Emerging viruses in the Felidae: shifting paradigms.
ABSTRACT The domestic cat is afflicted with multiple viruses that serve as powerful models for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these diseases have been studied for decades revealing detailed insight concerning transmission, virulence, origins and pathogenesis. Here we review recent genetic advances that have questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis (FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV) mediated immune impairment to domestic cats rather than other Felidae species. The most recent interpretations indicate important new evolutionary conclusions implicating these deadly infectious agents in domestic and non-domestic felids.
- SourceAvailable from: Jean Kaoru Millet[Show abstract] [Hide abstract]
ABSTRACT: Feline coronaviruses (FCoV) exist as 2 biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). FECV causes subclinical infections; FIPV causes feline infectious peritonitis (FIP), a systemic and fatal disease. It is thought that mutations in FECV enable infection of macrophages, causing FIP. However, the molecular basis for this biotype switch is unknown. We examined a furin cleavage site in the region between receptor-binding (S1) and fusion (S2) domains of the spike of serotype 1 FCoV. FECV sequences were compared with FIPV sequences. All FECVs had a conserved furin cleavage motif. For FIPV, there was a correlation with the disease and >1 substitution in the S1/S2 motif. Fluorogenic peptide assays confirmed that the substitutions modulate furin cleavage. We document a functionally relevant S1/S2 mutation that arises when FIP develops in a cat. These insights into FIP pathogenesis may be useful in development of diagnostic, prevention, and treatment measures against coronaviruses.Emerging Infectious Diseases 07/2013; 19(7):1066-73. · 6.79 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cytotoxic CD8+ T-cell immunosurveillance for intracellular pathogens, such as viruses, is controlled by classical major histocompatibility complex (MHC) class Ia molecules, and ideally, these antiviral T-cell populations are defined by the specific peptide and restricting MHC allele. Surprisingly, despite the utility of the cat in modeling human viral immunity, little is known about the feline leukocyte antigen class I complex (FLAI). Only a few coding sequences with uncertain locus origin and expression patterns have been reported. Of 19 class I genes, three loci-FLAI-E, FLAI-H, and FLAI-K-are predicted to encode classical molecules, and our objective was to evaluate their status by analyzing polymorphisms and tissue expression. Using locus-specific, PCR-based genotyping, we amplified 33 FLAI-E, FLAI-H, and FLAI-K alleles from 12 cats of various breeds, identifying, for the first time, alleles across three distinct loci in a feline species. Alleles shared the expected polymorphic and invariant sites in the α1/α2 domains, and full-length cDNA clones possessed all characteristic class Ia exons. Alleles could be assigned to a specific locus with reasonable confidence, although there was evidence of potentially confounding interlocus recombination between FLAI-E and FLAI-K. Only FLAI-E, FLAI-H, and FLAI-K origin alleles were amplified from cDNAs of multiple tissue types. We also defined hypervariable regions across these genes, which permitted the assignment of names to both novel and established alleles. As predicted, FLAI-E, FLAI-H, and FLAI-K fulfill the major criteria of class Ia genes. These data represent a necessary prerequisite for studying epitope-specific antiviral CD8+ T-cell responses in cats.Immunogenetics 06/2013; · 2.89 Impact Factor
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ABSTRACT: The feline immunodeficiency virus (FIV) shares genomic organization, receptor usage, lymphocyte tropism, and induction of immunodeficiency and increased susceptibility to cancer with the human immunodeficiency virus (HIV). Global distribution, marked heterogeneity and variable host adaptation are also properties of both viruses. These features render the FIV-cat model suitable to explore many aspects of lentivirus-host interaction and adaptation, and to explore treatment and prevention of infection. Examples of fundamental discoveries that have emerged from study in the FIV-cat model concern two-receptor entrance strategies that target memory T-lymphocytes, host factors that restrict retroviral infection, viral strategies for replication in non-dividing cells, and identification of correlates of immunity to the virus. This article provides a brief overview of strengths and limitations of the FIV-cat model for comparative biology and medicine.Veterinary Immunology and Immunopathology 01/2014; · 1.88 Impact Factor
Viruses 2012, 4, 236-257; doi:10.3390/v4020236
Emerging Viruses in the Felidae: Shifting Paradigms
Stephen J. O’Brien 1,*,†, Jennifer L. Troyer 2, Meredith A. Brown 3, Warren E. Johnson 1,
Agostinho Antunes 4, Melody E. Roelke 2 and Jill Pecon-Slattery 1
1 Laboratory of Genomic Diversity, National Cancer Institute-Frederick, Frederick, MD 21702, USA;
E-Mails: email@example.com (W.E.J.); firstname.lastname@example.org (J.P.-S.)
