Carolyn SangokoyaProfessor Doug BrutlagGenomics and Bioinformatics9 March 2000Lessons from the Felidae: A Quest to Understand HIV and other Pathogenic Immunodeficiency VirusesFar from the limelight of the human and mouse genome projects, the FelineGenome Project is striking gold. Researchers at the National Cancer Institute's Laboratory ofGenomic Diversity in Frederick, Maryland expect to complete a genetic map far less detailedthan the those of the human or mouse, but equally (if not more) important and useful to the studyof human genetic diseases. The feline genome has proven to have an organization similar to thatof humans1. With cats and humans sharing almost 60 inherited diseases, including polycystickidney disease, diabetes, and certain common immune cell cancers, this genome should developinto a rich resource of genetic diseases that cannot be studied in mice2. Felines are also capableof similar infectious and acquired disease--- including its own version of AIDS, which is inducedby feline immunodeficiency virus (FIV)1. Surprisingly, however, the presence of FIV in wildcats does not cause AIDS. Seen in 25 felid species around the world3, this resistance to AIDSmeans that these cats may hold the key to fighting human deficiency virus (HIV) in humans byproviding an excellent model for understanding the evolutionary history of immunodeficiencyviruses, the coadaptation of virus and host, and approaches to intervention strategies againstlentivirus infections.Feline immunodeficiency virus was first isolated in 1986 from a domestic cat with AIDS-like symptoms-- an infection of the gut, skin lesions, respiratory tract infection, and wasting4.The owner brought the cat to Niels Pederson's lab at the University of California- Davis. At thetime, the only virus other than HIV known to attack the immune system's T-cells was Simianimmunodeficiency virus (SIV), a lentivirus that affects primates such as chimpanzees andmonkeys and is an immediate ancestor of HIV3. Pederson discovered the cat to have animmunodeficiency virus of its own, a virus belonging to a class known as retroviruses, whichinserts its genetic code into a host's DNA. FIV has been subsequently been found worldwide indifferent species of felidae. In 1989 Margaret Barr et al. at Cornell reported finding antibodiesto FIV in several captive exotic cats and in the wild Florida panthers5. In a search of over 2,000samples of frozen cat serum, Stephen O'Brien of the National Cancer Institute found that theprevalence of FIV among these was enormous3. Furthermore, it has been reported that thesewild members of the family Felidae (i.e., panthers, lions, and bobcats) harbor lentivirusesgenetically similar and morphologically analogous to FIV, but do not experience the AIDS-likesymptoms6. Thus the discovery of this pathogenic virus in so many different species (25) meansfirst that the virus is not new, and second, because it has not killed off the wild cat hosts,perhaps FIV has evolved over millennia into a symbiosis with its host.Because the FIV-infected wild cat species are healthy, the question remains as to whatdifferences among the viruses, their hosts, or virus-host interactions have determined this lack ofpathogenicity of FIV in various species6. By examining this feline virus, one can draw parallelsto SIV and HIV in relation to the delicate balance between pathogenic viruses and their hosts inthe outbreak of disease.Virus-host interaction is a major element in the study of pathogenic viruses and theirrelationships to one another. In studies of HIV and SIV, it has been demonstrated that variationsin the immune response of the host to the virus relate to pathogenicity. For example, unlikehumans, chimpanzees that are persistently infected with HIV-1 fail to developimmunodeficiency, suggesting a difference between the host species' permissiveness to thedisease, a factor that depends on how long the host has had to adapt to the virus7. Several strainsof SIVsm have been found which are not pathogenic in their natural hosts, sooty mangabey, butcause an AIDS-like disease when in contact with species that have no natural SIV infection, suchas Asian macaques7. The same can be seen in FIV, where the virus is currently pathogenic indomestic cats yet non-pathogenic in the wild species. A further parallel will show that HIV,which is currently pathogenic to humans, can someday become non-pathogenic and exist insymbiosis with the human host. This reasoning follows because the FIV sequence variation islower in domestic cats than in wild species2, illustrating, according to theory, that not enoughtime has been allowed for variety in this strain of the virus, thus its relatively large virulence.Moreover, HIV-1 has been in the human population for less than 100 years8, and its severitytherefore reflects the emergence of a new viral strain upon a large population that has no naturalinfection. The relative virulence of a pathogenic agent in this way may be determined by thelength of time that it has been available for coadaptation of virus and host populations. On the other hand, other elements can determine relative virulence. SIV studies havealso indicated that pathogenicity may be characteristic of specific virus-host combinations.While coadaptation of host and viruses in the African monkey species exists such that SIVinfection is widespread, yet non-pathogenic, macaques develop AIDS when infected with somestrains of SIV from sooty mangabey and African green monkey, but not from others8. Due to thefact the that these retroviruses mutate rapidly, the results of the macaque study may prove toshow that the SIV of the sooty manabey and African green monkey are "newer" strains than theone which the macaque has learned to live with. Thus host selective pressures on viralpathogenicity are another factor in differing virus-host interactions.Another lesson to be learned from the comparison of FIV, SIV, and HIV is thedetermination of the mechanism by which a host species becomes resistant to viral infection.The resistance is often already there among the natural genetic variation present in anypopulation6. It is through selective elimination of susceptible individuals and consequentincreased reproductive success of resistant individuals that the trait of resistance emerges and isnoted. A study has shown that long-time survivors of macaque SIV infection have higherantibody titers than macaques which succumb to disease
View Full Document
Unlocking...