Feline Immunodeficiency Virus

			12/6/95
			Hillary R. Gorman


















Feline Immunodeficiency Virus (FIV) is a single stranded RNA retrovirus, 
of the genus Lentivirus.  It is pleomorphic in shape and size, 
spheroidal, enveloped, and 80-100 nm in diameter.  Its surface is rough 
and has spikes evenly dispersed across it. Originally, it was assumed to 
be a variant of the Feline Leukemia Virus (FeLV), a lentivirus of the 
oncornavirus subgroup, but has been shown by immunological analysis to be 
a distinct virus.  Antibodies made against FeLV do not react with FIV, 
and FIV antibodies do not react with FeLV.

FIV has been the subject of a lot of research lately, as it is a 
reasonably good animal model for HIV, the AIDS virus. FIV contains a 
magnesium-dependent reverse transcriptase that  is closely related to 
HIV, and has the complex genome structure associated with the 
lentiviruses. Despite the similarity, however, FIV is highly species 
specific and there is no cross species pathogenicity.1

In early FIV infection (experimentally 21 days after infection) the 
majority of FIV infected cells are found in lymphoid organs,  
particularly in the germinal centers.  The thymic cortex is also a major 
site of early infection. In early infection, T lymphocytes are the 
primary target cell of the virus, but as the virus persists, it will 
infect a few mononuclear cells and macrophages. The normal feline CD4:CD8 
ratio is about 0.4 to 3.5 (median value approx. 1.1), but FIV infected 
cats have a significant decline in their CD4+ cell populations, leading 
to a decreased median CD4:CD8 ratio of about 0.5.This change is due to  
loss of CD4+ cells, not an increase in the number of CD8+ cells, and this 
has been demonstrated by flow cytometry analyses of T cell populations in 
naturally infected cats.  Interestingly, in vitro studies have shown that 
FIV will infect CD4+ and CD8+ cells with equal success, and it is 
suggested that FIV possesses a broad tropism for peripheral blood 
mononuclear cells. It may be of interest to note that in FeLV infection, 
the CD4:CD8 ratio is unchanged, suggesting that both populations are 
destroyed by that virus. 2 While FIV infection causes a rapid drop in 
Tcell numbers, the B cells are unaffected (although secondary B cell 
lymphomas may occur). In addition, after this rapid drop, the CD8+ cell 
population recovers, unlike the CD4+ cells, which do not. Within six 
months of infection there is a measurable depression of the immune 
response to pokeweed mitogen (an antigen which provokes CD4+ response).  
FIV infected cats also show depressed responses to lipopolysaccharide, 
and diptheria toxoid, having a particularly poor IgM response. There is 
decreased production of and response to IL-2 in conjunction with a 
hypergammaglobulinemia. Interestingly, even FIV+ cats with apparently 
normal CD4+ cell counts show a depressed response to diptheria toxoid. 
FIV shows a high preference for the CD4+ T cell over the course of  in 
vivo infection, and FIV+ cats appear to have normal populations of CD8+ 
and B cells as well as having normal levels of IgM and IgA. 3

Antibody specific for FIV can be detected in serum by ELISA, 
immunofluorescence, or western blot. There is presently no commercially 
available vaccine against FIV, although research continues to search for 
one. Despite the high antigenic variation of FIV, researchers from UC 
Davis reported good results as early as 1991 in the search for a vaccine, 
using fixed infected cells as well as inactivated whole virus. Continuing 
research published in April of 1993  by Yamamoto et al. reported data 
suggests that antiviral humoral immunity, possibly in conjunction with 
anticellular antibodies, was perhaps responsible for the previously 
reported vaccine protection.4

FIV, like other lentiviruses, is able to replicate in terminally 
differentiated cells, and has been documented to infect astrocytes, B 
cells, macrophages, and both CD4+ and CD8+ T cells, both in vivo and in 
vitro. Some isolates of FIV are also able to replicate in Crandell feline 
kidney (CRFK) cells. Because CRFK cells as well as the peripheral blood 
monomuclear cells express the feline homologue of CD9, the putative FIV 
receptor5, it would seem that there must be additional cellular factors 
present for replication to occur. This situation is similar to that 
observed with HIV-1, in which the mere presence of the CD4 receptor is 
not sufficient to permit replication to take place within all studied 
cell types.

Cell tropism of lentiviruses is known to be significant in the case of 
ovine lentivirus (macrophage-lytic isolates cause a lymphoproliferative 
disease in vivo, whereas nonlytic viruses do not cause clinical signs of 
disease), and strains of simian immunodeficiency virus (SIV) which 
demonstrate differing host cell ranges also vary in pathogenicity.  
Additionally, in early HIV-1 infection, non-syncytium-inducing 
macrophage-tropic viruses are isolated, whereas the isolation of 
syncytium-inducing, T cell-tropic viruses later signals the onset of 
AIDS.  Therefore, it seems clear that among these lentiviruses, there is 
a correlation between host cell tropism and pathogenicity. It is unknown 
at this time, however, whether or not a similar correlation exists 
between the cell tropism of FIV and its pathogenic potential.

