Feline Immunodeficiency virus

By: Emily Nutt

Introduction

Approximately 1.5 to 3 percent of all healthy cats in the United States are infected with Feline Immunodeficiency Virus or FIV. Sick cats are even more likely to contract FIV since they have a 15 percent chance of contracting the virus [2]. FIV is a type of lentivirus, a retrovirus that propagates at a slow pace. This slow propogation causes a huge gap of months to years from when the cat becomes infected with the virus and when it begins to show symptoms. A more widely known lentivirus is that of Human Immunodeficiency Virus or HIV. Unlike HIV, FIV infects cats through biting that occurs during fighting. HIV and FIV infect their host T-cells in a similar manor because they are both retroviruses.

All retroviruses use reverse transcriptase to covert their RNA genome into double-stranded DNA, which is then transcribed and translated to create new virions. These types of viruses carry the protein reverse transcriptase in side the viron instead of an early gene being translated to form the protein. In fact the reverse transcriptase is already bound to the viral RNA with a primer attached before the virus infects the host cell [7]. Like all viruses, retroviruses bind a receptor protein on the host cell and fuse with the host membrane. Once the capsid has been uncoated the RNA is converted to double-stranded DNA through the reverse transcriptase. The new DNA copy then enters the nucleus and integrates into the host genome. At first the viral genome is able to replicate slowly only creating a few virions and thus not directly affecting the host. The host cell’s RNA polymerase and ribosomes create virions through transcription and translation of viral genes. The viruses are assembled and then bud out of the host cell to infect new host cells [7]. After sometime the host cell can then generate a large amount of virions, thus causing the host to show symptoms of immunodeficiency. However it is unknown how this process of rapid viral growth occurs and why viruses like FIV can infect the host for months to years without the host showing symptoms.

The structure and process of lentivirus infections characterizes the three stages of FIV infection. The first stage of FIV is during the first two to four months after infection when the infected cat shows signs of short term illness. The infected cat may show symptoms like increased body temperature, and enlarged lymph nodes [1]. This short term illness could be a result of early and sparse virion replication in the host. In the second stage of FIV, the cat appears completely healthy with no signs of illness. However in the third phase of the illness the cat expresses signs of a compromised immunsystem. Signs of immunodeficiency include; weight loss, inappetence, high body temperature, gingivitis, infected lymphnodes, and abnormal cell growth resulting in tumors [1]. The three stages of FIV are similar to that of the stages of HIV, both stages of infection are characterized by the retrovirus lifecycle. The genome of FIV reveals important viral proteins and thus potential vaccine targets, as well as showing how the virus evolved.. The evolution of the virus explains how both domestic cats and exotic or non-domestic cats were initially infected with FIV. The viral evolution also reveals how the virus has mutated to become specialized for each species of cat. Further analysis of the genome of FIV and how it relates to the evolution of the virus is described below.

The Genome of FIV

All lentiviruses are made up of several key genes; gag, pol, env, rev, orfA and vif. Gag and Gag-Pol create the core of the FIV virion. The gag protein is modified post-transcription to create proteins for the viral matrix, capsid, and nucleocapsid. The pol gene produces a protease, reverse transcriptase, integrase and a protease-like protein. The protease-like protein is not found in primate lentiviruses. However it is found in FIV and maybe used to prevent misincorporation of the viral genome. Other evidence suggests that the protease like-protein is needed for efficient growth of infected T lymphocytes [8]. The vif protein is conserved in both HIV and FIV, and plays a role in the latency of FIV infection in cats. The rev protein functions as a stability and transport of unspliced viral RNA molecules to the nucleus of the host cell. Open reading frame A or orf A is induces host cell arrest at the second gap phase of the cell cylce [3]. Only gag and pol are the genes are in the primary viral genome and it is only after splicing that the other viral genes are expressed.

Splicing plays a key role in the expression of env, rev, orfA and vif genes of FIV. The vif and env genes are created through a single splicing of the primary transcript, while the rev gene arises from multiple splicing events. The figure reveals the different splice sites found for the FIV genome. Part (b) shows the different splice donor sites (SD) and the splice acceptor sites (SA) as well as the spliced mRNA produced from the genome [8]. The numbers by the spliced products reveal the kilo bases of each RNA product. The 4.4 kb mRNA contains both the orfA and env open reading frame. The larger mRNA contains the complete orfA gene [8]. There are two 4.4 kilo base mRNAs in the figure both seem to produce env and orf genes, however the 4.4 kilo bases with a longer orfA mRNA contains the whole gene of orfA. The 1.4 kb mRNA contains the three exons of the rev gene. The mRNA with 5.2 kb contains the vif gene in the larger mRNA product. The 1.7 kb mRNA contains pieces of both orfA and orfB, however the exact products these mRNAs produce is uncertain [8]. Splicing of the viral genome allows for FIV to carry a smaller genome that produces many different genes. The gag and pol genes remain quite conserved throughout different FIV strains, however the other genes vary greatly between different feline immunodeficiency viruses. This difference in env, rev, vif and orfA between types of FIV is due to different splice sites on the viral genome.

