What was not conveyed above was that AZT as a stand-alone drug provided only a temporary victory in the war against HIV/AIDS. Reverse transcriptase and evolution provided an escape route for HIV to avoid AZT. Specifically, the virus could mutate ever so slightly until it found, by random chance, a mutation that was resistant to the antiviral effects of AZT. Whereas other viruses that remained sensitive to AZT were efficiency dispatched, nature allowed the drug-resistant mutants to persist. Such mechanisms are well known, as we have seen with the widespread development of drug-resistant variants of bacteria such as methicillin-resistant staphylococcal aureus (MRSA) or multi-drug resistant tuberculosis (MDR-TB). However, nature has conferred particularly powerful abilities upon viruses such as HIV.
More accurately, evolution generally conveys upon viruses error-prone means to replicate their genetic material. To put this in perspective, think back upon the earliest publishing industry, which recalls images of monks with bald pates reproducing copies of canonical manuscripts by hand. Occasionally, one encounters significant errors, such as the dropping of one key word that caused the so-called “Wicked” Bible to instruct its followers, “Thou shalt commit adultery.”57 However, such gross errors in humans, bacteria, and most other living creatures are subject to rigorous fact-checking, and errors are efficiently identified and removed.
A very different situation arises in viruses. Evolution has largely removed the constraints on error checking. Mistakes are thus actually encouraged as a means to adapt to ever-changing environments and the immune system. Whereas the error rate committed by human polymerases is something on the order of one mutation per every ten billion, the mistake rate for HIV is closer to one in two thousand.58 Some mutations cause minor changes, but the majority are fatal. The result is the production of many viral particles that are doomed from the beginning. At first glance, this might seem like a very inefficient strategy, as most viral progeny erupting from an infected cell are dead or ineffective. However, recall that each infected cell may put forth thousands of viruses. Consequently, each virus sprouting from an infected cell is substantially different from its brothers and sisters. This additional genetic diversity is useful in their harsh reality, where the entire world is out to get them. While such changes evolved to allow viruses to adapt to constant attack from the immune system and outcompete other viruses to infect the next wave of victims, this same system was also rather useful in contending with man-made assaults from antiviral drugs. Unsurprisingly then, while AZT and other RT inhibitors carried the day shortly after their introduction in the mid-1980s, by the end of the decade these medicines were rapidly at risk of being consigned to obsolescence.
In recognition of this losing battle against HIV (and other viruses), humans relied upon their strengths in technology and growing knowledge of how viruses attack and defend. Within months after the first clinical studies with AZT, scientists recognized that drug-resistant HIV viruses were emerging via simple Darwinian selection. What was to be done? Investigators at Rockefeller University, working with scientists at Merck & Co., realized a combined assault upon HIV with multiple drugs, each attacking a different part of the HIV life cycle, might provide a challenge that would overwhelm the ability of the virus to parry several attacks at once.59 Such an approach had already proven useful for targeting many cancers, another set of diseases characterized by a high rate of mutation/evolution. The approach was popularized and advanced by David Ho, a Taiwanese-born American researcher who was among the first physicians to encounter HIV/AIDS while serving as an internal medicine resident at Cedars-Sinai Medical Center in 1981. By 1996, the combination of multiple different antiretroviral drugs showed impressive results, and Ho was named Man of the Year by Time magazine.60 The impressive results of combination therapy, also known as AIDS Cocktail Treatment—a moniker that falsely conveys a convivial image—allowed a diagnosis of HIV infection to evolve from a death sentence to a long-term medical malady, comparable in some ways to a diagnosis of high cholesterol or hypertension.
The combination of different medicines to combat HIV/AIDS leads us to the next militaristic analogy, that of “collateral damage.” A fundamental advantage of drugs like AZT is that they are more readily taken up and used by the viral polymerase (RT) than by the enzymes involved in the host (human) DNA replication. However, some of the drug is indeed utilized by human cells, and this so-called leakiness often results in the killing of these bystander cells. Such realities explain the military analogy to collateral damage, because many normal cells are killed or damaged by most antiviral drugs, and the consequences can be substantial. For example, the side effects of antimetabolites such as acyclovir and AZT often mimic those more closely associated with cancer chemotherapy: gastrointestinal distress, bone marrow suppression (e.g., anemia and lowered blood cell counts), and, in some cases, carcinogenicity.61 Hence, the combination of multiple and different drugs is not without its own set of lifelong issues, though some improvements have been achieved by cutting back the dose of some of the components of day-to-day therapy. Despite these enhancements, the side-effect profile of antiviral therapy can decrease compliance. One example is a “drug holiday,” or taking some time away from the medicine, perhaps at a time when one is on an actual holiday and thus at a time when one wants to feel their very best. Just a few days before David Ho was named Time’s Man of the Year, an article from a Stanford University team revealed the perils of drug holidays.62 Drug holidays relieve the pressure on HIV; as the amount of drug tapers down (and is not replenished), the virus gets an opportunity to test new ways to avoid the medicines. When the holiday ends and drug compliance resumes, even a short period of days may be sufficient to allow some of the virus particles to become less sensitive to the drug. The Darwinian race restarts, and inevitably enough of the virus will become sufficiently resistant that it can subvert the effectiveness of the new medicines and continue its path of devastation. Unless drug holidays can be eliminated, which seems impossible, the idea that we can “cure” HIV/AIDS will inevitably be proven false.