2 SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA;
E-Mails: email@example.com (J.L.T.); Melody.Roelke-Parker@nih.gov (M.E.R.)
3 Banfield Pet Hospital, 800 NE Tillamook Street, Portland, OR 97213, USA;
4 CIMAR/CIIMAR, University of Porto, Rua dos Bragas, 177, Porto 4050-123, Portugal;
† Present Address: Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg
University, St. Petersburg, 190000, Russia.
* Author to whom correspondence should be addressed; E-Mail: firstname.lastname@example.org;
Tel.: +1-240-446-1021; Fax: +1-301-662-1413.
Received: 1 December 2011; in revised form: 21 December 2011 / Accepted: 11 January 2012 /
Published: 7 February 2012
Abstract: The domestic cat is afflicted with multiple viruses that serve as powerful models
for human disease including cancers, SARS and HIV/AIDS. Cat viruses that cause these
diseases have been studied for decades revealing detailed insight concerning transmission,
virulence, origins and pathogenesis. Here we review recent genetic advances that have
questioned traditional wisdom regarding the origins of virulent Feline infectious peritonitis
(FIP) diseases, the pathogenic potential of Feline Immunodeficiency Virus (FIV) in wild
non-domestic Felidae species, and the restriction of Feline Leukemia Virus (FeLV)
mediated immune impairment to domestic cats rather than other Felidae species. The most
recent interpretations indicate important new evolutionary conclusions implicating these
deadly infectious agents in domestic and non-domestic felids.
Keywords: FIV; FCoV; FeLV; Felidae
Viruses 2012, 4
The aloof and elusive nature of domestic cats, Felis catus, the world’s most popular pet, is
endearing to some and exasperating to others. Including feral cats, there are 600 million to one billion
domestic cats worldwide, an astounding number for an animal that contributes little to nothing in the
way of work, milk or meat to the human endeavor. The domestic cat is the consequence of a
remarkable domestication experiment that commenced in near east Asia some 10,000 years ago, when
the shy and reclusive desert wildcat (Felis sylvestris) gradually morphed into the venerated, audacious,
and familiar human pet. Domestication processes began when Neolithic hunter-gatherers settled in
agricultural villages in a rich area of the Middle East we call the Fertile Crescent. These first farmers
cultivated wild precursors of corn, wheat and barley, while others herded and penned cattle, sheep,
goats and even pigs. The domestication strategy fed and clothed many more people than hunters could
support. Contemporaneously, the wildcats fed on scraps, befriended the settlers and began a legacy of
human companionship that is unprecedented in human civilization .
At first glance, the major benefit of cat domestication appears to be human companionship, but this
role is rapidly expanding to encompass issues in human health. Viral infectious diseases in cats have
patterns of evolution, virulence and pathogenicity that offer strong parallels to related viruses in
humans (Table 1). Feline coronavirus (FCoV), common in domestic cats, is a close relative of the
human SARS coronavirus that afflicted the world in 2003, when a reported 8096 infections
in 23 countries killed 774 people before the outbreak subsided . In the 1960’s, the discovery of
feline leukemia virus and its ability to recombine with host cellular oncogenes resulted in a better
understanding of numerous feline and human malignancies . Feline Immunodeficiency Virus (FIV),
first identified in 1986 as the causative agent of an AIDS-like syndrome in a California cat colony,
remains a compelling natural model of immunodeficiency pathogenesis, mirroring the HIV-AIDS
epidemic that has dominated the past human generation. Add to that feline calicivirus, feline herpes
virus, feline foamy virus and panleukopenia parvovirus; cat species provide a panoply of infectious
disease models for many devastating human diseases (Table 1).
