Contributing Causes of FIV Disease Progression
1. Viral Strain
2. Route of Infection
3. Age of Cat When Infected
4. State of Infecting Cat
5. Concurrent Illnesses
6. Immune Background
7. Environmental Circumstances
Click here to open a Glossary of Terms in a separate window.
Cats infected with FIV experience a wide variety of disease outcomes, ranging from rapid onset
of AIDS and subsequent death to an open-ended period of good health that may last an entire
lifetime. (For a discussion of the traditional “staging” of FIV infection, click here.) This variability sets FIV apart from HIV, which has a more clearly defined course and
prognosis and which is fatal in all but a relatively small number of circumstances. Laboratory
studies–supplemented by field observations and accounts–have identified a number of variables
affecting the pathogenicity of FIV infection. Some of these variables have been clearly tied to
projected life span; in others cases, the pace and expression of disease progression--and ultimate
outcome-- must be inferred from effects over a period of time that are projected into the future.
Data, as in so many areas of FIV research, is sometimes contradictory.
1. Viral Strain
FIV is divided into 5 clades, A,B,C,D, and E. The divisions are based on a > 15-30% difference
in amino acid sequences of the viral envelope. Clade does not seem to have a direct relation to
viral pathogenicity. Each contains strains of high pathogenicity (One clade C strain causes
disease incidence and severity so high that there is approximately 60% mortality within 18 weeks
post-infection) and low, the difference determined by statistically minor variations in genetic
makeup [de Rozìeres][Fuller]. In a study of neutralization of the virus by lysis (cell destruction)
via the complement system, two distinct isolates of FIV and their reaction to complement lysis
were compared. One proved more vulnerable than the other. Concluded the researchers, “It
appears that factors intrinsic to the virus isolate may influence the amplitude of
complement-dependent viral lysis” [Fevereiro]. These kinds of variable responses appear
repeatedly in comparative studies, the largest published in 2002 [de Monte]. In another study,
three cats were experimentally infected by the same route with three distinct strains of Clade A
virus, housed under the same conditions, and observed for over 8 years. The cat infected with
Petaluma, the original isolate from which the existence of FIV was demonstrated, developed
severe stomatitis/gingivitis, anorexia, emaciation, as well as pancytopenia and, and finally died
at 8 years and 8 months post-infection. Plasma viral load of the cat at AIDS phase was
considerably higher than that of the two healthier cats infected with different strains [Kohmoto].
Cell tropism (the particular types of cells that individual strains of virus are programmed to seek
out) is known to be important for determining pathogenicity. A study of two viral isolates
concluded that “restriction in cell tropism in vivo may at least partially account for the lack of
pathogenicity of these two FIV cloned viruses, and particularly FIV-pPPR, which was
nonpathogenic in the face of a persistent viremia.” [Dean]. Caution should be exercised in
applying laboratory results in many studies to actual situations. Researchers frequently select
strains of high pathogenicity in order to shorten the period of required observation and produce
clearly defined effects to observe and measure.
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References
Dean GA, Himathongkham S, and Sparger EE. Differential Cell Tropism of Feline Immunodeficiency Virus
Molecular Clones In Vivo. J Virol. 1999 April; 73(4): 2596–2603.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC104014/?
de Monte M, Nonnenmacher H, Brignon N, Ullmann M, Martin JP. A multivariate statistical analysis to follow the
course of disease after infection of cats with different strains of the feline immunodeficiency virus (FIV). J Virol
Methods. 2002 May 16;103(2):157-70. http://www.ncbi.nlm.nih.gov/pubmed/12008010?
de Rozieres S, Thompson J, Sundstrom M, Gruber J, Stump DS, de Parseval AP, VandeWoude S, Elder JH.
Replication properties of clade A/C chimeric feline immunodeficiency viruses and evaluation of infection kinetics in
the domestic cat. J Virol. 2008 Aug;82(16):7953-63. http://www.ncbi.nlm.nih.gov/pubmed/18550665?
Fevereiro M, Roneker C, de Noronha F. Enhanced neutralization of feline immunodeficiency virus by complement
viral lysis. Vet Immunol Immunopathol. 1993 Apr;36(3):191-206. http://www.ncbi.nlm.nih.gov/pubmed/7685130?
