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[ Also see A New Vaccinology for AIDS ]
[ Illustrations by Scott Bakal ]
But this seeming comfort is a dangerous delusion. As it turns out, we in the West have so far been spared infection with the same HIVs that are spreading elsewhere. The 1.5 million people infected with HIV in this country and Europe are only a small percentage of the 35 million to 40 million infected worldwide, and most of those cases--perhaps 25 million today--represent people recently infected in sub-Saharan Africa. Nearly all of them are afflicted by new subtypes of HIV-1, and nearly all such infections are associated with heterosexual transmission. Although the use of dirty needles or unprotected homosexual contact can also result in infection in those regions, these modes of transmission are of comparatively negligible importance.
So even as affluent, industrial nations deploy expensive therapies to cope with an infection that has struck a sliver of their populations, some of the world's most impoverished countries, where modern health facilities and practices are scarcely known, confront a virulent new epidemic. In parts of sub-Saharan Africa, the rate of infection in the general population is at least a hundred times the prevalence of HIV and AIDS in our own communities; for women and infants in the hardest-hit regions, the rate of infection is thousands, or even tens of thousands, of times higher. In some areas, nearly half of young adults are infected. The rate of infection has not yet peaked, but already in Zimbabwe and Botswana (the latter is among Africa's most economically successful nations, a regional leader in literacy and healthcare, and a country with little in the way of drug use), life expectancy at birth will be cut in half over the next 10 to 12 years, from perhaps 65 years down to about 33, solely as a result of this new AIDS epidemic.
Compassion alone ought to impel us to act, but if it does not, perhaps a review of HIV's frightening new eruption and its inevitable spread will. We need to determine to what extent the virus itself, as opposed to human behavior and genetics and chance, underlies this new AIDS epidemic, and to rethink our strategy for combating the disease.
EPIDEMICS AND EVOLUTION
In recent years, we have heard much about the rise of dangerous new infectious agents threatening to humans, ranging from the viruses that cause acute hemorrhagic fever to flesh-eating bacteria. Popular books, such as The Hot Zone and The Coming Plague, and movies such as Outbreak have made us beware the possibility that dangerous viruses may spread from species such as monkeys or rodents to humans, and from the tropical climates of Africa or South America to North America or Europe. Although viruses such as Ebola or Marburg can be deadly, they do not present much danger of widespread transmission, precisely because the infected individuals show very serious signs of that infection so soon after exposure, and because the diseases kill so rapidly. Only where a virus or other microbe infects someone for a long time before symptoms become evident will it be easily transmitted to a large fraction of the population. Among the newly emergent viruses infecting humans, of course, HIV is the classic example of such sub-symptomatic agents.
The frightening spread of HIV-1C is most pronounced in southern Africa. |
HIV apparently entered the human population within just the last 50 or 100 years; there is no evidence suggesting that these viruses were in populations of high-risk people even in Africa prior to the 1950s, for example. Both HIV-1--the "B" subtype found in the West and the other subtypes prevalent in Africa and Asia--and HIV-2, which infects less than a million people primarily in West Africa, appear to have originated in nonhuman primates.
Even as we have identified new viruses and microbes--recently including not only HIV, but the agents associated with human hepatitis B and C, the retrovirus associated with human leukemia, and the herpes virus associated with Kaposi's sarcoma--we have learned over the last 50 years that some infectious agents evolve very rapidly in association with the environment of their hosts. In some instances, rapid generation and selective survival of mutations lead to drug resistance--now a widespread problem, for instance, in treating malaria and tuberculosis. In other cases, evolutionary change enables the virus or other infectious organism to establish a course of lesser or greater virulence, or greater or lesser transmission efficiency, and thus to develop greater or lesser potential to cause major human epidemics. The classic example of evolutionary change involves the rabbit myxoma virus in Australia, where rabbits subjected to the disease as an agricultural pest-control measure rapidly evolved resistance to the virus, and the virus itself adapted so it became less lethal to the surviving rabbits; after all, a virus or microbe that exterminates its hosts soon finds itself without a home--an undesirable outcome in evolutionary terms.
Because this happens with most microbes and viruses over time, there is reason to believe that HIV may evolve in the human population. But for humans, who--unlike rabbits--do not have large litters at many intervals each year, the comparable immunoevolutionary adaptation--to attenuate the microbe or fortify the human population, or both--would probably take many hundreds of years. We cannot wait that long.
THE HUMAN IMMUNODEFICIENCY VIRUSES
Although hiv is a relatively small virus (it has 10 genes and only about 10,000 nucleotides or DNA "letters," while the smallpox virus, for example, has about 20 times as much genetic information), its structure and functions are nevertheless immensely complicated. Moreover, because the virus mutates very rapidly, its capacity for evading host resistance is amazing. These features make HIV the most important new infectious-disease challenge of the century.