Table 1. Examples of domestic cat viruses with human homologues *.
Feline Leukemia Virus (FeLV) 
Feline Immunodeficiency Virus (FIV) 
Feline Coronavirus (FCoV) 
Feline Sarcoma Virus (FSV) 
Avian H5N1 Influenza 
Feline Herpes Virus (FHV) 
Feline Foamy Virus (FFV) 
Feline Calicivirus (FCV) 
Feline Parvovirus (FPV) 
Feline Morbillivirus (CDV) 
* Many references exist for each virus in both cat and human, here we provide single references as examples.
Human T-Cell Leukemia Virus (HTLV) 
Human Immunodeficiency Virus (HIV-AIDS) 
SARS-Coronavirus (Severe acute respiratory syndrome) 
~20 Human Oncogenes 
Avian H5N1 Influenza 
Human Foamy Virus (No pathology) 
Human Calicivirus (Diarrhea, vomiting) 
Human B19 Parvovirus (Fifth disease) 
Human Morbillivirus (Measles) 
Viruses 2012, 4
In this review, we will attempt to highlight how recent advances in our understanding of three cat
viruses (FCoV, FIV, and FeLV) have revised conventional wisdoms. We illustrate how previous
tenets, based on limited available evidence, were revised and amended due to new insights from
genetic studies of cat populations.
2. Feline Coronavirus (FCoV) Pathogenesis in Domestic Cats
Feline infectious peritonitis (FIP) is a fatal, progressive, and immune-augmented disease of cats
caused by infection with feline coronavirus (FCoV). Coronaviruses are enveloped positive-stranded
RNA viruses that infect a wide range of vertebrate species . The clinical manifestation of FCoV
infection can present either as the pathogenic disease manifestation or feline infectious peritonitis virus
(FIPV) or the more common, benign or mild enteric infection (feline enteric coronavirus—FECV—
asymptomatic) [25,26]. Although FCoV is common in domestic, feral and non-domestic cat
populations world-wide (seroprevalence from 20–100%), less than 10% of FCoV seropositive cats
develop FIP [27-29]. Cats infected with FCoV that show no evidence of disease are thought to
represent chronic carriers of FCoV and may pose an FIP risk to other cats [27,30,31].
FIP pathology is characterized typically by severe systemic inflammatory damage of serosal
membranes and widespread pyogranulomatous lesions, occurring in lung, liver, lymph tissue, and
brain . Evidence suggests that the host immune system is crucial in this pathogenesis; both
profound T-cell depletion from the periphery and lymphatic tissues and changes in cytokine expression
are observed in end stage FIP [33,34].
Viral gene determinants likely play an important role in FCoV pathogenicity and virulence.
Coronaviruses are a large family of enveloped, single stranded, positive sense, non-segmented RNA
viruses. Characterized by a genome size roughly 30 kb in length, coronaviruses are the largest RNA
virus so far described . However, there is no effective treatment, vaccine, nor a diagnostic protocol
that can discriminate the avirulent FECV from the pathogenic FIP strains.
Conventional wisdom accepts the “in vivo mutation transition hypothesis” also called the “internal
mutation hypothesis” which postulates that viral mutations occur in healthy FCoV infected cats giving
rise to virulent virions that spread systemically and lead to FIP pathogenesis [36,37]. Although this
hypothesis has been widely cited [9,25,27,30,31,36–39] the precise nature of the mutation responsible
for pathogenesis has never been identified. Various studies have speculated that variants in the spike
protein, membrane protein, or NSP 3c  allow infection of macrophages, systemic dissemination,
and fatal disease manifestation [36,37].