Fuller FJ. Genes controlling retroviral Virulence. Adv Vet Med. 1997;40:135-55. Genes controlling retroviral
virulence. Adv Vet Med. 1997;40:135-55. http://www.ncbi.nlm.nih.gov/pubmed/9395732?
Kohmoto M, Uetsuka K, Ikeda Y, Inoshima Y, Shimojima M, Sato E, Inada G, Toyosaki T, Miyazawa T, Doi K,
Mikami T. Eight-year observation and comparative study of specific pathogen-free cats experimentally infected with
feline immunodeficiency virus (FIV) subtypes A and B: terminal acquired immunodeficiency syndrome in a cat
infected with FIV petaluma strain. J Vet Med Sci. 1998 Mar;60(3):315-21.
http://www.ncbi.nlm.nih.gov/pubmed/9560779?
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2. Route of Infection
Once again, laboratory results may, to some extent, reflect laboratory methods. “Parenteral” (i.e.,
by hypodermic injection) inoculation of virus to produce infection does not mimic natural
infection and may affect outcome. Under natural conditions, infection occurs either by tooth
penetration drawing blood or across a mucosal surface via the mouth or vagina. Up to 10,000
times as much virus can be required to infect by the latter as compared to the bloodborne route.
10 times more virus are required to infect across oral as compared to vaginal mucosa
[Burkhard/Dean]. Viral strain and route of infection can be closely tied together, with different
combinations showing different pathogenicities. In a 2002 study of two discrete Clade A and B
isolates introduced mucosally and intravenously, provirus (integrated virus) titers produced by
the B isolate were highest in cats exposed IV. In contrast, plasma RNA (free virus) titers were
higher in cats infected vaginally with the A isolate. In cats infected IV, CD4(+) lymphocyte
counts declined significantly regardless of viral titer. Decline in lymphoproliferative response
occurred in cats with both isolates, correlating with peak plasma viral load in B-infected but not
A-infected cats. Concluded the researchers, “These results establish that the kinetics of early FIV
infection differ with route of exposure as well as virus isolate and that properties extrapolated
from one virus isolate may not be universal” [Burkhard/Mathiason]. These differing kinetics can
be assumed to have long-term implications for disease expression. Mucosal transmission
involves a particularly complex set of interactions with other host factors, resulting in a variety of
outcomes. In a 2000 report of a study of a clade C strain involving oral-nasal, vaginal, and rectal
exposure, researchers noted, “In contrast to previous intravenous passage studies, a broader range
of host-virus relationships was observed after mucosal exposure.” Three categories of infection
were observed. “(1) rapidly progressive infection marked by high virus burdens and rapid CD4+
cell depletion (43% of vaginally exposed animals); (2) conventional (typical) infection featuring
slowly progressive CD4+ cell decline (61% of all exposed animals); and (3) regressive (transient)
infection marked by low and then barely detectable virus burdens and no CD4+ cell alterations
(22% of rectally inoculated cats)” [Obert].
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References
Burkhard MJ, Dean GA. Transmission and Immunopathogenesis of FIV in Cats as a Model for HIV. Current HIV Research, 2003, 1, 15-29. http://www.bentham.org/chivr/sample/chivr1-1/Burkhard.pdf
Burkhard MJ, Mathiason CK, O'Halloran K, Hoover EA. Kinetics of early FIV infection in cats exposed via the
vaginal versus intravenous route. AIDS Res Hum Retroviruses. 2002 Feb 10;18(3):217-26.
http://www.ncbi.nlm.nih.gov/pubmed/11839157?
Obert LA, Hoover EA. Feline immunodeficiency virus clade C mucosal transmission and disease courses. AIDS
Res Hum Retroviruses. 2000 May 1;16(7):677-88.
http://www.ncbi.nlm.nih.gov/pubmed/10791878?
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3. Age of Cat When Infected
Several studies of cats at different ages have concluded that age at the time of infection affects
disease expression and outcome. The very young and the relatively old are at a distinct
disadvantage. In a 1993 study, “neonatal, young adult, and aged specific pathogen-free cats
were experimentally infected with cat-passaged Petaluma strain of feline immunodeficiency
virus. The primary stage of illness . . . differed in severity and clinical signs. Generalized
lymphadenopathy persisted for the entire 42-week study period in neonatally infected cats, was
transient in young adults. . . . [T]wo aged cats became chronically and severely ill during the
study. One aged cat died with severe necrotizing transmural enteritis, while a second developed
chronic generalized staphylococcal pyoderma that was partially controlled with antibiotics.”
