 27.

    ODEs achieved popular recognition with the success of James Gleich’s book “Chaos: Making a New Science” in 1987. The type of “chaos” described in that book, that can occur with just three compartments (which we mention several times later for pedagogical reasons), will not play a role in this book. Another kind of “chaos” will, in higher-dimensional infection models: namely, that due to heterogeneity in reproduction.

  28. 28.

    Louis Bachelier’s thesis contained the first mathematical treatment of markets, based on the assumption that price shifts are like random walks. This work is stunning for physicists, as it develops most of the theory of Brownian motion usually credited to Einstein; the shock is partially relieved upon noting the thesis adviser, and learning that Poincaré lectured on Brownian motion at the International Congress of Physics in Paris, in 1900.

  29. 29.

    In fact, Einstein admitted that he had no idea whether what he was describing was identical with “the so-called …Brownian motion”; what he wanted to do was to overthrow Mach’s positivistic rejection of the reality of atoms.

  30. 30.

    Trials of vaccines in monkeys often use 1,000 MID50s (1,000 times one monkey-infectious dose that infects 50 % of the time), in order to avoid wasting money and resources.

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    W. David Wick

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Wick, W.D., Yang, O.O. (2013). Introduction. In: War in the Body. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7294-0_1

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