An alternative “circulating avirulent and virulent FCoV hypothesis” suggests that distinctive benign
and pathogenic strains of FCoV circulate in a population, and those individuals exposed to the virulent
strains, with the appropriate predisposition, develop disease sequelae. Virological precedence for this
possibility has been reported for dengue fever virus and equine Venezuelan encephalitis virus, both of
which demonstrate circulating virulent and avirulent forms [41,42].
To test between these alternatives, Brown et al. compared the FCoV gene sequence patterns among
FIP afflicted cats and FCoV infected asymptomatic cats collected from households in Maryland
between 2004 and 2006 . Brown et al.  reasoned that a phylogenetic analysis of virogene
sequences would be informative in discriminating between the two hypotheses as follows: if the
Viruses 2012, 4
“circulating virulent-avirulent FCoV hypothesis” were the case, then a “monophyletic” pattern of
FCoV variation would cluster pathogenic cats separately from healthy cats, since a circulating
pathogenic virus would have accumulated mutations over time to drift apart from the avirulent FCoV
strain. Alternatively if the “in vivo mutation hypothesis” were the case, then FCoV from healthy and
sick cats would cluster together (paraphyletic inter-mixing) in accordance with geographic locale
(i.e., phylogeographic clustering), and not pathogenic virulence.
Brown et al.  inspected the phylogenetic clustering of four FCoV genes (pol replicase; spike,
membrane and NSP 7b; Figure 1) in 56 cats (8 FIP and 46 healthy) from Maryland catteries. The
results, illustrated by the phylogenetic analysis in Figure 1, were definitive in clustering the virus from
sick FIPV cats together in a monophyletic group, quite distinctive from the FCoV derived from the
healthy cats. In one cat (FCA-4590) that progressed from a healthy FECV positive state to FIP disease
over the course of two years, the recovered virus from the earlier time point clustered with other FCoV
-innocuous strains while the virus isolated when the cat showed disease symptoms clearly grouped
with genetically distinct virulent FIP strains, as if the innocuous FCoV were replaced by a second
virulent FIPV strain (Figure 1).
Brown et al.  interpreted these results as supporting the concept that there were at least two
distinctive circulating forms of FCoV in Maryland, one which caused FIP, and a second that did not.
Further, they identified certain amino acid signatures of the membrane gene that were diagnostic of
FIPV versus avirulent circulating FCoV in the feral cat population. Although these results would tend
to support the circulating variant explanation, they need to be replicated and extended to other
geographic locales to accurately reflect variation possible in the world’s 700 million cats. One recent
study documented paraphyly (mixing) of FIP and healthy FCoV infected cat strains in Europe, which
would seem to complicate the interpretation . Thus, current evidence would suggest that FIP
etiology is more complex than either hypothesis alone would suggest. Perhaps the causative mutation
has not been found because multiple mutations may result in increased pathogenicity. It is also
possible that some strains are more prone to these mutations than others; a situation that would mimic
the circulating avirulent and virulent hypothesis, as well as explain the results seen in Brown et al.
Future studies exploring both viral and host genetic determinants of disease in FIP [45,46], should
reveal opportunities for the management of this disease including the possible development of ante
mortem screening tools for genetic disposition for disease as well as the discrimination of virulent
versus avirulent strains of FCoV.
3. Feline Immunodeficiency Virus: FIV Pathogenesis in Felidae Species
Feline Immunodeficiency Virus (FIV) was first discovered 25 years ago [4,47] as a cat lentivirus
with structural, genomic, and pathogenic parallels to HIV [48–50]. Infected domestic cats develop
symptoms of immune depletion including a precipitous drop in CD4 bearing T-lymphocytes,
neutropenia, lymphadenopathy and susceptibility to normally harmless bacteria, fungal lesions,
wasting, and rare cancers. FIV is endemic in feral cat populations and has diverged into several
phylogenetic clade types across the world [51–55].
