Feline Immunodeficiency Virus

Also known as: FIV

Description

Feline immunodeficiency virus is a retrovirus that causes immunodeficiency disease in the domestic cat.

Agent

FIV is a member of the lentivirus genus of the Retroviridae family. Retrovirus virions are are sensitive to heat, lipid solvents, and detergents but are relatively resistant to damage caused by ultraviolet light¹. The Retroviridae are enveloped viruses which contain a single-stranded RNA genome within an icosahedral nucleocapsid. Glycoprotein surface spikes are located on the envelope. Unusually, Retroviruses have a diplod genome: two identical copies of their positive-sense ssRNA are found on the virion¹. During viral replication, reverse transcriptase converts the ssRNA genome to ssDNA. This process is inherently error-prone, and the high rate of mutation gives rise to a wide genetic diversity of virus¹. A dsDNA can then be made from the ssDNA template. This provirus DNA then becomes integrated into the host genome by the actions of the viral enzyme integrase, and remains latent until transcription is initiated by the host cell machinery¹. Proviral DNA then serves as a template for the production of progeny ssRNA genomes and messenger RNA. Once the proviral DNA has been transcribe and translated, the virions assemble and are release by budding through the host cell membrane. This does not always cause lysis¹.

Many Retrovirus genomes contain oncogenes which may be expressed when integrated to the host genomes. However, oncogenes are not a requirement for tumour induction, and some Retroviruses can cause tumours without carrying oncogenes. The Retroviral genome has four coding regions. The "gag" region codes for the matrix protein, nucleoprotein and capsid, and "pro" encodes a protease¹. Reverse transcriptase is coded by the "pol" region, whereas "env" gives rise to the envelope and receptor binding. An additional, specific cellular transporter RNA is required for replication and present within the virion.

FIV was first discovered in a cat rescue facility in the United States where cats had been showing similar clinical signs to people with acquired immunodeficiency syndrome². Subsequently it has been shown that FIV has been present in the cat population since the late 1960s, and that the virus is very similar to the human retrovirus, HIV. However, despite these similarities, FIV is specific to cats, and people cannot become infected with the virus.

Transmission and Epidemiology

The major route of transmission is via saliva, especially through biting, and those cats exhibiting territorial aggression are most at risk of infection. Vertical transmission can also occur but the importance of this is not known. Venereal transmission has not been reported. Within households horizontal transmission can occur but the level of infection can be very variable. In some households only a single cat in a group may be FIV positive, whereas in others nearly every cat may be infected. Overall it appears that if fighting among cats housed together is rare, the prevalence of FIV is likely to be low.

Effective virus transmission requires an infectious inoculum, a portal of entry, and a susceptible host. Saliva from infected cats harbors FIV . virus burden in saliva parallels that of peripheral blood. acutely infected cats or terminal disease may be the greatest reservoirs of transmissible virus. acute stage of infection, virus can be detected in saliva prior to viremia On the opposite end of the clinical extreme, cats with AIDS are more likely to shed virus in the saliva and transmit the virus through bite wounds than cats in the asymptomatic stage of infection [61].

Cats with oral inflammation are probably more likely to shed virus in saliva than asymptomatic cats [56]. Gingivitis, stomatitis, periodontitis, and odontoclasia are among the most prevalent clinical signs of FIV infection [26,54]. concurrent herpesvirus infection [22] although a specific etiologic agent is not usually identified. Seroepidemiological surverys of the prevalence of FIV in the UK have shown that 13-19% of sick cats may be infected with FIV compared to 2-3% of healthy cats.

