The Coming Plague (77 page)
Authors: Laurie Garrett
Plasmids and transposons also had some influence over their own expression, once they gained entry into a cell. Many contained genes called integrons that integrated the mobile DNA into the organisms' genomes. Some had regulatory genes that could switch on and off both their own plasmid or transposon genes and key genes inside the microbial chromosome.
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In this way, DNA moved not only between various bacterial species but between entire families of organisms: between bacteria and yeasts, between plants and bacteria, between complex parasites and their hosts' cells.
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It required a very small leap of logic to conclude that retroviruses such as HIV, HTLV, and feline leukemia virus were originally transposons. Over time, these bits of mobile genes (in the form of RNA, rather than DNA) acquired various regulatory genes from the microbes they inhabited. With passing generations, they gained sufficient genetic sophistication to be able to manufacture hard protective shells or envelopes, inside of which would safely reside their RNA. This gave them, in Bernard Fields's lexicon, both payloads and delivery systems, allowing them to become viruses.
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Though dozens of different types of antibiotics had been in use against bacteria and some parasites since the 1940s, humanity had very few antivirals
at its disposal. As was the case with drugs aimed at bacteria, resistance was a critical problem shortly after introduction of the key antivirals: acyclovir, ribavirin, amantadine, foscarnet, ganciclovir, and the HIV drugs.
at its disposal. As was the case with drugs aimed at bacteria, resistance was a critical problem shortly after introduction of the key antivirals: acyclovir, ribavirin, amantadine, foscarnet, ganciclovir, and the HIV drugs.
By 1981 the U.S. genital herpes epidemic had reached crisis proportions in much of the world, so word of a drug that might cure the disease raised considerable excitement. Acyclovir, developed by the Burroughs-Wellcome pharmaceutical company, was a terrific success.
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The drug could prevent latent herpes viruses from resurfacing to produce genital disease, cold sores, shingles, and a variety of other disorders. Both in pill form and as a topical cream, acyclovir brought relief to herpes sufferers and was hailed as a revolution, much as penicillin had been four decades earlier.
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But even in the original promising studies, physicians noticed that cessation of acyclovir use could immediatelyâwithin less than twenty-four hoursâresult in a herpes surge, typically producing more severe disease in the patients than was seen in people who used placebos. That implied two things: the drug was unable to accomplish much more than forcing the virus to remain in hiding inside nerve cells, and it might be exerting selection pressure on the viral population that resulted in even more virulent pathogens.
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The drug could prevent latent herpes viruses from resurfacing to produce genital disease, cold sores, shingles, and a variety of other disorders. Both in pill form and as a topical cream, acyclovir brought relief to herpes sufferers and was hailed as a revolution, much as penicillin had been four decades earlier.
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But even in the original promising studies, physicians noticed that cessation of acyclovir use could immediatelyâwithin less than twenty-four hoursâresult in a herpes surge, typically producing more severe disease in the patients than was seen in people who used placebos. That implied two things: the drug was unable to accomplish much more than forcing the virus to remain in hiding inside nerve cells, and it might be exerting selection pressure on the viral population that resulted in even more virulent pathogens.
The most serious life-threatening herpetic ailment was encephalitis due to infection of the brain. By the late 1980s physicians all over the world were reporting horrendous herpes encephalitis relapses in their patients following cessation of acyclovir use.
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Well before acyclovir got the FDA's green light for commercial distribution in the United States, physicians close to its research efforts were worrying publicly about resistance. Some were even concerned about the chemical similarity between acyclovir and other available antivirals, saying that “the possibility of cross-resistance is at least worrisome.”
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Despite concerns about emergence of highly resistant herpes viruses, surgeons almost immediately began using the drug as a postoperative prophylactic much as they had long done with antibiotics,
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particularly for patients undergoing transplants and other procedures that required deliberate immunosuppression.
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particularly for patients undergoing transplants and other procedures that required deliberate immunosuppression.
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Scientists had long known that some herpes virusesâperhaps fewer than one in ten millionâwere naturally genetically resistant to acyclovir, meaning that even before acyclovir was invented, some of the viruses had an innate ability to outwit therapy.
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And researchers soon showed that resistant strains, once emerged and established within the human body, persisted for years, with or without continued use of acyclovir.
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And researchers soon showed that resistant strains, once emerged and established within the human body, persisted for years, with or without continued use of acyclovir.
