Carolyn Sangokoya Professor Doug Brutlag Genomics and Bioinformatics 9 March 2000 Lessons from the Felidae A Quest to Understand HIV and other Pathogenic Immunodeficiency Viruses Far from the limelight of the human and mouse genome projects the Feline Genome Project is striking gold Researchers at the National Cancer Institute s Laboratory of Genomic Diversity in Frederick Maryland expect to complete a genetic map far less detailed than the those of the human or mouse but equally if not more important and useful to the study of human genetic diseases The feline genome has proven to have an organization similar to that of humans1 With cats and humans sharing almost 60 inherited diseases including polycystic kidney disease diabetes and certain common immune cell cancers this genome should develop into a rich resource of genetic diseases that cannot be studied in mice2 Felines are also capable of similar infectious and acquired disease including its own version of AIDS which is induced by feline immunodeficiency virus FIV 1 Surprisingly however the presence of FIV in wild cats does not cause AIDS Seen in 25 felid species around the world3 this resistance to AIDS means that these cats may hold the key to fighting human deficiency virus HIV in humans by providing an excellent model for understanding the evolutionary history of immunodeficiency viruses the coadaptation of virus and host and approaches to intervention strategies against lentivirus infections Feline immunodeficiency virus was first isolated in 1986 from a domestic cat with AIDSlike 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 the time the only virus other than HIV known to attack the immune system s T cells was Simian immunodeficiency virus SIV a lentivirus that affects primates such as chimpanzees and monkeys and is an immediate ancestor of HIV3 Pederson discovered the cat to have an immunodeficiency virus of its own a virus belonging to a class known as retroviruses which inserts its genetic code into a host s DNA FIV has been subsequently been found worldwide in different species of felidae In 1989 Margaret Barr et al at Cornell reported finding antibodies to FIV in several captive exotic cats and in the wild Florida panthers5 In a search of over 2 000 samples of frozen cat serum Stephen O Brien of the National Cancer Institute found that the prevalence of FIV among these was enormous3 Furthermore it has been reported that these wild members of the family Felidae i e panthers lions and bobcats harbor lentiviruses genetically similar and morphologically analogous to FIV but do not experience the AIDS like symptoms6 Thus the discovery of this pathogenic virus in so many different species 25 means first 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 what differences among the viruses their hosts or virus host interactions have determined this lack of pathogenicity of FIV in various species6 By examining this feline virus one can draw parallels to SIV and HIV in relation to the delicate balance between pathogenic viruses and their hosts in the outbreak of disease Virus host interaction is a major element in the study of pathogenic viruses and their relationships to one another In studies of HIV and SIV it has been demonstrated that variations in the immune response of the host to the virus relate to pathogenicity For example unlike humans chimpanzees that are persistently infected with HIV 1 fail to develop immunodeficiency suggesting a difference between the host species permissiveness to the disease a factor that depends on how long the host has had to adapt to the virus7 Several strains of SIVsm have been found which are not pathogenic in their natural hosts sooty mangabey but cause an AIDS like disease when in contact with species that have no natural SIV infection such as Asian macaques7 The same can be seen in FIV where the virus is currently pathogenic in domestic 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 in symbiosis with the human host This reasoning follows because the FIV sequence variation is lower in domestic cats than in wild species2 illustrating according to theory that not enough time 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 severity therefore reflects the emergence of a new viral strain upon a large population that has no natural infection The relative virulence of a pathogenic agent in this way may be determined by the length 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 have also 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 SIV infection is widespread yet non pathogenic macaques develop AIDS when infected with some strains of SIV from sooty mangabey and African green monkey but not from others8 Due to the fact the that these retroviruses mutate rapidly the results of the macaque study may prove to show that the SIV of the sooty manabey and African green monkey are newer strains than the one which the macaque has learned to live with Thus host selective pressures on viral pathogenicity are another factor in differing virus host interactions Another lesson to be learned from the comparison of FIV SIV and HIV is the determination 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 any population6 It is through selective elimination of susceptible individuals and consequent increased reproductive success of resistant individuals that the trait of resistance emerges and is noted A study has shown that long time survivors of macaque SIV infection have higher antibody titers than macaques which succumb to disease earlier6 which suggests that disease resistance correlates with strength of
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