As if our story weren’t already sufficiently disheartening, another compounding problem is that some viruses have the frustrating habit of become “latent.” One example is retroviruses such as HIV/AIDS. These viruses (of which HIV is but one member) have the annoying habit of incorporating themselves into the DNA of their hosts (you and me), where they can hide out for months, years, or even decades.63 Sometimes these endogenous viruses (endogenous is a Greek term meaning “inside genes”) remain within our genetic material for days, years and even generations. A recent estimate suggests that as much as 5–8 percent of human DNA is composed of proviruses, also known as endogenous retroviruses (or ERVs).64 This knowledge should not be the source of disproportionate angst, as it is unlikely that innumerable viruses will spontaneously erupt. Indeed, most of these ERVs are ancient or no longer able to become infective. Quite the contrary—as our understanding, as well as the raw count, of ERVs has increased, we increasingly appreciate that the evolution of humans (and all other species) has been greatly assisted by ERVs, some of which can transfer genes among individuals and, in some cases, across otherwise disparate species.
Another form of viral latency is characterized by diseases such as genital and nongenital herpesvirus infections, including shingles. In these cases, the viral DNA does not incorporate into our chromosomes but instead coils upon itself, like a snake biting its tail, into a structure known as an episome. These episomes can remain quietly within the cell interior (known as the cytoplasm) and occasionally spin off progeny from time to time to test whether the conditions are right for the virus to reemerge en masse. As discussed earlier in the chapter, the reemergence is associated with the intermittent periods of latent and active infection associated with both genital and nongenital herpes, which tend to hide away in nervous system tissues. An even more dramatic example arises with shingles, a disease caused by herpes zoster virus, the same pathogen that causes the childhood disease known as chicke
n pox. Zoster hides away in the large dorsal root ganglia near the spinal cord. The persistent insurgent frequently tests the ability of the body’s immune response to target the virus. Failed attempts by the virus to re-emerge and renew attacks upon the body occur constantly but are quashed by the immune system and rarely cause noticeable symptoms. Under conditions of a weakened immune system, the virus may evade detection long enough to break out (literally). An early raiding party may consist of relatively few virus particles, which form small bumps on the skin, hardly noticeable and not particularly problematic. As the disease progresses, the bumps become blisters that fill with pus and eventually break open, spreading the infection further, encompassing large patches of skin and causing painful eruptions that can last for weeks. These outbreaks fortunately tend to be contained to a ganglion (a single group of nerve bundles that radiate from the spine). Thus, shingles tends to occur in almost linear outbreaks that follow the major sets of nerves, remaining on one side of the body or the other. Given that the infection occurs within and near key nerve endings, shingles eruptions are particularly painful and rank among the most problematic issues for patients, as well as for people who care for those with immunosuppression, such as elderly individuals.
Fortunately for those with an intact immune system, the response to zoster virus can be boosted with a relatively new vaccine. This provides a segue to return from discussions of the immune system and its varied microbial enemies to the concept of vaccination. While the statement about drugs inevitably failing to cure viral infections remains unfortunately still relevant today, we do have one proven weapon that has demonstrated extraordinary ability to prevent or treat disease: vaccines. We now turn to these vital treatments and resume our discussion of vaccines with an examination first of passive and then of active vaccination.
6
A Sense of Humors
In the last two chapters, we began to introduce an array of microscopic pathogens capable of causing death and disease. The list is never-ending, as new pathogens are discovered at an accelerating rate and evolution ensures new pathogens will forever plague our species. New threats and old in the forms of exotic pathogens such as methicillin-resistant Staphylococcal aureus (MRSA), chikungunya, Ebola, Zika, and Marburg virus have grabbed headlines around the world and are the source of much anxiety. As the world becomes smaller, hotter, and more crowded, the conditions are set for encounters with ever more pathogens. We have also seen that the development of new therapeutic interventions against microbial threats is particularly challenging and often provides only temporary relief due to acquired drug resistance. Rapid-fire successes in developing antibacterial therapies from the 1930s onwards created a false sense of security that our species had conquered the microbial world, but this complacency has been shattered with the emergence of antibiotic-resistant “superbugs.” Worse still, our ability to combat viral diseases has never met expectations and, for the reasons detailed in the prior chapter, likely never will.
