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									                         Feline Leukemia Virus
“Feline leukemia virus (FeLV) is a veterinary important disease. It is highly contagious and
                           causes immunosuppression in cats.”



                                    Written by:
                           Casey Maunder, Chiwah Lam,
                         Jaquenette McNeil, and Kali Maris

                                  Medical Virology
                                 Fall Semester 2006
                                University of Wyoming
            Contents (links on homepage):

 Introduction

 Epidemiology & Etiology

 Transmission/Exposure

 Pathogenesis

 Structural Characteristics

 Transmission

 Epidemiology and Exposure

 Clinical Signs & Symptoms

 Diagnosis

 Treatment

 Prevention/Control

 Vaccine

 Prognosis

 Geographical Distribution & Statistics

 Molecular Biology of the Virus

 Test Procedures

 Case Studies

 References and links

                                            2
Introduction

       Every year 1000s of domestic cats & kittens are euthanized based upon positive FeLV

testing. This is devastating to pet owners and although not 100% preventable, infection rate

can be reduced to less than 2% through conscientious vaccination regime and simple

preventive measures.

Epidemiology & Etiology

       Feline leukemia virus belongs to the Retroviridae family, genus Gammaretrovirus.

This virus exists in four sub types A, B, C, and T. FeLV–A is the most common of the three

and is found in all infected animals. FeLV-A is considered the least pathogenic although cats

infected with FeLV-A are at great risk of developing severe immunosuppressive disease.

FeLV-A recombination in vivo produces the other subtypes thereby making sub type A the

only transmissible form. Viral recombination leading to co infection of A with any one of the

other three can lead to a higher incidence of tumors or anemia associated with erythroid

hypoplasia.


Types of FeLV:

       The virus is broken into three groups based upon their occurrence and the effects they

have on the host. Infected hosts can have one, two or all types of virus.

      Group                 Occurrence                              Effects
     FeLV-A     occurs in all FeLV infected cats        causes severe immunosuppression
     FeLV-B     occurs in ~ 50% of FeLV infected cats   causes more tumors
     FeLV-C     occurs in ~ 1% of FeLV infected cats    causes severe anemia
     FeLV-T     new emerging sub-type                   causes immunodeficiency-inducing
                                                        cytopathic effects

                          (The Merck Veterinary Manual, 2006)




                                                                                               3
Transmission/Exposure

           Feline leukemia virus is a naturally occurring virus

and its incidence is a direct correlation to population

density. Infection rates are highest in catteries, multiple

cat households and cats that are free roaming; whether

feral or allowed outside access by owners.

           Persistently infected healthy cats are the major

reservoir of FeLV. Carriers excrete large quantities of

virus in saliva. There are up to 10^6 infectious FeLV

particles excreted per milliliter of saliva (Keller et al., 2005).

           The most common ways of contracting the disease (horizontal transmission) are by

nasal secretions (nose-to-nose contact), mutual grooming, shared food and water bowls, litter

boxes, sneezing, biting and blood transfusions.

           The most significant factor in resistance to FeLV is age. Infected queens spread the

virus (vertical transmission) to kittens during gestation, or shed virus in milk to nursing

kittens.

           Age and viral structure influence horizontal transmission in adult cats due to the

fragile nature of this enveloped virus.


Pathogenesis


           FeLV A is found in all FeLV infected cats and causes severe immunosupression.

FeLV B coinfection is found in 50% of FeLV infected cats and causes neoplastic diseases.

FeLV C coinfection is found in 1% of FeLV infected cats and causes severe anemia (Iyer,

2005).




                                                                                                  4
        FeLV related disorders include immunosuppression, leukemia, immune-mediated

diseases, reproductive problems, and enteritis. FeLV related immunosuppression causes

increased susceptibility to bacterial, fungal, protozoal, and other viral infections. Lymphoid

or myeloid leukemia develops in a third of FeLV persistent infections and the virus is

thought to also promote lymphoma in infected cats. Leukemia in cats is strongly associated

with FeLV infection that causes neoplasia in neutrophils, basophils, eosinophils, monocytes,

lymphocytes, megakaryoctes, and erythrocytes. Immune-mediated diseases include systemic

vasculitis, glomerulonephritis, and polyarthritis. Reproductive problems are common in

FeLV infected cats; over half of the infertile queens and queens that abort are FeLV positives.

Enteritis caused by FeLV manifests with clinical signs such as anorexia, depression, vomiting

and diarrhea (Merck, 2006).




                                            www.vet.uga.edu/VPP/clerk/iyer/index.htm

                                            Neonatal deaths associated with feline leukemia virus

                                            infection (image courtesy of Noah’s Arkive, the

                                            University of Georgia).