All variants of the HIV virus have an outer surface with protein projections that are coated with sugar molecules. These protein projections attach to receptors on susceptible cells, including cells that touch the surface of the reproductive tract, where the infection takes hold, and cells in the blood, such as lymphocytes, that are destroyed when the immune response is compromised. As we have learned, the virus can quickly mutate the sugar-covered proteins on its outer surface, either to mask them so that an adequate immune stimulation does not occur, or to change them slightly so they can evade whatever immune response is mounted. That enables the virus to continue attaching to receptors on susceptible cells while defeating the surveillance mechanism of the immune response. The HIV virus can also evade immune detection by hiding in a latent, nonreplicating form within infected cells--a strategy also used, for example, by herpes viruses.
The estimated worldwide distribution of infections by HIV-1 subtypes, in millions of people, indicates the rapid eruption and virulence of the new HIV-1C epidemic. |
Complicating our understanding of HIV is its generation of distinct types and subtypes. But studying their diverse mechanisms and mutations may help us learn what we need to know to respond to the virus's effect on humans.
As an agent of human disease, for example, HIV-2 is less virulent than the HIV-1 family of viruses. Studies of female sex workers in Senegal show that HIV-2 is only one-fifth to one-tenth as easy as HIV-1 to transmit from person to person in West Africa. As few as 1 percent of infants born to mothers with HIV-2 become infected; for HIV-1 cases, a quarter to a third of infants become infected. And only a minority of individuals infected with HIV-2 actually develop lethal disease within 10 to 15 years, whereas almost everyone infected with HIV-1 develops lethal disease in that time period.
Although we know that HIV-2 originated from monkey species in West Africa, it is not yet certain how the HIV-1 viruses arose in populations of nonhuman primates. It is increasingly evident that HIV-1 as a group came into human circulation from populations of apes, such as chimpanzees, and it also appears that there have been multiple entries of the virus into people from different primates. It is also apparent that these HIV-1 viruses, so virulent and lethal in people, are not nearly so damaging in populations, such as chimpanzees, with which they have evolved; even inoculated chimpanzees rarely demonstrate signs of developing disease.
The five major subtypes of HIV-1 have appeared in different regions. HIV-1B is the virus of the West, HIV-1E of Southeast Asia, and HIV-1A and -1D caused the major epidemics of East and Central Africa during the early 1980s. The latter epidemics infected perhaps 2 to 8 percent of young adults who were at risk, and indeed caused quite serious epidemics in places like Uganda, which were then held up as examples of the disease at its worst.
Would that this were so. The HIV-1C epidemic that is blazing across southern Africa today is infecting a much larger fraction of local populations. Its prevalence and its rapid spread--the two are related--may reflect the genetic makeup of this type of the virus, and suggest its greater potential for causing larger epidemics than any other HIV the world has experienced before.
THE BIOLOGY OF THE NEW PLAGUE
This most important of the current hiv epidemics is being fueled by the highly efficient transmission of the HIV-1C subtype within the susceptible population. In the Republic of South Africa, for example, cities such as Johannesburg and Cape Town began to experience the same epidemic of HIV infection as the West did in the early 1980s, presumably as air travel enabled the virus to spread among high-risk populations, principally urban homosexual men. But during the early years of this decade, a new epidemic began, as HIV-1C spread by heterosexual transmission; already, the rates of infection considerably exceed the peaks recorded in Uganda a decade ago.
Now all of the countries in the world with the highest rates of HIV infection are in southern Africa: Namibia, Botswana, and Zimbabwe in a belt just above the Republic of South Africa; and then, with similar or slightly lower rates of infection, Swaziland, Lesotho, Zambia, Mozambique, and Malawi. All are experiencing the epidemic of HIV-1C. In each of these countries, heterosexual transmission is the only important mechanism for spreading the virus. Botswana was essentially free of AIDS as recently as the beginning of this decade. There and in Zimbabwe, 35 percent to 40 percent of all pregnant women are infected now; in some towns and villages, 50 percent are infected; and in young adults, aged 20 to 30 years, 45 percent to 50 percent are infected nationwide.
What causes such unprecedented rates of infection? Part of the answer may lie in the viral genome. HIV-1C is more likely than other subtypes to have a genetic determinant that causes it to interact with receptors expressed on cells that reach the surface of the human reproductive tract, such as those that line the vagina or the foreskin of the penis.
Beyond this enhanced ability to infect these cells, the protein products involved in activating the latent virus genome--inducing viral replication--have become enhanced, too. These signaling mechanisms are more robust in HIV-1 than in HIV-2, and more robust still in HIV-1C than in other subtypes. This is particularly true, and perhaps particularly important, for tumor necrosis factor alpha (TNF-alpha), a tissue substance released from diseased or damaged cells--for example, those affected by venereal diseases of the mucosa in the reproductive tract. Where such venereal infections are present, we see higher levels of this TNF-alpha in bodily fluids, especially vaginal fluids or semen. This substance is known to have an ability to activate production of HIV--and to do so more efficiently for HIV-1C than for other HIVs.
Given greater interaction with cells, and greater viral activation, we see with HIV-1C higher loads of virus in the body, the blood, and the reproductive-tract fluids; higher levels of excreted virus; and thus, in turn, higher doses present to expose uninfected individuals. All of these factors probably work together to enhance the chances that transmission will occur.
