The history of HIV is brief but dense. It is filled with aggressive debates, politics, human tragedy, a rich vein of research in medical science, and a dramatic change in drugs and tests in 1996 that translated immediately into better health and longer life.

AIDS was first described in 1981. The first report, of a small num­ber of gay men with pneumocystis pneumonia, was relegated to the sec­ond page of the Centers for Disease Control’s weekly bulletin.

AIDS is following the same history as the other newly detected mi­crobes of the past twenty-five years—Legionnaires’ disease, toxic shock syndrome, Helicobacter pylori, and Lyme disease. In each case, the dis­ease was described, the responsible microbe identified, the diagnostic test created, preventive strategies developed, and treatment, usually with an antibiotic, found. With the same approach and with the help of pub­lic health, many older infectious diseases have lost their menace. These diseases have been some of the great epidemics in the history of medi­cine: diphtheria, measles, mumps, whooping cough, polio, tetanus, rheu­matic fever, tuberculosis, nephritis, cholera, and typhoid fever. Twenty years ago, smallpox was eradicated throughout the world. This incred­ible success story, however, may have established an unrealistic expec­tation that faced with a new microbe, modern medicine wins easily. Still, the precedent is established, and if the plague is bad enough, the com­bined efforts of public health, medical research, and medical care will succeed.

HIV has turned out to be a formidable enemy. To begin with, many features of HIV infection are unique. One unique feature is its persis­tence. Once HIV is incorporated into the body’s genes, it stays there for the rest of life. Other viral infections—the herpes viruses, for instance— are also persistent, but unlike HIV, they are usually dormant. HIV is usu­ally in a state of constant growth.

Another unique feature is that HIV infection is primarily transmit­ted by sexual intercourse and injection drug use at a time when injection drug use is an epidemic and attitudes about sexual experiences are lib­eral. Asking people to modify their sexual behavior is a form of disease control that has never been successful. Asking people to stop their drug abuse is another sad tale.

Still another unique feature is that HIV attacks the very system de­signed to protect the body against attack. As a result, people with HIV infection are not usually sick because of the virus, but because of other infections that seize the opportunity presented by weakened immune de­fenses. In addition to these unique features, HIV is also formidable be­cause it has an extraordinary rate of mutation. By midstage in the in­fection, the average person has a million different forms of the virus; by late stage, over 100 billion different forms. Any virus with this property changes its appearance so fast that no single vaccine or drug is likely to target all variants; influenza virus has the same property and therefore requires a new vaccine each year. The highly-publicized problem with antibiotic resistance happens with HIV just as it does with common bac­teria. Thus, some of those mutant strains of the virus will be resistant to a drug designed to kill them and will flourish in its presence. The result is that many or most drugs directed against HIV are likely to be effec­tive only temporarily. The same problem of resistance applies to poten­tial vaccines.

In fact, most of medicine’s success in controlling infections with drugs has been with bacterial infections rather than viral infections.

Despite these difficulties, however, progress in the war on AIDS has been substantial. The first drug, AZT, was found effective in 1986 and approved shortly thereafter, in 1987. In the next few years, a series of related drugs followed: ddI, ddC, d4T, and 3TC. All these drugs worked, but only temporarily: clinical trials between 1986 and 1994 showed that these drugs extended life by six to twelve months at best. Further trials between 1993 and 1995 showed that two of these drugs taken together worked better than one. But progress was clearly slow, the available drugs flawed, and the challenge high. Professional meetings on HIV in­fection were filled with smug satisfaction about progress in preventing complications and with boring and somewhat unconvincing presenta­tions about drugs named with letters and numbers.

So in 1996, with the stunning changes in managing HIV infection, the optimism was unprecedented. Three interrelated developments came in rapid sequence. First was the demonstration that in the average per­son, HIV produced 10 billion new viruses every day. This demonstra­tion not only clarified the central role of the virus in causing AIDS and its complications, but it also implied that the virus had to be the target of any therapeutic attack. The second development was viral load test­ing, a new method of determining prognosis and response to treatment. The viral load test meant that physicians no longer had to wait until their patients got drastic decreases in CD4 counts or pneumocystis pneumo­nia or wasting or even died to find out if the treatment was not work­ing. With viral load testing, the physician could tell within two to four weeks whether the drug was knocking back the virus. The third devel­opment was new drugs that, though requiring a complex regimen, were far more potent than their predecessors.

By 1997, the real progress of 1996 was obvious, and in cases of HIV infection followed to 2000, this progress continued. For the first time in the history of the disease, death rates from AIDS in the United States were down by 60 to 70 percent. Rates of hospitalization and rates of progression to AIDS were down by 60 to 80 percent. Rates of trans­mission of HIV from mother to baby were way down. AIDS wards throughout the country were running at 30 to 50 percent occupancy. And one life insurance company was bold enough to offer life insurance to people with HIV infection.