There are six stages of feline leukemia infections:

Stage 1: The virus enters the cat through the pharynx infecting the local epithelial cells,

lymphocytes, and macrophages. The infected white blood cells disseminate to lymph nodes

and begin to replicate.

Stage 2: Primary or transient viremia, a brief presence of the virus in the blood stream and

dissemination of the virus to lymphoid system.

Stage 3: The lymphoid system is infected and the virus further disseminates throughout the

body.
                                                                                                 5
                                          [Necropsy of FeLV infected cat showing acute hemorrhages in colon,

                                          serosal surface and regional lymph nodes (Cornell, 2006).]




Stage 4: The hemolymphatic system and intestinal tissues are infected. Unless the cat’s

immune system fights off the virus, the disease continues to develop into stage 5.

Stage 5: Secondary or persistent viremia is established. The bone marrow becomes infected

and releases infected neutrophils and platelets into the blood.



Stage 6: The cat body is overwhelmed by the infection and the virus starts to appear in

mucosal and glandular epithelial cells (Paustian, 1999).

       About 40% of the FeLV infected cats develop immunity and eliminate the virus, with

16% of these successful viral eliminations due to minimal exposure to the virus. The other

24 % confers resistance to the disease at stage 4, which occurs around 16-18 weeks after the

infection began. About 20% of the cats enter a latent stage in where reactivation of the

disease occurs when the cat becomes stressed. About 5-10% of the cats enter a sequestered

stage in which viremia is limited, intermittent, or even absent. The remaining 30% of cats go

through the disease from stage one to six resulting in death due to any of the feline leukemia

associated diseases (Iyer, 2005). Cats diagnosed with FeLV persistent infection may die in

months or stay asymptomatic for up to 4 years. FeLV cats that develop immunity to the virus

may shed infectious FeLV during the transient viremia lasting from one to two days and for

as long as eight weeks. FeLV cats with persistent viremia shed virus for the rest of their lives

and serve as a source of infection to susceptible cats (Paustian, 1999).




                                                                                                               6
       Rare secondary disorders associated with FeLV can cause neuropathy presenting as

hind limb paralysis and anisocoria (unequal size of the pupils). Moreover, cats with FeLV

are susceptible to other diseases, especially FIA (Feline Infectious Anemia or

Hemobartonellosis)




Clinical Signs and                                     Symptoms



                                                         www.lbah.com/feline/felv.html




       Symptoms of FeLV include fever, persistent cough, labored breathing, vomiting,

decreased weight, loss of appetite, mouth sores, and frequent infections. Besides these

symptoms, more severe signs of this viral infection may exist such as tumors, anemia,

enteritis with associated bloody diarrhea, and reproductive problems.

Diagnosis




                                                                                            7
       Cats presenting with the above-described symptoms, should be tested for feline

leukemia in clinic using the ELISA snap test. The ELISA is a solute-antigen test that detects

free antigen in fluid and is most reliable when serum or plasma is tested. The following are

the steps to run an ELISA snap test ( from www.lbah.com/feline/felv.html)


Specialized equipment and training is needed to accurately run the ELISA test. The bottle

with the dark blue top is the reagent used to start the chemical reaction needed to read the test.

A few drops of blood are all that is needed. The test kit the blood will be placed into is called

a Snap test, because the right hand side of it is snapped down to complete the test.




After being placed in the reagent solution, the blood is transferred to the diagnostic test kit

well. The blood immediately starts flowing towards the white circle in the center of the test

kit. It takes 30-60 seconds to reach the white circle




                                                                                                  8
When the blood flow reaches the center circle the kit is activated by pushing down on the

elevated area on the right side of the test kit. After a few seconds the blood starts flowing

back to the left.




The blood eventually flows all the way back to its starting point. After 10 minutes a blue dot

appears, signifying that this cat is negative for both FeLV and FIV.




The three different type of positive results that are possible:

                     FeLV Positive FeLV and FIV                FIV Positive
                                   Positive




There is an additional test for the FeLV called the IFA (Immunofluorescent Antibody) test

that checks for evidence of the virus in white blood cells. This test is used to confirm a

positive ELISA test, and it is indicative of a persistent infection. It is not used as an initial
                                                                                                    9
screening test like the ELISA test because it can miss the initial stage of virus infection in the

blood stream. The IFA tests for the presence of FeLV structural antigens (eg, p27 or other

core antigens; see below virus structure) in the cytoplasm of cells suspected to be FeLV-

infected. In clinical practice, peripheral blood smears are usually used for the IFA test, but

cytological preparations of bone marrow can also be used.


