FIV CONTRIBUTIONS TO HIV STUDIES

Sheila O. Medeiros, Sandra R. R. Simonetti, Jos P. Simonetti, Bruno R. Simonetti,

Hermann G. Schatzmayr

Laboratrio de Ultra-estrutura Viral, Departamento de Virologia, Instituto Oswaldo Cruz,

Fundao Oswaldo Cruz.

Corresponding author:
Sheila O. Medeiros, Laboratrio de Ultra-estrutura Viral, Departamento de Virologia, Instituto
Oswaldo Cruz, Fundao Oswaldo Cruz, Avenida Brasil 4365, 21040-900Rio de Janeiro, RJ,
Brazil.
Tel: +55 21 2598-4355
Email: smedeiros@ioc.fiocruz.br

Key words: feline immunodeficiency virus, human immunodeficiency virus, animal model,
retrovirus

ABSTRACT
The paper describes comparatively FIV (Feline Immunodeficiency Virus) and HIV
(Human Immunodeficiency Virus) in relation to their genomic structure, molecular
characterization and treatment by antiretroviral drugs, pointing out the strong similarities of both
viruses. The FIV models in relation to transmucosal transmission studies, antiviral and gene
therapy, vaccine development, thymus disfunction and cytokine production are also discussed.
The authors conclude that FIV experimental models are a most valuable tool in order to better
understand the basic HIV pathogenesis, including efficacy of antiretroviral drugs.
INTRODUCTION
Retroviruses were originally described in animals and became an important model for
studies at both cellular and molecular levels, contributing to relevant aspects of oncogene
discovery, reverse transcriptase enzyme properties (Coffin et al. 1997) and the characterization of
the first human retrovirus, human T cell lymphotropic virus type I (HTLV-I) (Poiesz et al. 1980,
Gallo 2005).
The first retrovirus isolated from felines was Feline Leukemia Virus (FeLV) (Jarrett et al.
1964) which has been associated with a wide variety of clinical syndromes including Feline
Acquired Immunodeficiency Syndrome (FAIDS); despite the fact that the diagnostic test results
from many infected animals were persistently negative (Hagiwara 1990). In 1987, other
approaches were introduced in the studies on feline immunosuppressive conditions, after the
isolation of a distinct retrovirus from one FeLV persistently seronegative feline that evolved to
AIDS (Hagiwara 1990, Pedersen et al. 1987). It was originally named Feline T Lymphotropic
Virus (FTLV) due to the cell type for the in vitro isolation of the virus and its tropism for
peripheral blood lymphocytes from infected animals (Sparger 1993). In 1988 it was named Feline
Immunodeficiency Virus (FIV) according to the International Nomenclature of Viruses
(Desrosiers 2001).
Retrospective studies done in Japan (Furuya et al. 1990) and England (Gruffydd-Jones et
al. 1988) demonstrated that antibodies to FIV antigen were detected in feline serum samples
dating from 1968 and also from the 1975 to 1976 period respectively, showing viral circulation in
the domestic feline population prior to the first description in the literature.

