FIV: PREVENTION AND TREATMENT
Julie Levy, DVM, PhD, DACVIM Gainesville, FL
En PROC. 22nd ACVIM 18 MINNEAPOLIS, MN 2004
INTRODUCTION
Feline immunodeficiency virus (FIV) is a lymphotrophic lentivirus that, like HIV in humans, causes an
acquired immunodeficiency syndrome (AIDS) in domestic cats. FIV is related morphologically and
biochemically to HIV but is antigenically distinct. Both viruses also share a similar pattern of pathogenesis,
characterized by a long period of clinical latency during which immune function gradually deteriorates.
Eventually, AIDS develops and is accompanied by opportunistic infections, systemic diseases, and
malignancies. It is the close relationship between HIV and FIV that has kindled interest in the use of FIV as
an animal model for the study of lentiviral immunopathogenesis.
PATHOGENESIS
Within the first few weeks of FIV infection, both CD4+ (helper T cells) and CD8+ (cytotoxic-suppressor T
cells) cells decline. The initial lymphopenia is followed by a robust immune response, which is characterized
by the production of FIV antibodies and a rebound in CD8+ cells above preinfection levels. This results in a
persistent inversion of the CD4+:CD8+ ratio. Over time, both CD4+ and CD8+ cells gradually decline. In
HIV, distinctive clinical stages can be defined based on absolute CD4+ cell count. A CD4+ cell count of
¡Ü200/µl is an AIDS-defining condition in HIV infection. It is more difficult to assignn clinical stages of
disease to cats, because FIV appears to be less pathogenic than HIV. Although chronic inflammatory
conditions and opportunistic infections are more common in cats with low CD4+ cells, other cats appear to
remain healthy. It is generally recognized that cell-mediated immunity is more profoundly affected than
humoral immunity. Chronic inflammatory conditions, neoplasia, and infections with intracellular organisms
are more common than infections controlled by antibodies. FIV-infected cats appear to respond adequately to
vaccination and frequently develop a polyclonal hypergammaglobulinemia characteristic of nonspecific
stimulation of humoral immunity.
VIRAL TRANSMISSION
Although the existence of FIV was first reported in 1987, there are extensive data indicating that cats have
carried the virus for a much longer time. FIV has a worldwide distribution in domestic cats, with infection
rates approaching one third of the cats in some populations. Strains of viruses related to FIV are also found to
infect at least 27 species of wild felidae. In the wild, it appears that a majority of lions are infected, but few
clinical signs are apparent. The greater diversity of viral nucleic acid sequences and the decreased
pathogenicity of wild cat strains compared with those that affect domestic cats suggest that nondomestic felids
have been living with lentiviruses for a longer time and that the domestic cat strains may have emerged more
recently from ancient nondomestic cat strains. This is reminiscent of the situation with HIV, which recently
made a jump from a related minimally pathogenic virus in monkeys to humans, in whom the virus is much
more virulent. Epidemiologic studies of domestic cats have long suggested that most cases of FIV infection
are acquired by horizontaltransmission among adult cats. Worldwide, adult male cats living outdoors
consistently compose the majority FIV-infected cats,and the risk is highest for sexually intact males. The
fighting and biting behaviour of this group of cats is believed to be the main cause of transmission. Infectious
virus is found in the saliva of FIV-positive cats, and the virus has been successfully transmitted via
experimental bite wounds. Interestingly, sexual transmission, the most common mode of transmission of HIV,
appears to be unusual in FIV, even though the semen of infected cats frequently contains infectious virus. In
an interesting mathematical model of FIV transmission within colonies of free-roaming cats, it was suggested
that FIV had little impact on the total population size and health. A low rate of transmission, the long
asymptomatic stage of infection, and death from other causes combined to minimize the effect of the
virus on feral cats. Such colonies existed at the carrying capacity of the habitat, regardless of whether FIV
infection existed in the group.