      PCR (polymerase chain reaction) PCR test detects FeLV provirus (DNA) and is
shown here.




       Often positive ELISA results can be found in asymptomatic cats this would then be

confirmed by IFA (immunofluourescent assay) or PCR amplification. Cats with negative

results and ymptomatic should also have IFA or PCR tests performed.

Tests performed in the WSVL:


The WSVL utilizes a rapid immunoassay (ELISA) for simultaneous detection of feline

leukemia virus (FeLV) antigen and feline immunodeficiency virus (FIV). Detection of FeLV

antigen is diagnostic of FeLV infection whereas the presence of antibodies to FIV indicates

that a cat has been exposed to FIV.
                                                                                                 10
Treatment:

       There is currently no cure for feline leukemia. However, it is possible for cats to

develop antibodies against the virus and fight it off on their own. There are some treatment

options for the disease, mostly aimed at fighting other infections that can occur in the

immunosuppressed-infected cat. These treatments are not to cure the disease, but to make the

cat’s quality of life better by treating other diseases caused by the viral infection. Antibiotics

can be used to fight off bacterial infections and cortisone has been used somewhat

successfully to reduce tumors in infected cats. Additionally, medications can be administered

that help to increase immune function including immunoregulin and interferon. Since

infected cats often have no appetite, they do not receive the necessary nutrients they need,

aiding to a weakened immune system. Vitamin supplements can be given orally to help the

cat replenish its exhausted nutrients. Feline leukemia causes pain and suffering to the host’s

owner, so because of this, many individuals choose to euthanize their cat.

       All regular vaccinations should be continued with killed virus except in the case of the

FeLV vaccine. Secondary infections must be addressed due to the limited immune response

of the animal. Antibiotics, steroids, vitamins, RBC enhancers, and immune stimulants are

recommended. Drugs that used in human medicine have had some success in treating cats

and in some cases, a 50% mortality rate was reduced by about 20%. These drugs include

AZT and Interferon Omega.

Prevention/Control

       Prevention of FeLV is simple, limit exposure, keep the cat inside, and follow the

vaccination protocol of a veterinarian. All new cats brought into the household should be

tested for feline leukemia and for those allowed indoor/outdoor access the vaccine becomes

necessary. In addition, the virus can be transmitted by fomites. Infected cats need to be

isolated and removed from the home. Contaminated food, water dishing, bedding and litter

                                                                                                11
boxes should be cleaned or discarded. The efficiency of the FeLV vaccine is approximately

80%.

Vaccine:

         There are several killed virus vaccines for feline leukemia virus that is very effective

and should be given to all cats and kittens that are not already infected, especially if the cat is

going to be around other cats. It can be given to kittens when they are 9 weeks old, with a

booster given 2-4 weeks later and followed by a yearly booster.




www.lbah.com/feline/felv.html                  www.winnfelinehealth.org/health/vaccination-

g...

Vaccines containing leukemia virus antigen (+/- other antigens) should be administered in the

left rear region (LR) according to manufacturer's recommendations.

FeLV      2 doses    1 year later,   Follow testing recommendations as published in the AAFP/AFM
killed    3-4 wks    then annually   Recommendation for Feline Retrovirus Testing. Recommended for
          apart;                     use in cats with high risk of exposure.
          1st dose
          > 8 wks;
          2nd dose
          >12 wks




Prognosis

         There is no specific treatment for feline leukemia and no known cure. Cats with

cancer associated with FeLV have an average survival time of six months.



Geographical Distribution & Statistics


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        Noted for its attack on felids, FeLV is one of the most devastating feline diseases

worldwide. However, the frequency of infection varies greatly depending on the cat’s age,

health, environment and lifestyle (Cornell, 2006). Furthermore, cats that are young or old, ill

and live outside have a 13% higher chance of becoming infected. Only about 3% of

American cats contract this disease (Harms, 2006). “Males are 1-1/2 times more likely to be

infected than females (Nash, 1997). Cats that have severe bacterial infections and cats with

toxoplasmosis will have a 50% and 75% chance of also having FeLV infections (Animal

Health Channel, 2006). Though these numbers are relatively high, the largest infectious rates

are in catteries and multi-cat homes. All and all this disease is very serious, and it is

estimated that less than 20% of infected cats will survive more than three years after being

infected (Saidla et al., 2006).