Interest in the FIV studies has already increased. Besides its role as an important pathogen
for domestic felines, the similarities found between FIV and the human immunodeficiency virus
type 1 (HIV-1) have made felines the animal model for Lentivirus studies in many aspects
(Moench et al. 1993; North & Lacasse 1995; Miller et al. 2000), including its possible use as a
vector in gene therapy (Buchschacher & Wong-Stall 2000; Buchschacher 2001; Sauter & Gasmi
2001; Djalilian et al. 2002; Silva et al. 2004).
The present study aims to report the similarities and differences between FIV and HIV,
highlighting certain FIV contributions as a model for HIV studies.
Classification.
FIV and HIV are classified in the Retroviridae family, Orthoretrovirinae subfamily,
Lentivirus genus according to their morphology, the magnesium-dependent reverse transcriptase
enzyme activity and their pathogenic role (Bendinelli et al. 1995, Bchen-Osmond 2004). FIV
and HIV are morphologically similar, highly specific to the susceptible host and are genetically
distinct (Egberink et al. 1992).
Genomic structure.
As seen for all exogenous retroviruses, the FIV genome is composed of three open
reading frames (ORF), gag, pol and env coding for viral structural and enzymatic proteins
(Tomonaga & Mikami 1996). They are flanked on both sides by long terminal repeats (LTR)
composed of the untranslated 3element (U3) and promoters, the untranslated 5element (U5) and
repeated R sequences. LTRs enclose sequences for the genome transcription and the poly (A) tail
(Bendinelli et al. 1995). Gag and pol genes and env gene in some extension are conservative.
Other env gene regions, particularly those coding for specific-antibodies binding sites, are highly
variable (Hartmann 1998; Murphy et al. 1999).
FIV has accessory regulatory genes such as vif, ORF-A and rev (Fig.1) like HIV, but in a
different way, FIV pol gene codes for triphosphate deoxyuridine enzyme, dUTPase (DU), which
is able to reduce dUTP cellular levels avoiding the development of viral mutations due to its
incorporation into the viral cDNA (Miller et al. 2000). The dUTPase allows FIV replication in
quiescent cells or in those presenting low potential of cellular division such as macrophages
(Miller et al. 2000)
In the HIV infection, the Vpr protein assumes the DU function, acting to incorporate the
uracyl DNA glycosilase into the virions and similarly facilitates the viral replication in
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macrophages (Chen et al. 2004). Both HIV and FIV genomes code for Rev, essential for the
nucleus export of the unspliced and spliced viral RNAs, which is mediated by its binding to the
Rev Response Element (RRE). Vif protein is also present in both viruses and is important to
allow the viral spread and to infect non-permissive cells blocking the host antiviral response.
Genes present in the HIV genome coding for Nef, Vpr and Vpu proteins are not find in the FIV
genome. On the other hand, that has an additional accessory protein, ORF-A (or ORF-2) that
shares many functional properties with the HIV Vpr (Dunham 2006).

Human immunodeficiency virus type 1 genome

Feline immunodeficiency virus genome

Figure 1: Diagram showing FIV and HIV-1 genomic organization

Molecular characterization.
As seen for HIV, FIV also exhibits genetic variation among the viral subtypes as well as
geographic differences in clade distribution (Dunham 2006). Up to now, five FIV subtypes have
been identified, named A, B, C, D, E (Sodora et al. 1994, Hohdatsu et al. 1996, Pecoraro et al.
1996). This classification is based on the env gene analysis by comparison of a 684 nucleotides
sequence in the V3 to V5 region (Sodora et al. 1994, Pecoraro et al. 1996). Diversity higher than
4

30% in the amino acid sequences classifies the subtypes (Burkhard & Dean 2003). Recently,
partial sequences belonging to the F subtype were included in the GenBank database (access
AY139105-AY139112) (Reggeti & Bienzle 2004).
Inter- and intra-subtype variation and the number of subtypes described until now are
lower than those related to HIV (Yamamoto et al. 2002). Viral variation can occur as the
evolutionary consequence of quasispecies from infected felines but also as recombinant forms
following a super-infection process (Dunham 2006).
Infection.
FIV infection and HIV infection share many clinical characteristics, including a chronic
course, immunodeficiency development and the occurrence of peripheral and central nervous
systems abnormalities (Fox & Phillips 2002). They differ in their transmission mode, as HIV
natural transmission occurs through the mucous surfaces while FIV transmission occurs mainly
through the bites.
The 43kDa protein, CD134 (OX40), was recently described as the FIV binding receptor in
the host cells and the CXCR4 proteinas the co-receptor (Shimojima et al. 2004; de Parseval et al.
2004, de Parseval et al. 2006). HIV uses CD4 molecules as the primary binding receptor and
CCR5 or CXCR4 as the co-receptors. In spite of the difference both viruses can infect activated
CD4 lymphocytes resulting in similar disease development, characterized by a progressive
immunodeficiency (Dunham 2006).
FIV cellular tropism is more permissive than observed for HIV. Primarily infected cells
are the CD4(+) T helper lymphocytes. As infection progress other cell types are also infected,
CD8(+) lymphocytes, B cells, macrophages, dendritic cells and astrocytes. At the chronic
infection stage, the virus can be isolated from a large variety of host cells (Levy 2002).
Treatment.
FIV infection treatment is that of support even though many antiretroviral drugs used in
HIV infection treatment have been tested by in vivo and in vitro studies. They have been used in
the treatment of naturally and experimentally infected domestic cats showing moderately
successful results (Hart & Nolte 1995, Hartmann et al. 1997).
The non-nucleoside reverse transcriptase inhibitors (NNRTIs) are highly HIV-1 specific
and do not work properly against HIV-2 (North et al. 1990). North and Lacasse (1995) observed

