Underground drugs are neither approved nor in the process of being approved by the FDA, but are widely taken without prescription by people with HIV infection. Underground drugs are claimed to attack HIV or to strengthen the immune system. The claims are not supported by clinical trials, sometimes only because the trials have not yet been done, sometimes because medical researchers are not sufficiently convinced of the drug’s potential merit to do a trial at all.     In most cases, underground drugs are not prescribed by physicians; people get them through sources like buyers’ clubs, AIDS activist groups, or associates in other countries. Because people with HIV infection feel an understandable need to have some control over their medical treatments, many physicians tacitly accept their patients’ use of underground drugs, provided the drug does no harm and provided it is not substituted for traditional drugs. Indeed, even the FDA seems to accept the existence of underground drugs, not by official endorsement, but simply by not vigorously attempting to stop their use.     Despite the passive acceptance of underground drugs, a word of caution is necessary. Underground drugs for HIV infection are often fads, hot today and gone tomorrow, that follow a distinct route. First, someone claims that the drug might do something desirable to HIV or to the immune system; next, the information spreads rapidly through the network of AIDS advocates; then, the drug is imported or made in basements and sent to large numbers of people; and finally, the drug is dropped because it has side effects, because clinical trials show it to be useless, or simply because enthusiasm fades. Numerous drugs have followed this route: ribivarin, HPA-23, and dextran sulfate are the most notable. All three drugs are now dead or near dead; but during their moment in the sun, hundreds or thousands of people went to Mexico for ribivarin, to Paris for HPA-23, or to Japan for dextran sulfate.     Dextran sulfate is a good illustration of the problems of underground drugs. The medical journal Lancet published the observation that dextran sulfate seemed to inhibit HIV in the test tube. The information spread widely; many people went to Japan, where the drug was available, to get it, and eventually buyers’ clubs imported massive amounts of it. The medical community, though never particularly impressed with the test tube data, thought it necessary to test a drug now being taken by thousands of people. The first round of studies showed that the drug was harmless even in large doses. The next round of studies explained the harmlessness: less than 1 percent of the drug, when taken by mouth, was absorbed by the body; over 99 percent of the drug went into the toilet bowl. Another round of studies was done to see if dextran sulfate would work when injected. The results showed that injected dextran sulfate not only didn’t work, but more HIV were present at the end of treatment than at the beginning.     The dextran sulfate story highlights the complicated interplay between medical researchers, AIDS advocates, and the FDA. In retrospect, all three parties seem to be acting in the best interests of people with HIV infection, and all three seemed to do what appeared to be right at the time.*191\191\2*

Probably the most difficult problem is that some people equate making love with getting sick. They worry about getting sicker themselves, they worry about making other people sick. They feel guilty having sex. They mourn the loss of the sexual life they once had. They feel violated by the virus; the virus invaded their bodies when they were doing something enjoyable and natural. And all these feelings come at a time when people intensely need the closeness that sexual intimacy brings. “We’ve seen couples pull apart,” said Dean. “We need closeness a lot more now.”     Another problem for some people is that they feel safer sex is no fun. Safer sex seems to detract from spontaneity and a feeling of relaxation. It sometimes seems to add a barrier of constraint or artificiality between partners.     In addition, some people not in long-term sexual relationships fear that if they meet someone they like, they will have to begin the relationship by telling that person something unpleasant to hear. Perhaps that person will respond by rejecting them. Perhaps that person will spread the information about their diagnosis.
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Mention the “natural environment” and most people think of the plants and animals that exist in places not yet overrun with humans. Our minds perceive the natural environment and the human environment as very distinct—an old-growth redwood forest is put neatly in one category and a New York City subway in the other. The natural environment in which we evolved consisted of savannas, meadows, and forests. Now we live in enclosures of steel, glass, plastic, and plaster. Most of the animals that share these unnatural environments with us—our dogs and cats—are domesticated; that is, they are different from their wild ancestors, genetically altered through human influences on their breeding. In this sense they are all unnatural. So too are virtually all the plants and animals we eat, whether or not their packaging dubs them “natural.” Many of us spend most of our waking hours looking through glass plates at the changing patterns of light generated by electrical current. It is easy to come to the conclusion that we have left virtually all of the natural world behind in our movement toward an ever more technologically sophisticated civilization.
That conclusion is wrong. We accept it because our perceptions of nature are profoundly biased by our size. Being large animals, we easily recognize all the organisms at the large end of the spectrum of life. We are hopelessly inept at recognizing in our daily experience the far greater number of organisms so small they cannot be seen with the naked eye. These microscopic organisms are parts of nature too. And when we moved from caves made of rock to caves made of wood, metal, plaster, and glass, we did not exclude them from our daily existence in the way that we excluded lions, wolves, eagles, and frogs. Some microbes have been added to our immediate environment as a result of our closer association with domestic animals over the past ten thousand years. Only a tiny minority have been excluded—those that were sufficiently harmful to us to make us care about them, and were sufficiently vulnerable to be knocked out by antibiotics or vaccines. The rest have come along for the ride, often changing, to be sure, but changing in ways that are not fundamentally different from the ways they have been changing throughout our quarter-million-year tenure as a species on earth.
Our intimate natural environment has always included an abundance of invisible organisms. Now we are familiar with the tiny minority that cause us obvious problems, and we are slowly but increasingly becoming aware of the rest—as microscopes make visible the invisible, and molecular techniques reveal their chemical footprints. Still, we continue to ignore microbial wildlife because most of it does not cause obvious problems for most of us.