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At the molecular level there were several different ways herpes viruses could become resistant to acyclovir, and it was clear that some mutations observed in clinical settings were newâthat is, the virus mutated during exposure to acyclovir. In many cases the viruses could become invulnerable with a simple point mutationâone tiny change in their DNA. The most successful genetic changes were those that affected one of two key viral
enzymes: DNA-polymerase, which the virus used to make copies of itself; and thymidine kinase, a chemical also crucial to viral replication. Mutations in these enzyme genes cost the viruses a great deal: they became resistant, but at the cost of some powers of infectiousness and virulence. The trade-off was overcome, in part, by the intermingling of the mutant viruses with normal ones that still possessed the powerful genes. So, for example, virus populations hidden inside human nerve cells would be protected from the drugs and the immune system until they were activated and exited their protective neural seclusion. The normal viruses would possess the genes that allowed that exiting process and warded off the immune system, while the less virulent mutants were prepared to survive acyclovir.
enzymes: DNA-polymerase, which the virus used to make copies of itself; and thymidine kinase, a chemical also crucial to viral replication. Mutations in these enzyme genes cost the viruses a great deal: they became resistant, but at the cost of some powers of infectiousness and virulence. The trade-off was overcome, in part, by the intermingling of the mutant viruses with normal ones that still possessed the powerful genes. So, for example, virus populations hidden inside human nerve cells would be protected from the drugs and the immune system until they were activated and exited their protective neural seclusion. The normal viruses would possess the genes that allowed that exiting process and warded off the immune system, while the less virulent mutants were prepared to survive acyclovir.
In 1992 British scientists warned, “There is a possibility that [acyclovir]-resistant strains of herpes simplex virus with epidemic potential eventually will emerge and reduce the efficacy of this drug. The time-scale for the emergence of such resistance is unclear.”
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That epidemic acyclovir resistance would eventually occur seemed an inevitability to most observers: the only issues were when and where. The answer, it turned out, was AIDS. Because of the overlapping epidemiological risks of AIDS and many herpes viruses, people battling the first disease often suffered horrible bouts of the second. AIDS physicians began in the late 1980s putting patients with histories of prior herpetic illnesses on prophylactic acyclovir, or treating occasional flare-ups of herpes with longer durations of the drug. Not surprisingly, by 1989 virulent acyclovir-resistant mutants appeared in AIDS patients.
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In 1990 an otherwise healthy twenty-seven-year-old American came down with genital herpes. Because his case wouldn't respond to normal acyclovir treatment, the young man came under the care of National Institutes of Allergy and Infectious Diseases physician Stephen Straus, a longtime acyclovir expert. Straus treated the ailing man with ever-higher doses of acyclovir, eventually stopping when he reached toxic levels that were six times that normally used to treat the infection.
It was the first time Straus had seen such a case in an otherwise immunologically healthy adult. The patient wasn't infected with the AIDS virus, and hadn't suffered any prior ailments or required surgery. The patient, who was gay, had three sexual partners during the 1990 period in which he got infected. One of the partners was dually infected with HIV and the mutant herpes virus. Straus believed that the herpes mutant had first developed in the immunocompromised HIV-positive man and then had been passed sexually to the unfortunate twenty-seven-year-old.
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The new mutant was distinctly dangerous because it had not traded off virulence for persistence. Furthermore, the mutant possessed the ability to resist another antiviral drug: ganciclovir. It was a multiply resistant, fully pathogenic virus that could be sexually transmitted.
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The new mutant was distinctly dangerous because it had not traded off virulence for persistence. Furthermore, the mutant possessed the ability to resist another antiviral drug: ganciclovir. It was a multiply resistant, fully pathogenic virus that could be sexually transmitted.
“And now my suspicion is that this [mutant strain] will become more
frequent, but the pace of that increase in frequency is unclear,” Straus said.
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frequent, but the pace of that increase in frequency is unclear,” Straus said.
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HIV-positive Americans and Europeans were treated to a pharmaceutical cornucopia that helped them survive one microbial onslaught after another. And many individuals were simultaneously taking more than a dozen different drugs. Furthermore, physicians who failed to control herpes infections in their AIDS patients using acyclovir often switched to drugs that were designed to treat other viral diseases. Ganciclovir and foscarnet, for example, were primarily used to treat cytomegalovirus (CMV), which commonly struck HIV-positive people. As acyclovir failures were increasingly reported, many physicians switched to the two anti-CMV drugs.
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Unfortunately, resistance to both ganciclovir and foscarnet quickly emerged among cytomegaloviruses that were infecting HIV-positive individuals. It was as if one plague of contagious immunosuppression was fostering a subset of mini-epidemics of viral resistance.
CMV resistance to ganciclovir or foscarnet seemed by 1992 to be an inevitable consequence of prolonged use of either drug in HIV-positive individuals. Physicians had to balance the need to control herpes and mild CMV infections during early stages of HIV disease against the necessity of having something in reserve that would still workâto which the microbes wouldn't be resistantâduring the final throes of AIDS. In particular, a significant percentage of long-term AIDS survivors would go blind, victims of CMV retinitis, if the viral strains in their bodies developed resistance to both drugs.