that neither NNRTIs inhibited FIV RT. Auwerx et al. (2004) demonstrated the differences present
in the FIV RT structure that prevents NNRTIs and FIV RT interaction.
The analogue reverse transcriptase inhibitors (NRTIs) are effective against FIV infection
(North et al. 1990). HIV-1 RT and FIV RT similarities allowed demonstrating the efficacy of the
analogue reverse transcriptase inhibitor zidovudine (AZT, 3azide-3deoxythymidine) that
blocked FIV in vitro replication (Zhang et al. 2004). Other in vitro studies using NRTIs such as
lamivudine (3TC) and abacavir (ABC) associated with AZT also inhibited FIV replication (Bisset
et al. 2002).
The rapid emergence of viral strains that are resistant to antiretroviral monotherapy
suggests that combined therapy is more effective for FIV infection treatment (Zhang et al. 2004).
FIV and HIV proteases present a very similar quaternary structure but their substrate
specificities and inhibitors are distinct (Lin et al. 2003; Miller et al 2000). Therefore, PR
inhibitors used in the HIV therapy do not inhibit FIV PR (Miller et al. 2000). Lin et al. (2003)
described the differences found in the 11 amino acids present in the substrate binding site in FIV
and HIV proteases which are related to this specificity.
Highly active antiretroviral therapy (HAART) or NRTIs associated with a protease
inhibitor have demonstrated efficacy by diminishing plasmatic viral load and improving CD4(+)
T cell counts in human AIDS patients (Torres & Barr 1997; Opravil et al. 2000). However, the
lack of a FIV specific protease inhibitor hampers this treatment schedule (Bisset et al. 2002).
FIV model contributions.
Cat model.
The nonhuman primate (NHP) model has been used in HIV studies, as simian
immunodeficiency virus (SIV) infection and HIV infection in human beings have many
similarities. However, FIV infection in cats also closely resembles that of HIV and certain antiHIV drugs are effective against FIV, showing a similar toxicity. There are some advantages using
the cat model instead of NHP model, due to the small size and the relative ease of handling cats.
Cats are also easier to breed and have a shorter breeding cycle than macaques (Miller et al. 2000).
Transmucosal transmission studies.
Morphological similarities between these two viral particles led up to development of
transmucosal transmission studies. Studies using the vaginal and rectal transmucosal models,
demonstrated that nonoxynol-9 (N9) contraceptive jelly and 5-bromo-6-methoxy-5,6-dihydro-3azidothymidine-5-(p-bromophenyl)-methoxy alaninyl phosphate (WHI-07) effectively prevented
6

transmucosal FIV transmission using FIV infected cell inoculums (Moench et al. 1993). WHI-07
either alone or in combination with vanadocene (VDDTC), has clinical potential for the
development of a contraceptive anti-HIV for sexually active women (DCruz et al. 2004).
VDDTC is a potent spermicidal and WHI-07 is a dual-function aryl phosphate zidovudine
derivative, showing potent anti-HIV and spermicidal activities (DCruz et al. 2004).
Antiviral therapy.
The FIV protease structure model was applied for the development of protease inhibitors
with broad efficacy (Lee et al. 1998). The strategy was based on observations that various potent
HIV inhibitors were less-efficient FIV protease inhibitors (Lee et al. 1998). HIV and FIV
protease have 23% amino acid identity and active-site structures are almost super-imposable.
Designing protease inhibitors with a similar alpha-carbon structure and diverse substrate
specificities, such as FIV protease, results in effective inhibitors against drug resistant HIV.
Based on first studies, TL-3 was truly a broad-based protease inhibitor as shown by its ability to
inhibit efficiently the in vitro replication of human, simian and feline immunodeficiency virus, in
the micromolar range (Lee et al. 1998). Optimer Pharmaceuticals licensed this compound but
FDA or USDA approval has not been applied for yet. Recently, TL-3 showed efficacy in vitro
against human coronavirus (SARS-CoV) (Wu et al. 2004).
Vaccine development.
The feline model offers a good opportunity to investigate the viral subtypes relevance to
vaccine development. Specifically, it is possible to vaccinate animals with antigen(s) derived
from one subtype and to challenge the immune response with the virus derived from other
subtypes (Dunham 2006).
The first commercial vaccine against FIV was developed, consisting of inactivated viruses
derived from both clades A and D (Pu et al. 2001), which has been shown to protect against
another clade B virus (Pu et al. 2005). Such cross-clade protection gives hope for HIV vaccine
development, implicating that protective epitopes are possibly conserved between the clades
despite the genetic variation (Dunham 2006).
Neuroaids.
The ability with which FIV rapidly and persistently infects the cat central nervous system
(CNS) offers an excellent experimental model to investigate the temporal course of AIDS
neuropathogenesis (Dow et al. 1990).
The cat is an useful animal model to study the age-dependent neurological manifestations
of the lentiviral infection for the following reasons: 1) the physiological maturation of the sensory
7

