From Viral Sex: The Nature of AIDS
(pp. 81-85)
by
© 1998 by Jaap Goudsmit.
Used by arrangement with Oxford University Press, New York.
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Editor's note: In Viral Sex, Jaap Goudsmit addresses some fundamental questions about AIDS, first among which is, where did it come from? Goudsmit, one of the world’s leading AIDS researchers, traces the origins of the HIV virus to a simian immunodeficiency virus (SIV), which has long infected various African apes and monkeys. SIV, however, causes no disease in its simian hosts. A devastating aspect of the virus, Goudsmit tells us, is that it practices "viral sex" - it not only produces offspring almost identical to the parents (as do most viruses), but, through sexual reproduction, can create a recombinant population of variants. These variants adapt easily to a new host, so the virus successfully transferred from simian to human, with the fatal results that have become all too familiar to us.
Goudsmit provides a fascinating and detailed account of how researchers have sought the roots of HIV, and tracked its movement from the African rain forest to the rest of the world. Here he describes some of the detective work involved in the search. Having determined a relationship between the type of HIV called HIV-2 and a variety of SIV (SIV sm) found in the West African sooty mangabey, researchers wondered what other SIVs might have given rise to HIV-1 (the culprit in the infections we see) and HIV-0, a more localized strain.
Could some other monkey or ape be the source animal for HIV-0 and HIV-1? Ever since AIDS emerged, researchers have favored this possibility but, despite much speculation, had no promising leads until the late 1980s. Then van der Groen and Piot decided to take action. Suspecting chimpanzees, they tested fifty wild-caught animals for HIV, hoping to detect SIV. Captured in different parts of the rain forest of Gabon, the chimpanzees were largely adult animals housed in the Primate Center of Gabon in Franceville. Only two animals, both preadult females, tested seropositive. They were infected but showed no sign of disease. The first, born in the rain forest of northwestern Gabon, was captured at six months by hunters who had shot her mother. (Unfortunately, commercial hunters usually kill the mother, as chimpanzees are extremely dangerous when defending their young.) The animal was acquired as a pet by a European family who lived in Gabon. The second seropositive chimpanzee was captured at age two when hunters killed her mother in the rain forest of northeast Gabon. The young animal was wounded and died a week later, so her virus was not isolated.
However, the virus of the first young chimpanzee was isolated in Antwerp. To encourage virus multiplication and facilitate isolation, infected cells from the animal were grown for ten days with uninfected human or chimpanzee white blood cells. Once isolated, the virus was labeled SIV cpz-gab 1 (i.e., first chimpanzee strain from Gabon) and examined by electron microscopy. Enlarged thirty-five thousand times, the virus looked like a member of the HIV/SIV family, but more exact proof was needed.
As we know, individuals infected with HIV generate antibodies that react (i.e., recognize and bind) to certain proteins of those viruses. Some antibodies react to envelope proteins embedded in the viral coat. Others react to proteins at the inner core of the virus particle. HIV/SIV viruses vary widely in their envelope proteins but share many core proteins, conserved from the common ancestor.
When antibodies to core proteins of one virus react to those of other viruses, this cross-reaction proves family relationship. Studies have shown, for example, that HIV antibodies react to core proteins from the SIVs of sooty mangabeys and mandrills (SIV sm and SIV mnd). Studies in our lab have shown that sera of HIV-infected individuals react to the core protein of EIAV, a lentivirus of horses, but not to the proteins of lentiviruses of sheep and goats. This closeness of HIV and SIV to EIAV has provided an important clue to the family history that will be discussed in chapter 8.
So the Belgian group expected that HIV-1 and HIV-2 antibodies would react to core proteins of SIV cpz-gab1, and they were right. However, whereas antibodies to both HIVs recognized its core proteins, only HIV-1 antibodies recognized the envelope proteins of SIV cpz-gab 1. Their signatures were nearly identical, showing very close relationship and even suggesting that SIV cpz was the ancestor of HIV-1.
The Belgians subsequently found that core proteins of SIV cpz-gab 1 were recognized by antibodies in sera of a mandrill infected with SIV mnd. However, the core proteins were not recognized by antibodies in sera of an African green monkey infected with SIV agm. To complete the story these researchers then reversed the experiment. They asked themselves if sera from the infected chimpanzee would react with proteins of HIV-1 and HIV-2 and SIV mnd and SIV agm. They found that chimpanzee sera bound firmly to both core and envelope proteins of HIV-1. It bound only to core proteins of HIV-2, SIV mnd, and SIV agm. This provides strong evidence that SIV cpz is closer to HIV-1 than to HIV-2, and that SIV cpz and HIV-1 have the same origin - or that one originated from the other.
The Belgians made several striking discoveries. First, SIV cpz-gab 1 was closest to HIV-1 of all HIVs and SIVs then known. Second, this Gabonese SIV was only distantly related to HIV-2 and SIV mnd. Third, the SIV of sooty mangabeys was closer to SIV agm than to SIV cpz or SIV mnd. Final proof of the pudding came from preliminary genetic analysis. If seen as a strain of HIV-1, SIV cpz-gab 1 was highly divergent in the same way as HIV-0 but still within the family, just as SIV sm and HIV-2 are within the same family.