To a physician working in an HIV clinic, the shift of events was dra­matic. The typical office visit of 1995 was occupied largely by warnings: about complications, about the importance of preventing complications, about using CD4 counts to track the rate of decline. In 1996, the typi­cal office visit was an explanation of progress in the field, a description of treatment options, a discussion about when to start therapy, a review of drug toxicities, and viral load testing. For many of us, the new treat­ment was as close to a miracle as medicine ever gets. One patient had a CD4 count of 9, a late-stage complication with MAC bacteremia, and a life prognosis of six months; he now has a CD4 count of over 500 and has returned to work. Another patient who had wasting and had lost 50 pounds is now a weight-lifter. A young woman with PCP and a CD4 count of 4 in 1995 decided, despite her odds, to go on a respirator; she now has a CD4 count of 500, has had no detectable virus for eight years, and lives a healthy life.

These are not isolated exceptions. A statistical analysis in 2006 of a large population of people with HIV infection shows that on average, HAART lengthens life by 179 months, or about fifteen years.

What will come next is hard to predict for any human endeavor, but especially for the field of HIV infection. When the virus was first dis­covered in 1983, the idea that a virus could become an integral part of a human gene seemed highly unlikely. Even though we now know that’s true, still we’re able to control the virus. But we face big challenges.

• We have no cure. No one with HIV has ever eradicated the virus, either spontaneously or with antiviral drugs.

• The drugs are potent, but their regimens all require three or four drugs and a level of adherence not required in any other field of medicine.

• The drugs have side effects—fat redistribution, blood lipid prob­lems, diabetes—that can be long-term and that were a complete surprise and are still not understood.

• Resistance to drugs limits the treatment of every other infectious disease—pneumonia, sinusitis, tuberculosis, malaria, influenza, as well as HIV infection. By 2005 about 10 to 25 percent of new HIV infections were with strains of HIV that had at least one major re­sistance mutation.

• Everyone agrees that prevention is a high priority. We also have good evidence that so far, prevention efforts have failed. Although progress in treatment has been extraordinarily successful, progress in prevention has not. In the United States, the estimated number of new infections in 1990 was 40,000; in 2005 it was also 40,000. The rest of the world is no better: the global burden of HIV dis­ease is now double what the World Health Organization thought in 1990 that it would be by now. About one-third of people with HIV infection in the United States don’t know they have it and therefore continue risking transmission of the infection. Prevent­ing transmission by tracing the sexual contacts of people with the infection is standard practice for nearly all sexually transmitted diseases except this one.

Even though the future remains unpredictable, some high-priority developments are in process and are likely to change the field.

• Treatment simplification: Therapy will get easier. The first-line treatment will likely be reduced to one or two pills per day, and each pill will contain two or three drugs.

• Testing: Testing will get easier. The blood test to detect HIV, the CD4 cell counts, and the viral load tests are about as accurate as they can get, but they should become cheaper and faster. The re­sistance test still needs work: interpreting it requires special ex­pertise, and even then, the experts disagree. The current tests for “minority species”—that is, viruses that are hidden in the body that can cause trouble in the presence of the right drug—find only the dominant 80 percent and are being refined so they will find the other 20 percent.

• Drug side effects: We are likely to find the cause of the “metabolic syndrome”—the fat redistribution, the lipid problems, and dia- betes—and will find drugs without those side effects. We’ll also develop effective methods for predicting who gets those side ef­fects.

• Genetics: With the identification of the human genome, the field of genetics has exploded. So far, the explosion has not translated into the windfall of diagnostic tests and therapeutic drugs that ge­neticists promised, but fulfilling the promise is just a matter of time. For the field of HIV infection, genetics should eventually be able to explain why some people never get HIV despite hundreds or thousands of exposures; why some people who go untreated progress through the infection rapidly and others remain appar­ently well for twenty years; why some people have the metabolic syndrome side effect with certain protease inhibitors and others don’t; why 5 percent of people with HIV infection have unusual reactions to the drugs, like the abacavir hypersensitivity reaction, or the serious liver disease that can accompany nevirapine. Ge­netics determines the extent to which the immune system and drugs control HIV. So understanding genetics should dramatically improve the prospects for both a therapeutic vaccine and anti­retroviral therapy.

• Therapeutic vaccine: Since HIV infection first surfaced, efforts to develop a vaccine to prevent it have been extensive and well- funded. The effort has attracted the best immunologic scientists in the world and has resulted in amazing discoveries in immunology and vaccine strategies. But apparently the prospects for a preven­tive vaccine are little better now than they were in 1985. Hopes for a therapeutic vaccine—a vaccine not to prevent HIV infection but to control it—are much higher. A therapeutic vaccine would control HIV much the way the immune system does, once it rec­ognizes the virus. A good therapeutic vaccine would augment the immune response, and though it would not cure HIV infection, it would reduce or even eliminate the need for pills and the accom­panying nuisances of remembering them and suffering the side ef­fects.

• New antiviral drugs: HIV therapy began in 1987 with one drug, AZT, and now has over twenty; and the pipeline is rich with new drugs. Particularly important are the new classes of drugs, drugs that the virus has never seen and for which it has no resistance. The classes attracting the most attention are integrase inhibitors and attachment inhibitors.