Neutropenia , persisting decrease in CD4:CD8 ratio, and loss of absolute CD8+ lymphocytes
were all more severe in newborn and aged cats than in young adults, and antibody response to
FIV was weaker in the aged cats during the acute phase of infection. Researchers concluded,
“Although there are some differences between FIV infection of cats and HIV infection of human
beings, age at infection influences the severity of disease in both species”[George]. A second
study two years later, working only with kittens, likewise concluded that age was a significant
factor. “We found that FIV effects were modulated, albeit incompletely, by age as has been
reported for SIV infection (2). Approximately 60% of 12- and 16-week old age cats developed
the rapid disease syndrome, whereas (8-week-old) animals had 100% mortality with lower titer
virus input” [Diehl].
Neonates particularly have been intensively and repeatedly studied. There is broad agreement
that, as a group, cats infected with FIV by their mothers in utero, during birth, or from nursing
experience accelerated disease progression. One report states, “Cats infected in utero or at birth
tend to exhibit accelerated progression of disease and decreased postnatal viability” [Rogers].
Another, “Perinatally infected kittens develop similar clinical signs, alterations in CD4+ and
CD8+ T cell subsets, antibody responses, and immune dysfunction as FIV infected adult cats
although rapid progression and failure to thrive are also noted” [Burkhard]. Several studies
compare adults and neonates, identifying more extensive thymic lesions in the latter, the thymus
being the organ where T cells mature and differentiate. In one, the infected kittens had higher
viral burden without the characteristic retreat after acute infection has subsided. “The viral loads
in adult and newborn cats have been compared following injection with feline CD4+ FeL-039
line cells acutely infected with feline immunodeficiency virus (FIV). The level of virus genome
in peripheral blood mononuclear cells (PBMC) increased progressively . . . in the newborn cats,
whereas the virus genome was apparently cleared . . . in the adult cats. Immunohistochemical
staining of thymus of the FIV-infected newborn cats showed clusters of viral antigen-positive
cells. These results indicate that FIV infection of the newborn cat results in higher virus loads
than infection of the adult cat” [Tokunaga].
Maternal infection does not always yield a doomed kitten. As elsewhere noted, mothers
infected artificially in the laboratory may not be directly comparable to those infected naturally.
Anecdotally, cats “born with FIV” have sometimes done well. One study has documented a
variety of outcomes in the same litter. “Regression of feline immunodeficiency virus (FIV)
infection was observed in seven of nine vertically infected kittens born to two chronically
infected mother cats. . . . All seven cats remained asymptomatic although CD4 and CD8 T cell
counts were in the low normal range throughout the study. By contrast, two additional perinatally
infected littermates that were persistently virus isolation positive developed rapid CD4 depletion
and progressed to terminal immunodeficiency by 9 weeks of age. Thus FIV infection can be
downregulated and/or sequestered to extremely low levels barely detectable with the assays
available, although absolute clearance of virus may not occur” [O’Neil].
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References
Burkhard MJ, Dean GA. Transmission and Immunopathogenesis of FIV in Cats as a Model for HIV. Current HIV
Research, 2003, 1, 15-29 15 http://www.bentham.org/chivr/sample/chivr1-1/Burkhard.pdf
Diehl LJ, Mathiason-Dubard CK, O'Neil LL, Obert LA, Hoover EA. Induction of accelerated feline
immunodeficiency virus disease by acute-phase virus passage. J Virol. 1995 Oct;69(10):6149-57.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC189512/pdf/696149.pdf
George JW, Pedersen NC, Higgins J. The effect of age on the course of experimental feline immunodeficiency virus
infection in cats. AIDS Res Hum Retroviruses. 1993 Sep;9 (9): 897-905.
http://www.ncbi.nlm.nih.gov/pubmed/8257637?
O'Neil LL, Burkhard MJ, Obert LA, Hoover EA. Regression of feline immunodeficiency virus infection. J Virol.