Vertical transmission, which is common in HIV, appears to be infrequent with FIV in nature. Certain strains
of virus appear to be more likely to cross the placenta. Similar to HIV, FIV can be passed to kittens through
the placenta, during the birth process, or via the milk. In contrast to the relative ease with which kittens can be
experimentally infected via their mothers, in nature, FIVpositive queens rarely infect their offspring. The
practical aspect of transmission research arises when clients present kittens for routine testing or when one of
the cats in a household is found to be infected with FIV. Although kittens that nurse chronically infected
queens are unlikely to become infected, they readily absorb colostral antibodies against FIV. Testing such
kittens will result in a false-positive result, because diagnostic tests detect antibodies, not antigen. Most such
kittens are truly uninfected, and colostral antibody titers decline over a period of several months. Therefore, a
diagnosis of FIV infection should not be made on the basis of an antibody test before the age of 6 months.
Because transmission by casual contact, such as sharing litter boxes and food dishes is uncommon, it is
relatively safe to keep an FIV-positive pet in a household with other cats if the cats do not fight. However, in
one study of a household with a large number of cats, 9 of 26 cats were FIV+ at the beginning of the study,
and an additional 6 cats became infected over the next 10 years without evidence of fighting.
DIAGNOSIS OF FIV INFECTION
The American Association of Feline Practitioners recommends testing all cats for FIV. However, test sales
figures indicate that a majority of cats are never tested. The mainstay of clinical screening for FIV infection is
detection of circulating antibodies against FIV. Because FIV produces a persistent infection from which few
cats recover, detection of FIV-specific antibodies in blood has been considered to be a reliable indicator of
infection. Patient-side immunochromatic lateral flow antibody tests are commonly used for screening cats,
and Western blot (WB) or IFA antibody tests are recommended for confirmation of infection. Diagnostic
testing for FIV is discussed in more detail in Session 198.
CLINICAL DISEASE SYNDROMES
The course of clinical disease following infection with FIV is dependent on a number of factors, including the
age and health of the cat at the time of infection, the dose and route of virus inoculation, the strain of the
virus, and the immunologic background of the cat. Experimental infections of cats with different backgrounds
have helped to differentiate primary viral effects from those that develop only in the presence of disease
cofactors. For instance, there are marked differences in the development of disease syndromes
in laboratory-reared specific pathogen-free (SPF) cats compared with random-source cats previously exposed
to common feline pathogens such as upper respiratory infections and parasites. In one report of cats followed
for 4 years after experimental FIV infection, both SPF and random-source cats experienced
immunodeficiency marked by progressive inversion of the CD4+:CD8+ cell ratio and decreased mitogen
responses. The random-source cats went on to acquire an AIDS-like syndrome characterized by
stomatitis, recurrent respiratory disease, diarrhea, and weight loss. In contrast, several SPF cats developed Bcell lymphoma or neurologic disease, which are believed to represent direct viral effects, but not AIDS. This
suggests that various infectious cofactors have a profound influence on the clinical course of cats infected
with FIV. During natural FIV infection, most cats experience a prolonged asymptomatic period of several
years following seroconversion. The most common disease syndromes diagnosed in the FIV-positive patients
are stomatitis, neoplasia (especially lymphoma and cutaneous squamous cell carcinoma), ocular inflammation
(uveitis and chorioretinitis), anemia and leukopenia, opportunistic infections, and renal insufficiency. Both
central and peripheral neurologic disease complicates the course of HIV infection of humans, and the same is
true of FIV. The dementia of human AIDS is often characterized by a slight decline in cognitive ability or
behaviour, changes that may be too subtle to recognize in cats. In some cats, however, obvious central and
peripheral neurologic disease occurs and may take the form of seizures, striking behaviour changes,
anisocoria, or paresis. Sensitive electrodiagnostic tests such as nerve conduction velocity and brain stem
auditory evoked potentials may detect abnormalities in clinically normal FIV-infected cats.
Neurologic abnormalities tend to respond favorably to treatment with zidovudine (AZT); in many cases, there
is marked improvement within the first days of therapy. Chronic ulceroproliferative stomatitis is the most
common disease syndrome induced in cats with long- standing FIV infection. Interestingly, this syndrome
occurs only in cats that are also exposed to other infectious agents in addition to FIV, and does not readily
develop in SPF cats. Concurrent calicivirus infection is often identified in the oral cavity of cats with FIVassociated stomatitis and may be one of the infectious cofactors capable of inducing stomatitis in combination
with FIV.