                                                                                               13
Molecular Biology of the Virus (from Principles of Virology (Flint, 2000)


 Retrovirus
 life cycle:




               (Attachment, uncoding, replication and release of FeLV virion)




Structural Characteristics

       Feline leukemia virus is a member of the family Retroviridae and has a single-

stranded RNA (ssRNA) nucleic acid. There is considerable diversity between various types

of retrovirus; the following is a generalized description of the particle. There is a universal

   Name               Protein                                 Function
 MA p12 p15      Matrix Protein        lines envelope
   CA p27        Capsid Protein        protects the core; most abundant protein in virus particle
   NC p10    Nucleocapsid Protein      protects the genome; forms the core
    PR              Protease           essential for gag protein cleavage
    RT       Reverse Transcriptase     transcribes the RNA genome
     IN             Integrase          integration of the provirus
   SU p70     Surface Glycoprotein     outer envelope glycoprotein; virus antigen
  TM p15E   Transmembrane Protein      inner component of the mature envelope glycoprotein
                                                                                                    14
nomenclature for retrovirus proteins:

        Table 1


The eight proteins above are necessary for replication. The SU glycoprotein is responsible

for receptor binding; the TM glycoprotein holds the SU glycoprotein to the envelope and is

responsible for membrane fusion. The MA protein is located inside the membrane and has an

amorphous shape and the CA

protein is also inside the

membrane and is icosahedral.


        Feline leukemia virus is a

tumor-causing virus (Cornell

University, 2006). This virus has




                                                                    Genome
     Outer Envelope
                                                                    Surface Glycoprotein
          Protease                                                  Transmembrane
                                                                    Glycoprotein

                                                                    Matrix
          Integrase
                                                                   Capsid
 Reverse Transcriptase
                                                                    Nucleocapsid

                                (Retrovirus: Generalites)
a simple linear genomic structure and survives in its host by suppressing the immune

response to the virus. The virus inhibits its host immune responses by using surface

glycoprotein 70 and transmembrane anchor protein 15 (Jarrett, 1999). Both proteins are

immunosuppressive agents and are coded by the env gene shown in this diagram and the table

1.

                                                                                             15
        Because this is a retrovirus, it carries the enzyme reverse transcriptase. By using the

viral ribonucleic acid (RNA) as a template, the reverse transcriptase is able to make a DNA

copy of the template and integrate that strand into the genetic material of the infected host

cell as a provirus.


        Feline leukemia virus belongs to the former genus oncoviruses. Recently, this genus

was re-classified by the International Committee on the Taxonomy of Viruses into four

distinct categories. Feline leukemia fits into the category gammaretrovirus. The genomic

structure of this virus comprises 5' and 3' long terminal repeats (LTR's) and three genes: gag,

pol and env; the total genome is about 9,600 base-pairs (Jarrett, 1999). Each gene encodes

for a particular structure shown here.


   Gene                                                Function

  gag                  encodes the core proteins of the virion: the MA (matrix), the CA
                       (capsid) and the NC (nucleocapsid)

  pol                  encodes the enzymes concerned with
                       replication and integration ( reverse transcriptase & integrase)

  env                  encodes the glycoproteins of the envelope
                       (surface glycoprotein SU & transmembrane protein TM)

The gene order looks like this: 5'cap -Simple -and- complex
                                       gag - pol env 3'poly(A).         retroviruses

    Retrovirus structure
    (generic)




                                         (Structure & Genomic Organization of FeLV &
                                         other associated simple Retroviruses)
                                gag, pol, and env
                                    Gag protein proteolytically processed into
                                          MA (matrix)
                                                                        16
                                   •NamesCA (capsid) MW
                                          are associated with
                                   •CapsidNC (nucleocapsid)
                                          of variable shape (conical in
                                         lentivirus)
       The infections of the four FeLV subgroups, FeLV A, B, C, and T are receptor specific.

Sampling and amplification of felid cDNA it was found that approximately 90% of the amino

acid sequences identified, share those sequences with human thiamine transport receptor 1

(THTR 1) (Mendoza, 2006). This study was done to test FeLV to determine any possible

transmission to humans. All studies done involving zoonotic properties of the FeLV viral

transmission to humans have been inconclusive.

Recent literature findings           From Principles of Virology,
                                     Flint 2004)
       -Endogenous FeLVs ( enFELV) may affect the pathogenicity of exogenous FeLVs.

Subgroup B FeLV, a recombinant between exogenous and endogenous FeLVs, may attenuate

infection with the nonrecombinant virus. On the other hand, the recombinant subgroup C

FeLV induces aplastic anemia in infected cats. Also, insertional polymorphisms in enFeLV

may contribute to the development of feline cancer (Roca, 2005).