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As was the case with acyclovir resistance in herpes viruses, CMV invulnerability to ganciclovir and foscarnet was achieved by single point mutations in the viruses' DNA coding for either DNA polymerase or a key kinase.
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It was tempting to conclude that a commonality of mutation sites existed for highly divergent types of viruses. And, indeed, in 1993, physicians from around the United States reported treating patients who had foscarnet resistance in
both
their herpes simplex and cytomegalovirus populations. The resistance was of clinical significance, and in some cases the patients also suffered acyclovir-resistance, leaving doctors with no good treatment options.
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It was tempting to conclude that a commonality of mutation sites existed for highly divergent types of viruses. And, indeed, in 1993, physicians from around the United States reported treating patients who had foscarnet resistance in
both
their herpes simplex and cytomegalovirus populations. The resistance was of clinical significance, and in some cases the patients also suffered acyclovir-resistance, leaving doctors with no good treatment options.
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Further complicating decisions about the uses of these drugs were indications that the herpes-type viruses could directly stimulate the activation signals within the HIV genome, promoting production of more AIDS viruses. Seen first in test-tube experiments, the microscopic partnership between the viral species was confirmed in 1993 in studies of six gay men in Los Angeles who were simultaneously infected with herpes simplex-1 and HIV. Not only did the two viral species stimulate one another, but they shared cellular homes and intermingled so completely that a sort of hybrid virus âpart HIV, part HSV-1âappeared.
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The most notorious drug resister was the human immunodeficiency virus
itself. From the moment azidothymine, or AZT (trade name: Zidovudine) was introduced into use on AIDS patients it was clear that the window of opportunity for its utility was limited by the virus's ability to mutate into a resistant form. Initially thought to be an event that emerged in AIDS patients after two or three years of AZT use, it became clear that some strains developed resistance almost immediately following exposure to the drug. And there were indications that AZT-resistant strains of HIV could be transmitted from one person to another.
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itself. From the moment azidothymine, or AZT (trade name: Zidovudine) was introduced into use on AIDS patients it was clear that the window of opportunity for its utility was limited by the virus's ability to mutate into a resistant form. Initially thought to be an event that emerged in AIDS patients after two or three years of AZT use, it became clear that some strains developed resistance almost immediately following exposure to the drug. And there were indications that AZT-resistant strains of HIV could be transmitted from one person to another.
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Physicians followed the models already set for treating bacteria in the face of resistant antibiotics: they added on other drugs, either in sequence or in combination with AZT. So ddI (dideoxyinosine), ddC (dideoxycytidine), nevrapine, FLT (deoxyfluorothymidine), zalcitabine, 3TC (3-thiacytidine), and carbovir (didehydrodideoxyguanosine) were tried as alternatives or adjuncts to AZT.
Resistance emerged to all of them.
One thing the drugs shared was their target: the key enzyme used by HIV to make a DNA copy of its RNA genome, reverse transcriptase. As Howard Temin had shown during the late 1980s, HIV was one of the most mutable microbes on the planet. And the key to that mutability was the reverse transcriptase enzyme. Helpful mutations could persist for years, even be passed from one human host to another.
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Not surprisingly, there were soon HIV strains that were multiply resistant to AZT plus other antiviral drugs, or to combinations of ddI, ddC, and others.
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So grim was the situation that the head of San Francisco General Hospital, Dr. Merle Sande, threw his hands in the air in a deliberately dramatic gesture at a National Institutes of Health meeting and bellowed, “We need better drugs!”
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So grim was the situation that the head of San Francisco General Hospital, Dr. Merle Sande, threw his hands in the air in a deliberately dramatic gesture at a National Institutes of Health meeting and bellowed, “We need better drugs!”
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Such sentiments were echoed by doctors who were trying to treat influenza infections in acutely ill elderly individuals infected with amantadine- or rimantadine-resistant strains of the virus.
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In short, it seemed that viruses, because of their rapid reproduction rates and high degrees of inherent mutability, were even more likely than bacteria to find ways around the drugs humans threw at them. Piling on more drugs, or using drugs in higher doses for longer periods of time, hadn't prevented the emergence of untreatable bacterial strains. Why did pharmaceutical companies and physicians believe such tired old antimicrobial tactics could defeat viruses?
“You can't expect physicians to be concerned about public health,” Mark Lappé had opined one sunny spring afternoon in his Berkeley office at the University of California. It was 1981 and Lappé's book
Germs That Won't Die
had just been released. No one had yet heard of AIDS or drug-resistant clinical viruses or chlorine-resistant
Legionella
.
Germs That Won't Die
had just been released. No one had yet heard of AIDS or drug-resistant clinical viruses or chlorine-resistant
Legionella
.
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