The identification of SIV cpz-gab 1 immediately launched a heated debate. Two hypotheses were advanced to explain the closeness of SIV cpz and HIV-1. A skeptical camp argued that this SIV was really a human virus. Either the Belgian group had inadvertently contaminated its cultures with HIV or the chimpanzee baby was infected on capture by an HIV-positive hunter. This skepticism was based on the fact that so few seropositive chimpanzees had been found (only two of fifty), and only one strain had been isolated.
However, the other camp argued the exciting hypothesis that SIV cpz-gab 1 was actually the ancestor of HIV-1. It had a very plausible explanation for why only two of fifty chimpanzees were SIV-positive. In general, adult chimpanzees cannot be captured alive without great danger, so hunters usually capture very young animals. Since we know that vervets, grivets, and other monkeys are SIV infected only after reproductive age, this may well be the case with chimpanzees. Although the fifty chimpanzees were between two and fifteen years old, virtually all were captured before reproductive age so, naturally, few were SIV-infected.
This argument may sound convincing, but the scientific community wanted more testing of viruses and chimpanzees, so the Belgians complied. Their next sample included forty-four wild-caught chimpanzees living in Belgium or the zoo of Abidjan, Ivory Coast. Luckily, one chimpanzee tested seropositive for HIV antibodies, showing SIV infection. He was a young male, approximately four years old, who had been brought illegally to Belgium from Zaire as a pet. When seized by customs officials at the Brussels airport, he was two or three years old. When his virus was isolated in Antwerp, it was called SIV cpz-ant. It was closely related to SIV cpz-gab 1 - but how closely? If too close, skeptics would dismiss both viruses as Belgian contaminations in the laboratory. Was the second virus different enough to confirm circulation of SIV cpz strains in the wild?
Evidence against lab contamination included the fact that the young male with SIV cpz-ant landed at Brussels with a two-year-old male that was seronegative. Ever since their confiscation, these two males have been inseparable cage-mates, but the seronegative animal has remained so. If lab contamination had occurred, it probably would have affected both animals. The two chimpanzees have now shared a cage for seven years, but the virus has not been transmitted in saliva, urine, feces, or even in blood exchanged during their occasional scuffles. Apparently only sex transmits this virus in nature, and the male with SIV cpz-ant was never introduced to the female with SIV cpz-gab 1. So it seemed the seropositive male had been infected in the wild, but suspicion remained, especially since both SIV cpz viruses had been isolated in the same laboratory. Finally, comparison of the viral genes ended all speculation. It showed that all the Belgian SIV cpz and HIV viruses were independent isolates, clearly related but distinct enough that all must be genuine.
A few years later, the Belgian work was further confirmed by independent researchers working in the United States. They were headed by Beatrice Hahn, who had left Gallo's lab for the University of Alabama at Birmingham. Her group found a third chimpanzee virus now called SIV cpz-us. Its host had died, so the virus could not be isolated, but genetic analysis of viral gene fragments from postmortem tissue showed that this chimpanzee virus was closely related to the two others and to HIV-1 and HIV-0 strains.
About this same time, the Belgians performed genetic analysis on gene fragments from the second Gabonese chimpanzee - the one that died of wounds a week after her capture in Africa. They identified a strain called SIV cpz-gab 2, bringing the grand total to four.
These findings should convince everybody that SIV circulates among chimpanzees in the wild, and that these viruses are harmless to the chimpanzee despite their close relationship to HIV-1 and HIV-0 viruses. Unfortunately, the chimpanzee studied by the Hahn group has a mysterious background. Nobody knows where it came from, and persistent skeptics have suggested that this chimpanzee, along with the Belgian chimpanzees, was not infected by SIV but by HIV acquired through inoculation with human blood.
This is actually not as far-fetched as it sounds. In the 1950s and 1960s, especially in Zaire, commercial hunters routinely inoculated newly captured baby chimpanzees with human blood to vaccinate these valuable animals against human diseases. The skeptics claim that such practices introduced HIV to chimpanzees, who now circulate the virus as SIV. This idea deserves mention but seems extremely unlikely given the genetic distance between the HIV and the chimpanzee viruses. The SIV cpz-ant and SIV cpz-gab 1 and 2 isolates show too much interstrain variation to have branched from HIV just a few decades ago.
Jaap Goudsmit is professor of virology and chairman of the Department of Human Retrovirology at the University of Amsterdam, the Netherlands.
Photograph by Michael K. Nichols/National Geographic Image Collection.
Endlinks
Recombinant HIV Subtypes Emerging - the author, at the 12th World AIDS Conference, focuses on the significance of viral subtypes to HIV disease.
Viral Diversity in AIDS: Origins and Implications - summarizes the opening session of the 35th annual Interscience Conference on Antimicrobial Agents and Chemotherapy concerning viral diversity of HIV in terms of both its origin and subsequent recombination. Free registration required.
Recombination in HIV: An Important Viral Evolutionary Strategy - a summary of HIV genetic recombination, including the origin of contemporary HIV clades.
HIV-1 Genetic Variability: Implications for the Development of HIV Vaccines - a discussion of genetic variability of HIV in light of the development of HIV vaccines.
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