As the sexual revolution of the 1960s was setting the stage for more enlightened public attitudes toward homosexuality, a strangely mutated virus may have crossed the species barrier from monkey to man in central Africa.
Two decades later, these events were linked by a mysterious disease that has been called everything from "the gay plague" to "the predominant public health issue of our time."
Known as acquired immune deficiency syndrome, or AIDS, it is caused by a virus called human T-cell lymphotropic virus, or HTLV-3. It first showed up in homosexual men in Los Angeles and New York in 1981. Since then it has infected between 600,000 and 1.2 million Americans and killed more than 6,000.
"We don't know its absolute origin, but it probably came into man very recently," says Dr. Robert Gallo, director of the National Cancer Institute (NCI) laboratory that isolated HTLV-3 in the spring of 1984 and showed that it causes AIDS.
"HTLV-3 probably entered man 20 years ago," says Gallo, although a close cousin could have existed in monkeys for 20,000 to 50,000 years.
How the virus jumped from monkey to man remains unknown, although other viruses, such as jungle yellow fever virus, have crossed the species line before. One hypothesis suggests that African green monkeys, which live in close proximity to humans, transmitted the virus by biting people.
There also are some clues to how the virus moved from Africa to America.
During the mid-1970s, there was a cultural exchange of some 10,000 people between Haiti and Zaire, both French-speaking countries, says NCI associate director Dr. Peter J. Fischinger. The virus may have crossed the Atlantic in that exchange and then moved from Haiti to New York after the island became a popular vacation spot for gay men.
But AIDS has yet to move strongly beyond the homosexual community in the West, in part because "this virus is not easy to transmit," Fischinger says. It has about the same infectiousness as hepatitis B, and is much less infectious than viruses that cause chicken pox and flu.
But comparisons end there. HTLV-3 is like no other human disease virus. It's a retrovirus, a type of virus that stores its genetic information in a chemical called ribonucleic acid, or RNA. Almost every other organism -- from virus to bacteria, fungi, plants, insects, fishes, birds and mammals -- stores its genetic information in deoxyribonucleic acid, or DNA.
That subtle difference is somewhat like recording a symphony on a vinyl record or a cassette tape. The same music can be recorded, but the way it is recorded and stored determines how it must be processed before it can be used.
The first evidence of the existence of a family of human retroviruses came out of Gallo's lab in 1978, while he was searching for viruses that cause cancer. These stripped-down bits of biological material exist somewhere below the level of organisms usually considered to be alive.
All viruses are essentially mindless replication machines geared to produce new viruses endlessly. To understand how they work, think of the floppy disks used in home computers. By itself, a disk is useless. It must be slipped into a computer before the information it contains can come alive. Once inside the computer, a disk can use the computer's machinery to replicate the programs it contains. These copies of its programs can be used in other computers and, in a sense, infect their memory banks with its information.
Viruses work somewhat the same way. By themselves, they are useless bits of genetic information without the ability to reproduce. They have to get inside a living cell before they can come alive and make copies of their genetic programs, which exist simply to make more viruses.
To enter a cell, the specially shaped protein coat of a virus must match receptors -- portals of entry -- on the cell surface. If a virus's protein coat fails to fit the cell's receptor -- as a key fits a lock -- no infection occurs.
The proteins that wrap HTLV-3 have a special affinity for helper T-cells, a master control cell in the body's immune system, its defense against foreign invaders. HTLV-3 also has been found in brain cells and other white blood cells.
To take command of the DNA-based T-cell, however, the RNA-based retrovirus must use a special enzyme called reverse transcriptase to translate its genetic information into the more standard DNA.
Once the HTLV-3 genes have been converted into chunks of DNA, they can become randomly integrated into the human DNA already in the cell. It's like randomly dropping 20 pages on making tacos into the middle of the maintenance manual for the B1 bomber.
"Retroviruses have the capability to become part of you," says NCI's Fischinger.
Once inserted, the HTLV-3 can lie dormant for weeks before it causes disease. Or it can lie quietly for a year or two or even 10 or 20 or 40. No one knows.
It is these periods of latency and occasional activation that may explain why there is such a long lag time between exposure to the virus and development of the disease. Typically, the latency period is two to five years.
To activate the HTLV-3 genes, a leading theory holds, the infected T-cells must begin to divide -- which they typically do when preparing to create more T-cells to fight some other infection. As the T-cells divide, the HTLV-3 genes become activated and begin making large numbers of new viruses. This destroys the T-cell and floods the blood with new viruses that go on to infect other T-cells.
"With HTLV-3, to do damage, the virus has to replicate and go from one cell to another," says Dr. Samuel Broder, NCI's deputy clinical director. "At each step, it has to go through the monotonous business of converting itself from RNA to DNA, and then to replicate and produce new viruses , it has to go from DNA back into RNA."
The HTLV-3 viruses continue to replicate and destroy T-cells until few remain and the host's immune system fails.
At this point, the victim has AIDS. The power of the AIDS virus is that it attacks the cells it should fear most: The white blood cells known as helper T-cells. The helper T-cell "is a regulatory cell, a command cell of the immune system," says NCI's Broder. T-cells play a pivotal role in mounting an attack by the body's defenses against an invader. "If you wanted to destroy the immune system with a minimum of work, you would design HTLV-3," Broder says. "If you damage the regulatory capacity of the T-cells , other cells in the immune system become lost."
To stop the destructive virus, Broder and others are searching for drugs that can interrupt HTLV-3's life cycle. Several of the drugs now under study seem to block the reverse transcriptase enzyme.
Since this enzyme is a viral enzyme with no human counterpart, it may be possible to selectively poison reverse transcriptase -- which would block the infection of new T-cells by preventing the conversion of the virus's genetic information from RNA to DNA. Previously infected T-cells would die and be removed naturally from the body.
At this point, there is no cure for AIDS. And no matter what therapies are used, says Broder, "I don't think it will be possible to treat HTLV-3 with short-term interventions. The virus may find a reservoir in some cells through genetic integration . It is hard to know when the virus may wake up and start replicating. It is going to be hard to absolutely clear this virus so it will never come back."
A number of other researchers are trying to develop a vaccine to prevent the initial HTLV-3 infection.
Vaccines work by alerting the immune system to telltale characteristics of a virus, specifically, the unique shape of proteins on the surface known as antigens. "A safe vaccine would be an antigen preparation," Fischinger says. "No one will feel comfortable inoculating with an infectious retrovirus."
But the HTLV-3 mutates at a rapid rate, in part, says Gallo, because "reverse transcriptase is an error-prone enzyme." These errors in translation modify the viral gene as it becomes integrated into the human genes, and these modifications change the viral proteins specified by these mutated genes.
The highest amount of variation seems to occur in the very proteins that would be targeted by a vaccine, which are called envelope proteins, Gallo says. Just as flu vaccines have to be updated every year because the strains of flu mutate so much that an old vaccine will no longer protect an individual receiving it, the same may happen with an AIDS virus.
Some estimates suggest that the mutation rate for AIDS viruses is 100 to 1,000 times higher than for influenza. Several dozen different strains of HTLV-3 already have been identified.
NCI's Fischinger, who oversees vaccine development, says the mutation of envelope proteins is making vaccine production more difficult. But scientists are looking for a portion of the envelope protein that does not change. If such a stable portion can be found, then it could be used to create a vaccine that would be effective against all strains of the virus.
"We now have vaccine preparations which have gone into monkeys, and we are getting responses," says Fischinger. "We are getting antibodies. Now we have to challenge the monkeys with the virus to see if their antibodies will be protective."
In the end, it all comes back to the monkeys.