       -Recently, two endogenous feline leukemia viruses, enFeLV-AGTT and enFeLV-

GGAG were isolated and sequenced, with prevalence of 8.9% and 15.2% respectively, in a

survey of domestic cats. The two enFeLVs, however, were not found in the genomes of

related species previously known to harbor enFeLVs. The result indicates these enFeLVs are

of recent origin and are replication competent (Roca, 2005).

       -An 11-month-old captive-bred male neutered bobcat (Felis rufus) was diagnosed

positive for feline leukemia virus. The FeLV isolate’s specific gag sequence was amplified by

DNA polymerase chain reaction (PCR) and aligned with known domestic cat FeLV’s. The

source of virus was suspected to be a domestic cat that was a surrogate nurse. FeLV in

nondomestic felids is rare. Introduction of FeLV virus into free-living populations could

have serious consequences; therefore measures to prevent the introduction of this virus to

nondomestic felids are warranted (Sleeman, 2001).



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                             References & Links
Aiello, Susan E., et al. The Merck Veterinary Manual. 8th edition. MERCK & CO., INC.
        National Publishing Philadelphia. 1998.

Animal Health Channel. Feline Leukemia Virus. 2006.

Cornell University College of Veterinary Medicine. Feline Leukemia Virus. 2006.
       http://www.vet.cornell.edu

Flint, S.J. et al. Principles of Virology. ASM Press. Washington, D.C. 2000.

Harms, Nicole. Feline Leukemia Virus. July 2006. http://www.associatedcontent.com

Iyer, D., LeRoy, B. E., and Latimer, K.S., and Moore. Feline leukemia virus infection – a
        review. College of Veterinary Medicine, University of Georgia, Athens, GA. 2005.
        http://www.vet.uga.edu

Jarrett, Oswald. Strategies of retrovirus survival in the cat. Veterinary Microbiology. 1999.

Keller, Gomes; Tandon, R.; Gonczi, E.; Meli, M.L.; Hofmann-Lehmann, R.; Lutz, H.
        Shedding of feline leukemia virus RNA in saliva is a consistent feature in viremic cats.
        Veterinary Microbiology. October 2005.

Leukemia virus in a Captive Bobcat. Journal of Wildlife Disease, 37: 194-200.

Mendoza, R., Maria M. Anderson, M.M., and Overbaugh, J. 2006. A putative thiamine
     transport protein is a receptor for feline leukemia virus subgroup A. J Virol. 80: 3378–
     3385.

Nash, Holly. Feline Leukemia. Foster & Smith, Inc. 1997.
       http://www.peteducation.comNational Center for Biotechnology Information (NCBI).
       August 1998. http://www.ncbi.nlm.nih.gov

Paustian, T. Microbiology and Bacteriology: The world of Microbes. 1999-2006.
       http://www.bact.wisc.edu

Roca, A.L., Nash, W.G., Menninger, J.C., Murphy, W.J., and S.J. O’Brien. Insertional
       polymorphisms of endogenous feline leukemia viruses. 2005. J Virol. 2005 April 79:
       3979–3986.

Roca, A.L., Pecon-Slattery, J and S.J. O’Brien. Genomically Intact Endogenous Feline
       Leukemia Virus of Recent Origin. J Virol 2005 April 78: 4370-4375.

Saidla, John E. and Jeffrey E. Barlough. Cornell Book of Cats. November 2006.
        http://www.vet.cornell.edu/fhc/

Sleeman, J.M., Keane, J.M., Johnson, Brown, R.J., Sue Vande Woude. 2001. Feline

Steinberg, Dr. Dietrich. Feline Leukemia. “Vet News & Views.” 2004.
       http://www.creatures.com
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The Merck Veterinary Manual. Feline Leukemia Virus and Related Diseases: Introduction.
      “Feline lymphoma & leukemia, Lymphosarcoma.” Merck & Co., Inc., 2006.
      http://www.merckvetmanual.com

The Murray Lab: Computational Biology. “Macromolecular interations in subcellular
      targeting.” http:www.maat.med.cornell.edu/retrovirus/gamma/FLV.html

Windy Hollow Veterinary Clinic. Disease Information.
      http://www.windyhollowvet.com/diseaseinfo.html

http://www.winnfelinehealth.org

http://www.vet.cornell.edu/

http://www.merckvetmanual.com

www.felineleukemia.orgwww.felineleukemia.com

www.animalhealthchannel.com

Picture references:
http://www.apetsblog.com
http://www.sxc.hu/photo
http://www.sciencemag.org/cgi/reprint/287/5459/1828.pdf
http://www.lbah.com/feline/felv.html
http://en.wikipedia.org/wiki/Polymerase_chain_reaction




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