Evolution of FIV

FIV is host specific making small mutations to evolve for each species of cat it infects. These mutations are typically occur in genes other than the pol gene. This gene is highly conserved in all lentiviruses because it contains the gene for reverse transcriptase a protein unique to all retroviruses [4]. Divergence in FIV genes changes the viral proteins, structure and function thus allowing the virus to evolve to be species specific.

Genomes of various FIV strains have been sequenced from the Felidae family and these FIV genomes are labeled by the species they infect. Several Felidae species are Puma concolor ( cougar), Panthera leo (African Lion), Otocolobus manul (Pallas cat), and Felis catus ( domestic cat). The strains of FIV that infect each species are labeled FIV and then the first letter of the genus and the first two letters of the species name that the virus infects. Thus FIV-Fca is the strain of FIV that infects Felis catus. The table reveals the gene divergence of Puma concolor, Otocolobus manul, and Felis catus from Panthera leo[6]. In general the table shows that there is more divergence in env, vif, and orfA genes of FIV-Ple from the other cat species.

FIV-Ple genome has the least divergence from FIV-Oma  genome, followed by FIV-Fca and the most divergence from FIV-Pco [6]. The similarities between FIV-Ple and FIV-Oma reveal that the two strains of the virus evolved from a common ancestor.  Compared to the FIV-Oma genome, the pol gene of FIV-Ple is most related to the pol gene of FIV-Oma. The env gene of FIV-Ple is least related to the env  gene of FIV-Oma.  The next closest relative of FIV-Ple is FIV-Fca. Despite the large genetic divergence between env of FIV-Fca and env in FIV-Ple, both env genes share two common sequences [6]. Two regions of env gene in FIV-Ple are very similar to the same regions found in the env gene of FIV-Fca. The only part of the env gene that is similar to FIV-Oma is the exon used for the rev gene. This variation of the  env gene reveals that recombination with FIV-Fca may have occurred. Recombination may also have occurred with another strain of FIV that has yet to be sequenced [6]. Scientists believe that a recombination event occurred in the  env gene of FIV-Ple because it is most divergent from the genome of FIV-Oma. Since FIV-Oma and FIV-Ple are so similar it is assumed they diverged from the same ancestor and thus should have more similar env genomes. However since the two strains do not have similar genes, then recombination during the evolution of FIV-Ple seems most reasonable explanation  for this difference[6].  Despite the differences in the env gene of FIV-Ple overall the viral genome is most closely related to FIV-Oma. 

The gene variation of different strains of FIV reveals that the virus must evolve to fit each species of cat. Although only several viral genomes of several cat species have been completely sequenced, it is clear that each strain of FIV is species specific. This evolution of FIV to fit each particular species of cat is reasonable because each species of cat is different. For example each species of cat may have different T-cell receptors and thus the virus would have to mutate to bind to the new T-cell receptors [9]. It has also been shown that the feline immunsystem produces viral restriction factors that will limit unadapted viruses. Thus each strain of FIV must mutate to avoid the viral restriction factors of each feline species. The strains of FIV would also have to mutate to avoid each species conventional immune responses. The immune system of each species would vary because most species live in different environments and are thus affected by different pathogens. Differences in feline immune responses, restriction factors and T-cell receptors would cause each strain of FIV to mutate so that the virus could successfully infect each feline species.

The genomic variation of each strain of FIV not only reveals how FIV is able to mutate to avoid different immune systems of feline species, but it also reveals the evolution of FIV throughout felines in particular the Felidae. The Felidae is a family of cats that includes domestic cats, lions, leopards, cheetahs, hyaenidae, and cougars.

Relationship of FIV to other Lentiviruses

Include some current research in each topic, with at least one figure showing data.

Conclusion

Overall paper length should be 3,000 words, with at least 3 figures.

References

[Sample reference] Takai, K., Sugai, A., Itoh, T., and Horikoshi, K. "Palaeococcus ferrophilus gen. nov., sp. nov., a barophilic, hyperthermophilic archaeon from a deep-sea hydrothermal vent chimney". International Journal of Systematic and Evolutionary Microbiology. 2000. Volume 50. p. 489-500.

Edited by student of Joan Slonczewski for BIOL 238 Microbiology, 2009, Kenyon College.

Include some current research in each topic, with at least one figure showing data. [edit] Conclusion

Overall paper length should be 3,000 words, with at least 3 figures. [edit] References

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