This comfortable state of affairs is made possible by henchmen that mercilessly identify, tag, poison, blast, and eat the microbes that trespass on our biological turf. The number of these henchmen within each of us is greater than the number of people on earth, and they are organized into one of the most remarkable inventions that has graced the globe: the immune system. After studying the immune system for about a century, we still do not understand just how remarkable it is. Our minds, at least at present, have proved too feeble. Like the brain, the immune system stores information, communicates, and makes decisions. It also patrols, enforces, and attacks with an efficiency and ruthlessness that make the Gestapo look quaint.
The discovery of antibiotics is one of the great achievements of medicine. But these medications are like children’s toys compared with the extraordinary complexity of the immune system’s miniature enemy-detection sensors, communication systems, and teams of specialists. These specialists are more diverse and more flexible than the members of any police force. The best specialists are selected for the job. The numbers of these specialists are increased as necessary according to communiques from other specialists. New kinds of specialists are created when the old specialists do not quite have the right abilities. When the mission is accomplished, the force of unnecessary specialists is reduced to just a few of the best, who are poised to go through the whole process again more quickly if the same kind of adversary shows up.
These teams of specialists include individuals that make specific tags (antibodies) that are put on microbes so other members of the army (macrophages and other phagocytic cells) can recognize, surround, and capture each invader. The invaders are then disposed of with chemical weapons such as peroxide. Some specialists, such as the macrophages, take body parts of the engulfed pathogens and mount them on stalklike structures on their surface much like the victors in human conflicts mounted the heads of their victims on pikes. This “antigen presentation” sends a powerful message. Other cells, called helper T cells, contact the presented body part to see whether it fits their own recognition machinery. If the fit is tight, the helper T cell then reproduces itself prolifically; the progeny scout out other cells that can also recognize the specific enemy but have different talents at their disposal. When the helper T cell finds the same microbial body part on another type of immune cell, the helper cell says in chemical language, “Yes, you have found the enemy. Now use your particular expertise in the control effort.” Some of these other cells are demolition experts, called cytotoxic T cells, which then reproduce and move through the body to find infected cells. Infected cells will mount body parts of the pathogens on their surfaces, much as the macrophages do, but this mounting indicates their infected state—they are marking themselves for destruction. When a cytotoxic T cell with the right fit binds to the mounted body part, it blows up the infected cell.
One of the other major targets of the helper T cells are the B cells, which transform themselves into antibody-producing machines after contact with a T cell that carries news of a pathogen. The news is conveyed by an actual part of the destroyed pathogen that locks onto an antibody anchored on the B cell surface. The antibodies produced by these transformed B cells are the same molecule the B cells used to receive the news, but now they are released from the cell into the blood, lymph, and sometimes into the tears and saliva. When the antibodies encounter the pathogen part, they attach to it. When the pathogen part is still attached to an intact pathogen, the pathogen becomes coated with antibodies; it thus becomes recognizable by phagocytic cells like macrophages, which engulf and digest the mess.
Even with all the complex communication, mobilization, and destructive power, pathogens would still often overwhelm the immune system if the B cells of our fish ancestors had not evolved a clever trick hundreds of millions of years ago. The pathogens’ inherent advantage derives from their short generation time. The mutations and genetic rearrangements of infectious agents, coupled with their short generation time, provide them with a tremendous potential for staying well ahead of humans in the race between offenses and defenses and counterdefenses and so on. To deal with this disadvantage, the cells that generate antibodies play the pathogens’ game. They reproduce quickly, let loose with a high rate of mutations, and recombine the subunits of the instructions for specific antibodies, almost like replacing a few cards of a hand in a life-and-death game of poker. The newly invented antibodies are tested in the centers of lymph nodes to see if they work well. Almost none of them do. To nip the proliferation of bad ideas in the bud, the cells that came up with them are killed. But a few of the antibodies are better. The cells that produced them are allowed to live and encouraged to grow. The defense against the invaders improves. When the population of invaders is destroyed, most of the specialists that were marshaled are no longer needed and commit suicide; a few are left as memory cells to respond quickly should the same invader return.
This description, which only hints at the underlying complexity of immunological defenses, makes it sound as though these cells of the immune system have brains. Indeed, they act as if they had brains, but they do not. All the interactions are orchestrated by chemical signals and chemical responses. Chemical messages are released from one cell to another, across membranes, and to different parts within the cell to control the cell’s mechanical responses and its reading of genetic instructions. Individually, these defense cells do not have brains, but taken collectively, their ability to process and communicate information bears a surprising resemblance to the brain.
This magnificent immune system fails us sometimes because all this identification, communication, mobilization, reproduction, and fine-tuning takes time. While the immune system is performing these activities, the pathogens are busy reproducing and invading. Once the invasion is identified and the immune system mobilized, the outcome depends on how quickly the immune system can make up for lost time. When a novel pathogen is encountered, the time from the initial invasion to immunological control typically takes about a week. If the same invader is encountered by the person a month or a year later, the response time is much
shorter—typically a couple of days, thanks to the quick responses of the memory cells. It is so fast and effective that the person may not even be aware of the invasion. With the pathogen-host evolutionary arms race running neck and neck, the shorter time makes all the difference—the difference between illness and health, and sometimes between survival and death.
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