Recently, Bartonella henselae has also been implicated in stomatitis. Histologically, the mucosa is invaded by
plasma cells and lymphocytes, accompanied by variable degrees of neutrophilic and eosinophilic
inflammation. The cause of the syndrome is uncertain, although the histologic findings suggest an immune
response to chronic antigenic stimulation or immune dysregulation. In addition, the circulating lymphocytes
of cats with stomatitis have higher than normal expression of inflammatory cytokines, further implicating
immune activation in the pathogenesis of this condition. The most effective treatment is extraction of all teeth,
paying careful attention to removal of all of the roots of the teeth. In almost all cases of stomatitis in FIVpositive cats, long-term resolution of inflammation is achieved, and cats return to eating a normal diet.
PREVENTION OF FIV INFECTION
Test and removal programs conducted over the past 3 decades were very effective for eliminating FeLV
infection from breeding catteries and preventing the adoption of FeLV-infected strays. At the same time,
surgical neutering for population control became widely accepted, which decreased the production of FeLVinfected kittens, the primary source of new infections. In the 1980s, several vaccines against FeLV were
introduced, which further strengthened control of FeLV. Consequently, the prevalence of FeLV,
as well as its associated conditions such as lymphosarcoma, has steadily decreased during the past 20 years.
With the success of FeLV control as a model, can we expect similar methods to work for FIV? In many
respects, the answer is yes. Routine patient-side antibody tests are convenient, affordable, and highly reliable,
although no test is perfect. In general, FIV is even less infectious than FeLV. In contrast to FeLV, kittens
rarely acquire FIV from their infected mothers. Because FIV is primarily spread among male cats that fight
and bite, endemic infections in purebred catteries are uncommon. Cats that reside peacefully together within
households may not spread FIV among themselves. Thus, test and removal programs would be expected to be
very successful at creating FIV-free populations. However, FIV testing is still not as widespread as it could
be. Test sales in the US indicate that less than 10% of cats are ever tested for FIV. FIV is easily avoided by
preventing cats from encountering other cats of unknown status. An interesting philosophical chasm separates
the US from the UK in this regard. In the US, veterinarians and animal welfare workers encourage cat owners
to confine their cats to prevent hazards of outdoor life, such as trauma and infections. In the UK, such
confinement if often viewed as unnatural and inhumane, possibly contributing to some behavioral and health
problems.
Developing effective vaccines against FIV has proven to be a much bigger challenge compared to FeLV.
Many approaches have been taken toward the development of an effective vaccine against FIV, but the same
hurdles facing HIV prevention also apply to the feline virus. Both viruses have error-prone reverse
transcriptase enzymes, which enhance the mutation rate of replicating virus and increases the opportunity for
escape from immune surveillance. The viruses may also take advantage of specific antibody formation, using
antibodies to enhance pathogenicity or to enter cells via immune complexes. Strategies explored to date
include passive transfer of antibodies and immune cells, inactivated whole viruses, fixed infected cells, viral
subunits, naked DNA, mucosal vaccination, gene-deficient viral mutants, and various adjuvants. To date, no
approach has been completely successful in preventing infection after challenge, and in some cases
immunization paradoxically enhanced viral replication and disease expression. Many promising prototype
vaccines were only protective against the homologous strain from which the vaccine was derived; vaccines
were less effective when cats were challenged with more distantly related strains. This is problematic, because
cats in both North America and Europe may be exposed to a variety of strains (primarily A, B, and C).
Adding to the difficulty in developing vaccines with broad protection is the difficulty in determining whether
cats are truly free of infection following challenge. Recently, latent infectious FIV was isolated from necropsy
tissues of cats that had tested negative by PCR for circulating virus for more than a year past vaccination and
challenge. In another study, some cats experimentally exposed to FIV were negative by antibody testing, virus
culture, and PCR. Further studies revealed that these cats had potent antiviral activity mediated by CD8+ T
cells. When blood samples from these cats were cultured after the CD8+ cells were removed, infectious
FIV was recovered. Clinically, cats in both of these studies had been diagnosed as being free of FIV prior to
more extensive testing.