In multiple-cat households where FIV-infected cats intermingle with uninfected cats, the incidence of transmission over several years of contact appears to be very low when assessed by seroconversion to positive FIV-antibody status [54,62]. However, the transfer of virus through casual contact may be more frequent than initially reported when infection is defined by the presence of FIV nucleic acids and not by the harboring of infectious virus [14]. In a study reported by Dandekar et al, 20 specific pathogen free cats were co-housed with FIV-infected cats for 2 - 4 years, and 10 cats remained seronegative despite yielding FIV DNA from the blood and bone marrow by PCR and FIV RNA by in situ hybridization of mitogen-stimulated lymphocytes. Blood from these cats, however, was not capable of conferring productive infection, and these cats remained asymptomatic for the one-year duration of the study. This restricted form of FIV infection failed to elicit humoral immunity, a finding that resembled later reports of regressive infection of kittens following vertical transmission [1,43]. O’Neil et al. observed that some kittens infected with FIV from chronically infected mothers displayed a gradual reduction in virus load within cells of peripheral blood, resulting in a loss of antibodies to FIV within the first year of infection [43]. In this regressive form of FIV infection, cats lacking detectable FIV DNA in peripheral blood cells often harbored FIV DNA or low levels of infectious virus in tissues such as lymph nodes, thymus, spleen, bone marrow, and brain. Likewise, Allison et al. reported a progressive loss of detectable FIV DNA and infectious virus in peripheral blood lymphocytes over 14-month interval following maternal transmission of FIV belonging to clade A (FIV-Petaluma) or clade C (FIV-Pgmr) [1]. Preliminary data suggest that kittens with regressive infection remain resistant to infection following mucosal challenge [36].

It is well established that FIV is transmissible across mucosal surfaces, including those of the oronasal cavity, vagina, uterus and rectum [6,10,31,32,38,52]. Transmission of FIV across a mucosal surface may be enhanced by its ability to infect mucosal cells or by the capacity of cell-associated inocula to rapidly permeate the mucosa. Susceptible cells are abundant in the feline gastrointestinal tract as effector intraepithelial lymphocytes or lamina propria lymphocytes or in inductive sites such as Peyer's patches and lymphoid follicles [28]. Cell-associated vaginal inocula, but not cell-free inocula, appear to have the capacity to rapidly induce apoptosis of intraepithelial CD8+ lymphocytes of the intestinal tract, suggesting that the form of inoculum might influence the pathogenesis of mucosal infection [27]. Non-lymphoid cells such as follicle-associated intestinal epithelium become infected during transmission across the intestinal mucosa, although epithelial infection varies between studies [6,39]. Some populations of mucosal dendritic cells are susceptible to FIV infection, and these may migrate to the paracortex of lymph nodes soon after infection [39]. These populations differ from follicular dendritic cells in germinal centers, which bear FIV antigens but may not become truly infected [57]. Several molecules probably mediate the binding of FIV to dendritic cells. The best characterized is DC-SIGN, a C-type lectin that normally binds to ICAM-3 during interactions between dendritic cells and T cells [24]. DC SIGN mediates HIV infection of CD4+ T cells in trans by serving as a molecular chaperone for HIV as dendritic cells migrate from the intestinal mucosa to regional mesenteric lymph nodes and contact susceptible T cells [25]. Such a mechanism could explain the efficient transmission of cell-free FIV after mucosal inoculation [39]. Feline dendritic cells also appear to enhance the productive infection of both thymocytes and peripheral blood lymphocytes through a mechanism independent of DC-SIGN [59].

FIV isolates belonging to clade C have been extensively characterized in studies of mucosal transmission. Mucosally transmitted FIV-C (FIV-Pgmr), when administered by either oronasal, vaginal, or rectal routes, confers a spectrum of disease severity ranging from rapidly progressive to regressive [39]. A unifying lesion of the most pathogenic infections is the profound depletion of thymocytes and thymic dendritic cells [41]. An infectious molecular clone of FIV-C (FIV-C36) is thought to display enhanced properties for mucosal transmission, as illustrated by fetal-to-maternal transfer after experimental inoculation of nursing kittens [18]. Likewise, molecular clones of a clade B virus, FIV TM2, are infectious after vaginal exposure [32]. Within 1-2 days of experimental inoculation of oral or vaginal mucous membranes with clade C FIV, in situ hybridization identified infected CD3+ T cells and p55+ dendritic cells in the tonsillar, vaginal, or intestinal mucosa and in paracortical zones of regional lymph nodes [39].