Viruses 2012, 4
Figure 1. Phylogenetic tree of cloned feline infectious peritonitis (FIP) membrane
sequences (655 bp) from 19 healthy (feline enteric coronavirus (FECV); green) and 8
symptomatic (feline infectious peritonitis virus FIPV; red) cats . One cat, Fca-4590,
was sampled when healthy and then at death caused by FIP. Shown is the maximum
likelihood tree constructed from 655 bp of the membrane gene. The number of FECV and
FIP cases followed by the number of cloned sequences is indicated in parenthesis. The
labels for each sequence include location W, Weller Farm; F, Frederick Animal Shelter; S,
Seymour Farm; M, Mount Airy Shelter; A, Ambrose Farm), 4-digit cat identification
number, tissue source (fe, feces; af, ascites fluid; co, colon; li, liver; sp, spleen; in,
intestine; je, jejunum; ln, lymph node), 2-digit year (e.g., 04 = 2004), and number of clones
for each sequence. Bootstrap values are shown (MP/minimum evolution/ML) above
branches. Where ML tree was congruent with MP tree, branch lengths are indicated below
branches; the number of homoplasies is in parenthesis after the branch length. Virus
sequence obtained from cat no. 4590 in May 2004 and at the time of death due to FIP in
December 2004. The transitional individual serial samples are indicated with open circles
(first sample) and solid circles (second sample). Scale bar indicates substitutions/site.
FIV has infected many of the 37 described species of the Felidae family  (Table 2). It is
speculated that most cat species (Table 2) acquired the virus within the last 10–20,000 years, but
patterns of evolution within both virus and host genomes, suggest FIV may have existed far longer in
some species such as lion [57,58]. Phylogenetic analysis of individual FIV-isolates in a dozen or more
Viruses 2012, 4
species of felids [7,58–61] demonstrates reciprocal monophyly of FIV among various species (that is,
every lion strain has as its closest relative another lion isolate rather than FIV from a different cat
species) (Figure 2). These phylogenetic results supported the notion that although FIV occasionally
can move from species to species [62–64], these events are exceedingly rare, leading to a
monophyletic expansion of viral genome sequence diversity within every species, so that most cat
species carry their own distinct version of FIV [65–68].
Table 2. Summary of FIV prevalence tested by western blot (AB) and PCR in Felidae.
Species Common Name
European wild cat
African wild cat
Chinese desert cat
Rusty spotted cat 0/1 
Asian leopard cat
Andean mountain cat
African golden cat
Asian golden cat
Viruses 2012, 4
Table 2. Cont.
Species Common Name
Bold numbers = congruence between AB and PCR; shaded = free-ranging “+”; bold letters = PCR
free-ranging “+” animals.
Figure 2. Maximum likelihood phylogenetic tree of 72 non-identical FIV from seven
carnivore species based on a region of pol-RT (420 bp) [7,58,65]. Circles indicate subtypes
within FIVPle, FIVPco and FIVFca lineages.
Originally, the absence of clear clinical pathology among FIV infected felids in zoological
collections, and field observations of seemingly healthy (or asymptomatic) FIV in natural populations
of felids fostered the view that FIV is pathogenic in domestic cats but not in other free ranging species
of Felidae [60,87]. However, that conclusion now seems premature and over-simplified. For example,
Roelke et al. . mounted a detailed physical examination and associated clinical measures among 64
free ranging lions in Botswana and Tanzania between 1999 and 2006. They examined a suite of
Viruses 2012, 4
biochemical, clinical, and pathogenic manifestations of immune suppression and disease analogous to
pathogenesis observed in FIV infected domestic cats, in HIV-infected AIDS patients and in simian
immunodeficiency virus (SIV)-infected macaques (see citations ).
Multiple indications and sequelae of AIDS defining conditions were manifest amongst FIV infected
lions compared to FIV negative lions; the statistical associations are summarized in Table 3. First, a
marked depletion of CD4 bearing T lymphocytes was apparent in FIV infected lions, a prelude
to immune collapse in well defined AIDS [88,89]. In addition there were multiple elevations
in opportunistic infections (papilloma, gingivitis, dehydration during wet conditions, anemia,
hyperalbuminemia, weight loss in the face of abundant prey, abnormal red cell parameters, depressed
serum albumin, liver pathogenesis, and elevated gamma globulin). Further, spleen and lymph node
biopsies from nine free ranging lions revealed evidence of lymphoid depletion, the hallmark of AIDS
disease in human, cats and macaques. These findings strongly suggest FIV is contributing to the loss of
immune competence in these lions. A similar pathogenic study of wild SIV-infected chimpanzees also
revealed definitive evidence of pathology in that species after a decade of pronouncing chimps as
resistant to SIV .
