Prophylaxis against Feline Immunodeficiency Virus - some recent observations

Introduction
The discovery of feline T-lymphotropic lentivirus was first reported by Pederson et al in 1987. Since then, efforts have been on to study the pathogenesis and mechanisms of immune system break down that the virus induces in susceptible cats in order to develop effective strategies for prophylaxis.

Origins
The feline immunodeficiency virus belongs to the lentivirus subfamily of retroviruses. Among several studies which have been carried out on cloning of the FIV virus to understand the genomic sequence of FIV, those by Olmsted et al, Talbott et al, Maki et al. have obtained positive results.

Routes of transmission
In the case of FIV, several investigators have observed biting to be a principle route of transmission. In other studies, cats have been shown to be infected by both rectal and vaginal routes.

Incubation period and clinical signs
Cats that are naturally infected with feline immunodeficiency virus remain in an
asymptomatic carrier state for years. After the long, aysmptomatic period which may persist for many years, a gradual breakdown in the immune defences is seen. Affected cats may present with signs of upper respiratory infections, chronic enteritis, diarrhoea, neurological abnormalities, abortion, alopaecia, anaemia, gingivitis / stomatitis, and even recurrent ocular disease.

Pathogenesis and immune reactions
The FIV virus has an affinity for T lymphocytes and monocytes and induces these cells to form syncytia. The FIV provirus includes the structural genes for group-specific antigens (gag gene), envelope proteins (env gene) and reverse transcriptase (pol gene), as well as several short open reading frames just like the other lentiviruses. The gag gene is believed to be highly conserved among FIV strains Some investigators feel that peptide mimtopes of complex retroviral glycoproteins may have uses both in prophylaxis as novel vaccines and in the development of serological diagnostic tools. It has also been strongly felt among certain research groups that soluble factors represent important effector mechanisms in the control of lentiviral replication.

Prophylaxis
Many grey areas persist in understanding the aetiopathogenesis of the virus as well as the development of the immune response. Although several attempts have been made to develop a safe and effective vaccine, most of the clinical trials carried out so far show modest rates of success. It remains to be seen which of these trials outlined below will really move from the backdrop of the research scenario to the clinic.

In this brief article some recent attempts to induce effective prophylaxis in infected cats are highlighted.

Results show that a multi-subtype antigen vaccine may be more effective!
According to Pu et al at the Department of Pathobiology, College of Veterinary Medicine at the University of Florida, a multi-subtype antigen vaccines may be an effective strategy against the lenti family of viruses that cause immunodeficiency. This conclusion has been made on the basis of a recent clinical trial, that the investigators carried out to evaluate the immunogenicity and efficacy of an inactivated dual-subtype feline immunodeficiency virus (FIV) vaccine. The researchers observed that 80% of the dual subtype vaccinated cats were protected against low-dose FIV(Bang) (10 CID(50)) and subsequently against in vivo-derived FIV(Pet) (50 CID(50)) challenge. However, all the placebo-immunized cats were found to became infected. Besides this, it was also noted that the dual-subtype vaccination induced broad-spectrum virus-neutralizing antibodies and FIV-specific interferon-gamma responses along with elevated FIV-specific perforin mRNA levels.

Fixed cell vaccine vs whole inactivated virus vaccine in eliciting high titers of neutralizing antibody
In studying the immune response to FIV, several investigators have correlated a high titer of neutralizing antibody in cell-adsorbed sera with protection. Based on such observations, Giannecchini et al have reported that in-vitro studies, the fixed-cell vaccine that they used was more efficient at removing neutralizing antibody from immune sera in comparison to the whole-inactivated-virus vaccine which they reported to be significantly less effective.

Observation with FIV vaccine using cell associated FIV-M2 strain fixed with paraformaldehyde
The results of other studies using an FIV strain fixed with paraformaldehyde appear promsing!. Matteucci et al have explored the efficacy of an FIV vaccine that used a cell-associated FIV-M2 strain fixed with paraformaldehyde. The cats in the study were in a region where FIV was endemic, with a prevalence of 29 to 58% over an 8-year observation period. The investigators report that in their study, 0 of 12 immunized cats showed any evidence of FIV infection, while 5 of 14 control cats were infected.

Role of (MIDGES) gene expression vector vaccines in FIV
At the university of Zurich, Leutenegger and co-investigators have obtained some interesting results using gene expression vector vaccines. In their study, 4 groups of cats, each containing four animals, were immunized at 0, 3, and 6 weeks with minimalistic immunogenic defined gene expression vector (MIDGE) vaccines containing the gene(s) for feline immunodeficiency virus (FIV) gp140, FIV gp140 and feline interleukin-12 (IL-12), FIV gp140 and feline IL-16, or FIV gp140 and a CpG motif. The route of immunisation was intradermal with a gene gun using MIDGEs, coated on gold beads. Group five was maintained as the control. The investigators exposed all cats to virulent FIV one month after the final immunization. It was observed that cats immunized with FIV gp140 gene alone or with blank gold particles became highly viraemic and seroconverted by 4 weeks after infection. On the other hand, 75% of those immunized with FIV gp140 along with feline IL-12 did not become viraemic or seropositive.

Initiation of protective immunity using a live-attenuated FIV proviral DNA
In the opinion of other investigators, a vif deletion mutant may be a good direction to traverse on the route to making a safe attenuated lentiviral vaccine. The results obtained by Lockridge et al at the Department of Medicine and Epidemiology, University of California, Davis, show that inoculation with FIV-pPPR-Deltavif proviral DNA induces resistance to challenge with infectious FIV. In their clinical trial, a plasmid clone was developed which had an FIV provirus containing a deletion in the viral accessory gene vif (FIV-pPPR-Deltavif). The route of inoculation of the proviral DNA in the four cats was intramuscular. After 43 weeks, when the cats were challenged with the same proviral plasmid, anti-Gag antibodies were not detected but anti-Env antibodies were found in FIV-pPPR-Deltavif- immunized cats.

Defective feline immunodeficiency virus proviral DNA ( FIVDeltaRT )
Researchers at the department of veterinary pathology, at the University of Glasgow have been focussing on trying to understand the factors that play a role in influencing the feline cellular immune response. Lead investigator in the study, Flynn is of the opinion based on the results of their observations that a single intramuscular inoculation of defective feline immunodeficiency virus proviral DNA ( FIVDeltaRT ) DNA together with gamma-IFN DNA may be sufficient to induce virus-specific CTLs and protection.

Mucosal immunization with FIV vaccine
The results with using the mucosal route have been conflicting with variations in results observed from different groups. In a recently conducted trial too, the results have not been very encouraging. Finerty et al at the University of Bristol have reported that mucosal immunization via rectal and intranasal route does not give protection from rectal FIV challenge. However, the investigators report the induction of good, antibody and proliferative responses with improved IgG and IgA levels.

Conclusion
The development of an effective prophylaxis in the prevention and control of the lenti virus that causes feline immunodeficiency continues to pose a tremendous challenge to researchers working all over the globe. One is optimistic that with the recent progress in the field and the development of novel strategies, effective prophylactic measures that can successfully control the spread of FIV may be finally developed.