This brings into question the results of vaccine challenge studies that evaluate infection status by conventional
means. In July of 2002, Fort Dodge Animal Health released Fel-O-Vax FIV®, the first vaccine licensed for
the prevention of FIV. Fel-O-Vax FIV® is a dual-subtype vaccine containing inactivated subtype A
(Petaluma) and subtype D (Shizuoka) FIV combined with an adjuvant. Both cell-free and cell-associated virus
are present in the vaccine. The combination of 2 genetically distinct subtypes is proposed to induce broadspectrum virus-neutralizing antibodies, although the full range of protection is still unknown. Fel-O-Vax
is licensed for use in kittens 8 weeks and older. The primary inoculation series includes 3 doses administered
2 to 3 weeks apart.
Annual boosters are recommended thereafter, although the maximum duration of immunity is unknown. The
vaccine was challenged with a different type A strain of FIV (unspecified) 375 days after completion of the
primary series. Challenge virus was administered by intramuscular injection to mimic a bite wound. Viral
status was determined by culture and PCR every 2 weeks from 6 to 16 weeks post challenge. Cats with
positive results for either test at 3 of the 6 time points were considered persistently infected. Results
demonstrated that 17 of 19 unvaccinated controls (90%) became infected vs. 4 of 25 (16%) vaccinated cats,
resulting in a preventable fraction of 82%. This represents substantial protection against the challenge strain
of FIV, but it remains unknown how protective the vaccine will prove to be against other strains, particularly
those that do not belong in the A and D strain families. Because Fel-O-Vax contains whole virus, cats respond
to immunization by producing antibodies that are indistinguishable from those produced during natural
infection. Thus, vaccinated cats will test "false-positive" in currently licensed antibody-based FIV diagnostic
tests, including ELISA, immunochromatography, Western blot, and IFA. Kittens born to vaccinated cats will
also test false-positive due to their absorption of colostral antibodies from the queen. Test interference is
discussed in more detail in Session 198.
A paradoxical transient increase in susceptibility to FIV infection has been documented in cats following
immunization with either FVRCP or FIV vaccines. This may be due to the activation of lymphocytes
stimulated by vaccination. Activated and replicating lymphocytes are the preferred target for FIV. Although
this may not be clinically important for most cats, cats that reside with FIVinfected cats might benefit from
separation from the infected cats for several weeks following routine vaccinations.
TREATMENT OF FIV-INFECTED CATS
Although cats may eventually succumb to diseases related to FIV infection, it is possible for many cats to
enjoy an extended period of good health. Because many problems arise secondarily to the immunopathologic
effects of infection, it is frequently rewarding to treat these related conditions. Several studies have reported
that infected cats are likely to respond as well as uninfected cats when treated for lymphosarcoma,
cryptococcosis, stomatitis, and anemia, among other conditions. In HIV infection, it is well documented that
clinical outcome is improved when viral plasma burden is reduced. Current highly active antiretroviral
therapy (HAART) often reduces viral burden to undetectable levels, although true cures are not observed. The
result is that HIV patients are surviving longer with improved quality of life. HAART involves cocktails of
drugs taken throughout the day. Side effects are common. Antiviral therapy is also effective in FIV-infected
cats, although the drugs available to cats are limited and few controlled studies have been performed to
support their use. AZT is the most thoroughly studied anti-FIV drug in cats. AZT reduces plasma virus
load and improves CD4+ cell count. Recently, the nucleoside reverse transcriptase inhibitor stampidine (25100 mg/kg PO BID) was reported to reduce viral burden in chronically infected cats treated in a short-term
study. Other antiretroviral drugs have proved to be too toxic or ineffective in cats. Immunomodulators are the
most widely used medications in FIV. Immunomodulators are suggested to benefit retrovirus-infected cats by
restoring compromised immune function, thereby allowing the patient to control viral burden and
recover from associated clinical syndromes. Unfortunately, neither immunomodulators nor antiviral drugs
have received thorough evaluation in large long-term controlled studies in naturally infected cats.
REFERENCES
1. Levy JK, Richards J, et al. Feline Retrovirus Testing and Management. Compendium of Continuing Education for the Practicing
Veterinarian 2001; 23: 652-657,692.