Pathogenesis

The pathogenicity of FIV is strain dependent, and can vary widely. For all strains, feline lymphocytes and macrophages are the preferred cells for virus replication, and so FIV disrupts the function of the immune system. FIV gains entry to the cell via feline CD134, a surface molecule, and uses various chemokine receptors as secondary receptors^fmc. In acute infection, the virus spreads from the site of entry to the lymphoid tissues and thymus, where it first infects T-lymphocytes and then macrophages. Although both CD4+ and CD8+ cells can be infected by FIV and lysed in culture, the virus appears to preferentially destroy CD4+ cells. This intially results in a change in the ratio of CD4+ to CD8+ cells, from roughly 2:1 to less than 1:1^fmc. After several months of infection, an absolute reduction in CD4+ is appreciable.

Approximately three weeks after infection, cats may show the "primary phase" of FIV infection with malaise, lymphadenopathy and pyrexia. Viraemia peaks at 7-8 weeks and then declines, but increases again in the terminal stages of disease^viro. The host then remains asymptomatic for an indefinite period until cell-mediated immunity is disrupted by a decrease in the production of Th1 cytokines. In the advanced stages of infection, humoral immunity is also adversely affected. Although clinical signs are primarily due to changes related to T-cell populations, macrophages are the main reservoir of FIV in infected cats^fmc. These cells are capable of transporting virus to various tissues of the body, and also suffer impairment of function, such as an increase in the production of TNF. Microglia and astrocytes in the brain, and megakaryocytes in the bone marrow, can become infected with FIV^{fmc, viro}, and co-infection with feline leukaemia virus can increase the expression of FIV in many tissues, including the kidneys, liver and brain.

Signalment

Feline immunodeficiency virus occurs frequently in cats throughout the world, and similar viruses have been recovered from wild and zoo felids^viro. FIV infection increases in prevalence in older cats, and the average age at diagnosis is 5 years^fmc. Male cats are more commonly infected than females as they roam more and exhibit a higher degree of territorial aggression. There are no breed predilections.

Diagnosis

Laboratory Tests

• ELISA for serum antibody
  • False positives occur, particularly in the presence of maternal Ab
• Positives can be confirmed by lab work (Western blotting)

Pathology

On post-mortem examination, lymphadenopathy is seen. Intestinal lesions similar to those seen in feline panleukopenia virus infection may be apparent^fmc.

In early disease, lymphadenopathy is seen histologically to be due to follicular hyperplasia and infiltration of plasmacytes to surround the cortex. Later in disese, a mixutre of follicular hyperplasia and follicular depletion may exist, and in the terminal stages of FIV infection, follicular involution is the key feature^fmc. Lymphoplasmacytic infiltrates are seen in the gingiva, lymphoid tissues, spleen, kidney, liver and brain. Brain lesions also include perivascular cuffing, gliosis, neuronal loss, vacuolation of the white matter and, occasionally, the presence of giant cells.

Prognosis

The long-term prognosis for FIV-infected cats is guarded, but some cats will survive for many years following diagnosis. Around 20% of affected cats die within the first two years after diagnosis; this equates to a 20% mortality rate in the first 4.5-6 years after the estimated time of infection^fmc. In generally, the more chronic and severe the clinical signs, the worse the prognosis is.

Control

• No UK vaccine
• Healthy positive cats should have diagnose confirmed by further testing
• Isolate and castrate
• Preventative neutering of males

Links

• Feline Advisory Bureau FIV Factsheet

References

1. Wise, D J and Carter, G R (2005) A Concise Review of Veterinary Virology, IVIS.
2. Caney, S (2000) Feline immnunodeficiency virus: an update. In Practice, 22(5), 255-260.
3. Tilley, L P and Smith, F W K (2004) The 5-minute Veterinary Consult (Fourth Edition),Blackwell.
4. Johnson, C M (2005) Transmission of Feline Immunodeficiency Virus. Proceedings of the 56th Annual Meeting of the American College of Veterinary Pathologists and 40th Annual Meeting of the American Society for Veterinary Clinical Pathology.
5. Merck & Co (2008) The Merck Veterinary Manual (Eight Edition), Merial.
6. Morrision, W B (2002) Cancer in dogs and cats: medical and surgical management, Teton NewMedia.
7. Rand, J (2006) Problem-based feline medicine, Elsevier Health Sciences.