As most people infected with HIV do not actually die of HIV infection per se, rather from
subsequent opportunistic infections (e.g., pneumocystis, CMV, Kaposi’s sarcoma, candidiasis and
other infections) it seemed fair to ask whether FIV in large cats might contribute to secondary infection
pathogenesis. An opportunity to inspect this occurred during the mid-1990s in Tanzania when an
outbreak of canine distemper virus (CDV; a morbillivirus) eliminated ~1000 lions from the large
Serengeti populations in a 10 month interval . Because FIV prevalence in East African and
Botswana lions approaches 100% in adults, the potential influence of FIV on CDV pathology was to us
an interesting question.
Lions harbor six genetically distinct strains, or subtypes, of lion FIV (FIVPle) resolved by
phylogenetic analyses [57,58] (Figure 2). These strains have distinct phylogeographic distributions,
suggesting prolonged host association, perhaps predating the Late-Pleistocene expansions of lions
roughly 325,000 years ago . Two lion FIVPle strains, FIVPle E and FIVPle A, circulate in Botswana;
while three very divergent strains FIVPle A, B, and C occur in the Serengeti [92,93]. Perhaps
consequent of the highly social nature of lions, FIVPle infected lion populations have high prevalence
of seropositive individuals, approaching 100% in adult animals [7,57,92] (Figure 3a).
Troyer et al.  recently examined the association of FIV strains with relative survival (from
death) in the Serengeti lions during the CDV outbreak. A rather striking difference was seen in that
FIVPle B infected lions were twice as likely to survive CDV compared to lions infected with alternative
strains FIVPle A and FIVPle C (Figure 3b). The apparent FIVPle B associated protective influence was
evident whether individuals were infected with a single strain or with multiple strains (Figure 3b).
These observations would suggest that infection with FIVPle A or C might have increased the risk of
mortality upon secondary CDV infection. This inference that certain FIVPle strains predispose carriers
to CDV pathogenesis has some parallels with FIV strain-specific pathogenicity in domestic cats [95–97].
Further, the higher CDV mortality among of FIVPle A and C carrying individuals actually altered FIV
strain incidence causing a rise in FIVPle B and a drop in FIVPle C during the course of the CDV
outbreak (Figure 3c).
Viruses 2012, 4
Table 3. Medical conditions present in HIV, SIV and FIV infections found in FIVPle infected wild lions compared with FIVPle negative lions.
(Adapted from ).
% Affected # Individuals % Affected
Odds Ratio P Value
CD4 depletion Absolute number of CD4+ T-cells /mL in peripheral whole blood ±s.e. 0
Chronic Inflammatory Response
Erythrocyte sedimentation rate
(> 2 s.d. above mean)
Dehydration (> 4%)
Loss of Condition and Under Nutrition
Hair and coat abnormalities
Hypoalbuminemia (marker of cachexia) (serum albumin > 2 s.d. below mean)
Anemia (hemoglobin / PCV >2 s.d. below mean)
Cachexia/unexplained weight loss
Lymphoid response evidence
Histopathologic evidence: Lymphoid activation
Histopathologic evidence: Lymphoid atrophy & depletion
Observed in 3 FIV+ populations NA
<2 × 10−9
Viruses 2012, 4
Figure 3. Distribution, incidence and co-infection of canine distemper virus (CDV) and
FIV in Serengeti lions. (a) Map of approximate pride home ranges during the CDV
outbreak in April of 1994. Distribution of FIVPle subtypes by pride is shown here [87,93].