Investigating the issue of tropism, which is crucial for pathogenicity, 
researchers found it necessary to look for a tropism segment of the 
genome. In fact, the CRFK tropism has been successfully mapped to the 3' 
end of the FIV genome, and it has been proven that a single amino acid 
mutation in the V3 variable region of the viral envelope is directly 
responsible for the variation in cell tropism between two variants of the 
virus: clone pPET-113th replicates only in thymocytes, and clone 
pPET-113Cr replicates in both thymocytes and CRFK cells.  When the 
HindIII-NsiI envelope DNA fragment B was exchanged between these two 
clones, pPET-113Cr lost the ability to replicate in CRFK cells, and 
pPET-113th gained the ability to replicate in CRFK cells. Both clones 
retained the ability to replicate within lymphocytes, ruling out the 
possiblity that the switch caused pPET-113Cr to become completely unable 
to replicate.  Therefore, it should be generally accepted that the 
envelope gene of FIV contains at least one (HindIII-NsiI envelope DNA 
fragment B ) determinant for host cell tropism. 6 

Interestingly, this region of the genome (the V3 region) is also an 
important neutralization domain.  The fact that a tropism determinant and 
a neutralization domain are present in the same genomic region suggests 
that V3 is necessary for the entry of FIV into CRFK cells.  The mechanism 
by which V3 interacts with surface membrane proteins is also, however, 
unknown at this time.


As previously mentioned, feline CD9 has recently been proposed as the 
receptor of FIV, analogous to the HIV receptor CD4.  Research shows that 
a monoclonal antibody vpg15 immunoprecipitates from feline cells a single 
24,000 molecular weight species, which displays similarities to the human 
leukocyte antigen CD9. Data collected by JC Neil et al. show that the 
vpg15 antibody does in fact recognize the feline homologue of CD9 and 
implicate feline CD9 as a cellular receptor for FIV.7 The CD9 molecule is 
expressed on both the CRFK cells and the feline T cells, and monoclonal 
antibodies to CD9 can block infection of both cell types by FIV.  
Comparing FIV, then, with HIV, one might be tempted to look for a 
secondary factor on the host cell with which the V3 viral region might 
interact, because the V3 region of HIV is known to contain a tropism 
determinant, a major neutralization domain, and to interact with 
secondary receptor proteins (besides CD4).

Supporting the proposition that CD9 is not the only receptor is research 
done by Tompkins, et al., which described  in vivo tropism in 16 cats. 
This study found that  FIV demonstrates a broad tropism for peripheral 
blood mononuclear cells: while CD4+ cells did carry the highest burden of 
virus during the acute stage of infection, Ig+ cells carried a greater 
burden of virus in the chronically infected cats.8 

FIV is shed in saliva and often transmitted by bites. Many older male 
cats that spend time outdoors become infected, probably due to the 
fighting that occurs between territorial, free-roaming males.  Until 
recently it was believed that there was little if any vertical 
transmission, but recent research done by Dr. Hoover, et al.  at CSU 
shows otherwise.  Their work showed that pregnant cats acutely infected 
with FIV (FIV-CSU-2771) did transmit the virus to their offspring via 
prenatal and postnatal routes. Prenatal (in utero) transmission (70% 
overall infection rate during acute maternal infection) had various 
pathogenic consequences such as arrested development, abortion, 
stillbirth, low birth weight, and birth of viable, asymptomatic, but 
virus-infected and T-cell deficient kittens. Postnatal, milk-borne 
transmission was suspected after the isolation of both cell-free and 
cell-associated virus in both colostrum and milk, and was confirmed 
through a foster nursing experiment. 9 Research on this topic is 
continuing, as some suspect FIV vertical transmission may be a useful 
animal model with with to evaluate methods of preventing HIV positive 
mothers from infecting their babies.  

Additionally, it was shown that FIV could frequently be isolated from 
vaginal cells in both the pre and post partum periods.  Another project 
at Johns Hopkins showed that a single dose of 2 million FIV-infected cat 
Tcells delivered into the rectum or vagina would caused infection in 10 
out of 11 cats. Despite this data, it is currently believed that FIV is 
not sexually transmitted, although research may continue on that topic as 
well.10

When healthy cats live with infected cats nonaggressively, sharing food 
and water and engaging in normal grooming behavior, the virus is only 
rarely spread.

1Veterinary Immunology, 4th ed., Ian Tizard, WB Saunders, Philadelphia, 
1992
2Journal of the American Veterinary Medical Association, 199(10):1311-5, 
11/15/91, C.Novotney, et al.
3Journal of the American Veterinary Medical Association, 199(10):1311-5, 
11/15/91, C.Novotney, et al.
4Journal of Virology, 67(4):2344-8, 4/93, Yamamoto et al.
5Immunology, 81(2):228-33, Neil et al, 2/94
6Journal of Virology, 69(8):4752-4757, 8/95, Verschoor, et al.
7Immunology 81(2):228-33, Neil et al.,2/94
8Journal of Virology 67(9):5175-86, 9/93, Tompkins et al.
9Aids Research and Human Retroviruses, 11(1):171-82, Hoover et al., 1/95
10Aids, 7(6):797-802, Cone et al.,6/93