and motor components of the central nervous system (CNS) is well-defined; 2) techniques for
behavioral and neurophysiologic testing are well-established; 3) post-natal critical cortical
proliferation and synaptic formation occurs predominantly in the early post-natal period age and
4) post-natal closure of the bloodbrain barrier is delayed for approximately 30 days. Unlike cats,
people and non-human primates have closure of the bloodbrain barrier during the early stages of
gestation. Therefore, the cat can serve as an animal model to study lentiviral infection effects on
the CNS prior to the closure of the bloodbrain barrier without the need of fetal manipulation
(Podell et al. 2000).
Gene therapy.
Stable integration of the virus genome into the hosts genome is an advantage of all
Retroviridae family members for gene therapy use, although the use of HIV in gene therapy has
not been allowed due to safety concerns (Silva et al. 2004). The development of vectors
presenting less potential for human pathogenesis is the major reason for the FIV use in the
retroviral gene therapy research (Silva et al. 2004).
FIV was employed in the gene therapy of middle ear mucosal cells to treat chronic middle
ear disease, without adverse effects in the inoculated rats (Djalilian et al. 2002) and for the
treatment of hemophilia A. In this study Stein et al. (2001) injected a replication-deficient FIVbased vector encoding human factor VIII into factor VIII-deficient mice. Factor VIII expression
persisted for approximately five months and recipient mice survived an otherwise lethal bleeding
episode (tail clipping).
Thymus disfunction
A child infected in utero with HIV develops thymus insufficiency and progresses to AIDS
sooner than infants infected peri-partum. Nevertheless, thymus direct analysis is difficult due to
limited tissue access and variable timing of transmission. Domestic cats infected with FIV were
used in studies to evaluate thymus pathogenesis and the neonatal thymus was shown to be less
vulnerable to acute changes than fetal thymus (Johnson et al. 2001).
Cytokine production.
Changes in the cytokine profile have been reported in HIV infected humans without a
clear consensus as to whether changes represent a shift to type 2 cytokines, a loss of type 1
cytokines, a reversion to the T-helper 0 (Th0) phenotype or a general cytokine production
perturbation (Burkhard & Dean 2003). Changes in the cytokine expression at FIV infection do
not suggest a Th2 bias. Studies on the cytokine expression in the thymus from FIV-infected cats

suggested that both Th1 and Th2 cytokines can be suppressed or elevated in FIV-infected cats
primary and secondary lymphoid organs (Liang et al. 2000).
FIV model has been used to evaluate specific cytokine response to a secondary
pathogen. To address this question, FIV infected cats were challenged with Toxoplasma gondii
(Levy et al. 2004) and Listeria monocytogenes (Dean & Pedersen 1998). These studies showed
similar results. IL10 levels expression remained elevated in FIV positive cats challenged with a
secondary pathogen, whereas all other cytokines declined, like IFN or failed to be expressed
(IL2, IL12 and IL6). Studies concluded that FIV positive cats were not able to express a
protective Th1 immune response when challenged with a secondary intracellular pathogen.
Concluding remarks.
The FIV model provides a good opportunity to perform highly controlled and
comprehensive studies that would be unacceptably invasive or unethical on human volunteers.
The availability of specific pathogen free (SPF) cats allows study design with an adequate
number of animals to supply statistically significant data. Much research was done to characterize
FIV infection in cats and to demonstrate similarities to HIV infection in human beings. Through
this researche besides the similarities, many differences were found, which were interpreted as
weakness in the FIV model. However, the true utility of an animal model not just in sharing the
similarities. The differences should be carefully evaluated to understand the basic HIV
pathogenesis that should be best evaluated through productive collaborations of scientists
working on the human disease and those working on the animal model.
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