Presumably as a result of these higher rates of replication, HIV-1C viruses show higher rates of mutational drift than other forms of HIV. So despite the fact that this epidemic is considerably younger than the other epidemics, we see a wider range of gene differences among HIV-1C viruses than we see, for example, in all the 20-year history of the HIV-1B epidemic in the West or the epidemics of types -1A and -1D elsewhere in Africa. Given the higher rate of mutation, HIV-1C poses the potential problem of more rapid development of drug resistance--if and when drugs become available for treatment of infected individuals in southern Africa. This also warns us about how much more ominous HIVs of the next generation can become.
We also must recognize that within certain regions of Africa, portions of distinct HIVs are combining--joining the most successful genetic sequences--to form hybrid chimeric viruses at alarming rates. HIV-1C is already moving out to other regions by radial transmission--for example, to Tanzania, where it has become at least as prevalent as types -1A or -1D in places like Dar es Salaam. Quite remarkably, in places where all three types are present, hybrid chimeric viruses are forming in 40 percent to 50 percent of infected individuals. When people become infected with two HIVs at once and the viruses can replicate in the same cell, they reassort some of their genes, emerging with those genes that represent the best chance for virus fitness in the progeny. When this happens, we see that changes in the viral genome may preferentially occur in regions such as the gene that encodes for HIV's outer envelope--the part of the virus most involved in immune stimulation and in receptor attachment for infection of cells; quite obviously, the virus's ability to evade immune responses or alter receptor-attachment properties is a selection mechanism that the virus would like to maintain and improve. We also see such recombinations forcing selective retention of those regulatory regions of the viral DNA that are involved in activation of latent infection.
By any measure--ease of heterosexual transmission, infection efficacy, activation, and mutation or viral recombination--HIV-1C is already the cause of a powerful human epidemic, and a threat of worse to come.
A VACCINE STRATEGY
Turning from bench science to public health and medicine, how should we respond to the new AIDS epidemic in Africa? It seems clear that little or nothing can be done in the current scenario to treat the already infected population on a large scale with the best drugs. The usual drug therapies in the West cost $10,000 to $20,000 per patient per year, and are maintained for many years, if not for the life of the individual. Adherence to such treatment schedules appears to be surprisingly successful at saving lives--if infected individuals can successfully maintain themselves on such drug regimens. But even if the price of such drugs can be reduced quite substantially, how can the sub-Saharan nations hope to bear the cost when a third or more of their young adults are infected? In the West, the large burden of paying the bill, for a relatively small part of the population, is spread across most of the population of healthy, employed individuals. The demographic imbalance threatening Africa is starkly obvious even for more limited therapeutic options: suppose, as has been proposed, that HIV-infected pregnant women are given drugs in the months before they deliver, radically reducing the transmission of the virus to their newborns; in the most affected countries, it is realistic to expect most of those children to be orphaned within the next several years, as AIDS kills their parents.
So a logical approach would be the development of a vaccine. Indeed, even a poor vaccine--one that would protect, say, only 50 percent of exposed individuals, much as earlier versions of vaccines for tuberculosis or cholera did--could still save millions of lives in sub-Saharan Africa.
Vaccinology has undergone a revolution in the last decade. Many approaches to designing an HIV vaccine have received some serious research attention, and all are close to a point where they could and should be tried to see whether they offer some element of protection in regions where the epidemics are so devastating. Ironically, the very high incidence rates of new infection make it possible to test vaccine designs more rapidly (see "A New Vaccinology for AIDS.")
But we have to recognize that developing such a vaccine is unlikely to be a major goal of Western pharmaceutical companies. Their research is driven by the search for billion-dollar markets, not by products for which demand is much greater in the developing world--where people cannot pay. Given the likely cost of developing and testing an HIV vaccine--and the unlikelihood of its widespread use in the West if it proved effective in only a fraction of cases--there has been insufficient private attention to the issue of vaccine development, particularly for the epidemics that are so ominous in Africa.
Nor are single nations acting through their scientific research programs likely to be highly motivated to find a solution to epidemics in Africa. And international gatherings of national leaders are not likely to place health concerns for regions of the developing world among their highest priorities, or perhaps even on the agenda, given the usual focus on economic or political issues.
Yet we must remind ourselves that in the case of HIV epidemics, at least--and indeed for many other agents as well--infections like the outbreak of HIV-1C in southern Africa cannot be expected to remain geographically restricted for long. There are already indications that HIV-1C has crossed from Africa to western India, and a hybrid virus containing some of its sequences perhaps even to mainland China. So we have to predict that in the future--perhaps within four or five years, or perhaps in a relatively longer span of 15 to 30 years--viruses such as the new and more fit HIV-1C will also be a threat to the West. Addressing the problem as it exists now would, in the long run, benefit not only the developing-world populations already infected or at risk, but also ourselves. Neglecting the problem much longer may turn out to be a disastrous mistake.