(b) Comparison of survival between lions with (dark grey) and without (light grey)
FIVPle-B. Shown here are Chi-squared p-values. Fisher’s exact two-tailed statistics are
significant all subtype configurations (p = 0.028) and approaching significant for single
subtype infection (p = 0.072). (c) FIVPle subtype distribution over time. Lions that were
alive at the beginning of the CDV outbreak (N = 91) were sampled either prior to April
1994, during the month of April 1994, or after April 1994. Most of the 1994 sampling
occurred in April after the peak mortality (approximate time shown here as a grey bar).
Knowledge of subtype frequencies prior to April 1994 is primarily from samples collected
from those animals in previous years. These regressions are significantly different
(p = 0.001).
Viruses 2012, 4
Figure 3. Cont.
The statistical rigor associated with these conclusions is rather weak since the number of lions was
limited (total = 119 lions) and should be interpreted cautiously. Nonetheless, the striking influence of
FIV on lion immune function (Table 3), clinical disposition, and a potential ancillary role in CDV
mortality (Figure 3b,c) affirms that FIV is likely pathogenic in lions. However, the degree to which
viral pathogenicity is influenced by host genomics underlying the immune response, the role of
Viruses 2012, 4
secondary infections, stochastic events due to ecological and environmental factors, has yet to be
described. Nonetheless, FIV is a potentially harmful agent in free ranging lions, as for housecats, and
deserves further scrutiny in the other free ranging species afflicted with FIV [88,94].
4. FeLV Outbreak in Free Ranging Florida Pumas
Feline leukemia virus, a retrovirus of domestic cats, displays a prevalence of 1–8% among feral
cats worldwide. Transmission is usually by direct contact, and outcome after exposure depends on
several host and viral factors. In approximately one third of exposed cats, viremia is persistent and
eventually results in clinical syndromes including some combination of immunosuppression, anemia
and/or neoplasia [5,98]. Mortality among persistently infected domestic cats is high as 83% die
within 3.5 years .
Like other Type C retroviruses, FeLV induces immune suppression making the cats susceptible to
opportunistic infections and cancers. There are four naturally occurring exogenous FeLV strains
FeLV-A, -B, -C, and -T, that are distinguished genetically by sequence differences in the env gene and
by receptor interactions required for cell entry . FeLV-A is the predominant subgroup circulating
in feral cats and is often only weakly pathogenic . The endogenous feline leukemia provirus
sequences are transmitted vertically though the germ line as integrated provirus nested on several cat
chromosomes. Among infected cats the pathogenic subgroups, FeLV-B, -C, and -T, are generated
de novo by mutation or recombination in the env region between exogenous subgroup A virus and
endogenous proviral sequences [5,102–104].
FeLV infection among non-domestic cats of the Felidae family is rare. Most reported infections
involved captive animals that acquired FeLV by physical contact with FeLV-infected domestic cats,
and in nearly all cases that were followed, the virus was cleared by the infected individuals [105,106].
Therefore, it was postulated that FeLV pathogenicity did not occur in exotic felids, simply because
there were no endogenous FeLV present in species outside the domestic cat lineage. The outcome with
a Florida panther FeLV outbreak in 2001–2006 was unexpected and served to change this hypothesis
The Florida panther (Puma concolor coryi) is an endangered subspecies whose range was
contiguous with other puma populations . By the late 20th century, however, depredation,
exploitation, human population growth and habitat destruction had reduced the population to an
isolated relict population of fewer than 30 individuals . In 1995, a Florida panther restoration
management action relocated eight Texas cougars (Puma concolor stanleyii) to the Florida habitat in a
hopeful rescue of the threatened subspecies. The population rebounded to over 100 individuals,
doubling panther numbers, density, survival parameters and fitness [110–112].
Florida panthers have undergone continued surveillance from 1978 -2001 and routinely tested for
several pathogens, including FeLV . However, for the first time in early 2001, 23 panthers were
discovered to carry antibodies for FeLV by ELISA that was confirmed by Western Blot. Clinical
symptoms including lymphadenopathy, anemia, septicemia and weight loss rapidly appeared. Five
panthers shown to carry FeLV antigens in their sera subsequently died of diseases compatible with
FeLV etiology [105,107].