In contrast to the shroud of doom that currently pervades anti-infective medicines, rare, extraordinary, and enduring successes in the war between men and microbes have been achieved by vaccines. These vaccines were mostly discovered by mobilizing the immune systems of mice and men to recognize foreign invaders. We now return to the subject of the immune system.
You may recall from chapter 3 that the topic of immunology is extraordinarily complex. One subject not addressed in the earlier discussion was a key element of our body’s defenses: antibodies. The term antibody is widely known in popular culture, but it is not as well understood by many. These vital proteins are a key component of the milieu of biological substances that keep most people healthy and alive on a day-to-day basis. This chapter will focus on these magical substances that can alert the body to threats and then function as executioners. This subset of remarkable immune-triggering proteins conveys the ability to recognize virtually every molecule that has, can, or will exist in nature (and many others that do not).
Antibodies are the fulfillment of a concept known as a “magic bullet” as conceived originally by Paul Ehrlich. In 1878, the brilliant German scientist envisioned in his doctoral thesis hypothetical chemicals that could selectively target disease with exquisite fidelity and efficacy.1 This dream has largely been realized for eons by the immune system. More recently it’s been translated into modern medicine with the isolation or creation of these antibodies.2
As a means of understanding how and why antibodies and vaccines work, we will briefly recount a history of antibodies and distinguish how their isolation and use as medicines created an entirely new type of vaccine not envisioned by Edward Jenner (or even by Benjamin Jesty). Each one of us has the capacity to manufacture an extraordinary number (think of Carl Sagan’s catch-line of “Billions and billions”) of different antibodies. As we go through life, we encounter many potential threats to our well-being, including bacteria, viruses, fungi, and cancer cells. Antibodies provide one means the immune system has evolved to help distinguish and eliminate these potential threats (along with the cell-based treatments discussed above). Like the task facing T-cell, the complexity required to patrol for real and imagined invaders (bacteria, viruses, cancer cells, etc.) is enormous. Consequently, there must exist at least a comparable complexity in the ability of antibodies to recognize these manifold challenges.
The greatest strength and limitation of an individual antibody is that it can recognize only one small snippet of a chemical, cell, or protein. This site where the antibody binds its target is known as an epitope. One can only imagine the innumerable epitopes that exist in the natural world. As an analogy, there exist trillions upon trillions of different locks, yet the milieu of antibodies that each of us produces can serve as keys for each of these locks, and more.3, 4 Each of us contains the potential to recognize all potential types of foreign invaders, both real and imagined. The key word of this last sentence is foreign. As described previously, the body’s defenses are extraordinarily powerful. If directed against the body itself, an immune attack can kill quickly (such as an allergic bee sting) or slowly (as occurs with multiple sclerosis). Accordingly, antibodies that bind to “self molecules” (the cells, proteins, and chemicals that compose our bodies) must be identified and eliminated to avoid self-inflicted damage. The need to maintain extraordinary diversity to recognize “foreign” threats while not imparting collateral damage is the challenge confronting the body’s immune system. A sort of détente has been achieved through the process of evolution, which has devoted considerable energy and resources to the design and function of antibodies.
Antibodies are produced by B cells (more on these below). Each B cell in the body can create a different antibody, thus creating extraordinary diversity. How is this possible? At the most fundamental level, an antibody is a complex structure consisting of four different proteins, which are forged together in just the right way to form a structure with a striking resemblance to the letter Y. Each half of the Y is comprised of two proteins, a “heavy chain” and a smaller “light chain.” The heavy and light chains come together to form a dimer, a scientific term meaning a combination of two molecules. In turn, two identical dimers assemble into a full-sized antibody. Two arms of this Y-shaped structure are thus identical to one another and are the sites where the antibody binds to its antigens or targets. The third leg of the letter-Y will be discussed below but first, it is essential to point out how these target-binding portions of an antibody are generated and why they are able to recognize an extraordinarily diverse range of different molecules.
One tip on each chain of the four different proteins is known as the hypervariable region, a name that reflects a remarkable feature of these proteins. Whereas the chemical structure of virtually all other proteins is constant and hard-wired within an individual’s DNA, the hypervariable regions are intentionally capricious. Almost identical to the mechanism we described earlier to explain how T cell receptor diversity arises, the genes of antibody-producing
cells (known as B-cells for their initial discovery in an avian organ known as a bursa) rearrange and mutate to allow for an extraordinary number of potential targeting specifidies. As a brief recall, this feature arises because a handful of the protein combinations in these tips can include any of the twenty different amino acids that exist in nature. By having a relatively small number of such hypervariable sites, nature creates extraordinary diversity. Through a combination of random mutation and intentional reorganization, each B cell in the body has a slightly different variable region, both for the heavy and light chains, from that of their brother or sister B cells. For example, each person is estimated to produce something like one million million (a one with 12 zeroes behind it) different versions of a single antibody molecule.5
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