Viruses 2012, 4
The rapid appearance and spread of FeLV in this Florida panther population was unprecedented
among large cats and caused concern in the Felidae conservation community. FeLV was not thought to
cause serious disease in species other than in cats closely related to domestic cats (F. catus,
F. sylvestris, F. margarita, F. nigripes and F. bieti) because only these Felis species carry endogenous
FeLV sequences in their genome, a prerequisite for in situ development of recombinant and virulent
FeLV strains [5,102,103,113].
To explore the origins and the unusual virulence of the emerging FeLV strain in pumas,
Brown et al.  obtained infectious FeLV gene sequence (LTR and env genes; 2851 bp) from
several FeLV-infected Florida panthers. Alignment and phylogenetic analysis of panther FeLV gene
sequences and those from known domestic cat FeLV strains revealed three important aspects: (1) The
panther FeLV was clearly aligned with FeLV domestic cat type FeLV-A, the strain that is largely
avirulent until after recombination with endogenous sequences; (2) There was no evidence of
endogenous FeLV sequences within in the panther FeLV; and (3) The panther FeLV was closely
aligned with a highly virulent FeLV from domestic cats, FeLV-945. Although FeLV-9545 is
considered an FeLV-A strain, it has a distinctive envelop and LTR sequence that are different from
other FeLV-A strains. FeLV-945 is unusual is that its severe pathogenicity in domestic cats does not
involve recombination with the endogenous FeLV sequences [114,115]. A vaccination campaign was
initiated in 2006 and 52 Florida panthers were captured and vaccinated with no major FeLV incidence
reported to date.
An interesting corollary to the Florida panther FeLV outbreak is that FIVPco is endemic in this
population. Two distinctive strains were present in 2001, one from the original authentic Florida
panther and a second accidentally introduced in 1995 from FIVPco infected Texas cougars. FIV
incidence in the population was low (~15% in 1999–2000; ). By contrast, 13 of 17 panthers tested
during 2004–2005 in the FeLV-endemic region (76%; Figure 1) were FIV positive [105,107]. This
apparent elevation in FIV incidence among FeLV afflicted panthers raises the possibility of a role for
FIV-mediated immune depletion in FeLV pathogenesis. In domestic cats, FIV and FeLV co-infections
have resulted in conflicting interpretations [116–121].
The conclusion here is that domestic cat strains of viruses can cross species barriers with potentially
devastating consequences to fragile wild populations of large felids. In this case, the requirement for
endogenous FeLV recombination was abrogated and perhaps the resultant virulence was accelerated by
FIV immune suppression in Florida panthers. As in lions, FIV depletes puma CD4-T lymphocytes ,
so the possibility of FIV accessory role is feasible. Unfortunately, a similar outbreak has recently
occurred in wild populations of Iberian lynx , confirming that FeLV is capable of causing disease
in non-domestic felids, contrary to conventional wisdom.
Early attempts to characterize the genetics, epidemiology and pathogenicity of feline viruses
established the following accepted paradigms in viral disease: that fatal FIP resulted from a simple
single mutation from the benign FCoV; that FIV was host-adapted and innocuous in non-domestic
felids; and that FeLV-related disease could only occur in species within the domestic cat lineage and
always resulted from recombination with endogenous FeLV. However, recent studies augmented by
Viruses 2012, 4
technological advances as well as increased surveillance of free-ranging cat species are revising these
perceptions. FCoV strains may have different virulence, pathogenicity, and predisposition to FIP
causing mutations; etiologies may be complex and different in different areas, cats may harbor
multiple strains throughout their life, and diagnostic genetic profiles may someday be available. FIV in
wild African lions, once considered benign, is causally linked with AIDS-related symptoms in some
individuals, and some strains may increase susceptibility to co-infection and mortality. Fragile relic
populations of Florida panther and Iberian lynx, once thought immune to domestic cat FeLV, are
highly susceptible to certain strains that are able to emerge in new host species. Thus, several
conventional paradigms have been unseated by recent studies of virus-host interactions in the wild.
Conflict of Interest
The authors declare no conflict of interest.
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