1997 May 20;13(8):713-8. http://www.ncbi.nlm.nih.gov/pubmed/9168240?
Rogers AB, Hoover EA. Maternal-fetal feline immunodeficiency virus transmission: timing and tissue tropisms. J
Infect Dis. 1998 Oct;178(4):960-7. http://www.ncbi.nlm.nih.gov/pubmed/9806022?
Tokunaga K, Shoda K, Nishino Y, Mori S, Zhong Q, Zheng YH, Kishi M, Ishihara C, Kanda M, Ikuta K.
Maintenance of high virus load even after seroconversion in newborn cats acutely infected with feline
immunodeficiency virus. Vaccine. 1995;13(15):1393-8. http://www.ncbi.nlm.nih.gov/pubmed/8578815?
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4. State of Infecting Cat
Discoveries about HIV have sparked an interest among FIV researchers in the role of the
disease state of the infecting cat in the disease expression of the infected cat. A 1995 study of
kittens concluded that there was such a role. “[W]e examined whether virus from cats in the
asymptomatic or chronic phase of FIV infection was as pathogenic as that from acute-phase
infection or if there was evidence for in vivo selection of less pathogenic variants. . . . Mortality
and rate of disease progression were affected by . . . whether the virus source animal was in the
acute or chronic stage of infection” [Diehl]. A study of vertical FIV transmission (mother to
kitten) “ found that low maternal CD4 count (<200 cells per microl), longer duration of maternal
infection (>15 months), and maternal symptoms of clinical immunodeficiency correlated with
increased rates of mother-to-kitten FIV transmission, paralleling observations in human
immunodeficiency virus-infected women” [O’Neil]. A greater likelihood to infect does not
equate with an accelerated disease process in the infected, but does tend to bear out, in a general
way, a relationship between level of infection and possible effect on the next individual in the
line of transmission.
Numerous studies have also found a “correlation between the inoculated dose of virus and the
intensity and duration of clinical signs . . . ” [Moraillion]. In natural-infection situations, infecting
cats have varying amounts of virus in their saliva, reflecting their systemic viral load. A study
published in 2000 [Hokanson] reported as follows:
Acute mucosal pathogenesis of feline immunodeficiency virus is independent of viral dose in vaginally
infected cats. The effects of virus dose on host response were evaluated for the PPR strain of feline
immunodeficiency virus (FIV-PPR). Specific pathogen-free cats were inoculated intravenously with 50, 250
or 1250 TCID(50) of FIV-PPR. Two weeks after inoculation, virus was detected in 10(6) peripheral blood
mononuclear cells (PBMCs) of all infected animals, and the CD4(+):CD8(+) T lymphocyte ratios fell from
greater than 2 to approximately 1 in all infected animals within the first 8 weeks after infection. Provirus
detected in all groups using PCR and 10(3) PBMC was biphasic. Nine of 15 animals were positive between
weeks 2 and 4 p.i. and 14 of 15 were positive by week 8 p.i. Transient lymphadenopathy was detected in
most cats receiving 1250 TCID(50) and the 250 TCID(50) of virus, whereas no lymphadenopathy was
detected in the 50 TCID(50) group or the five uninfected cats. Animals that had received the largest dose
seroconverted earliest (on average at week 4.0) and those receiving the least seroconverted last (on average
at week 5.6). Neither neutropenia nor lymphopenia were detected. FIV-specific CTL responses of memory
effector cells could be detected in animals receiving all three doses but was highly variable among
individual animals. Neurological manifestations determined after 15 weeks p.i. were observed in most
infected cats, including two of the three that had received 50 TCID(50) of virus. However, the observed
neurologic abnormalities were markedly less severe in the animals receiving the least amount of virus.
Therefore, lymphadenopathy and neurologic signs of illness were less severe and seroconversion was
slower in the animals that received the lowest dose compared with those receiving the 250 and 1250
TCID(50) doses of the FIV-PPR strain.
Although it might be assumed that viral load reflects stage of infection, FIV viral load studies
have shown that there is wide variation of viral loads among cats grouped in the same disease
stage [Goto]. (See the page on “Determining Immune Status.”). Several recent studies have
involved mucosal exposure to varying amounts of virus, although, again, this was done without
an attempt to reproduce the actual conditions of natural exposure. Interestingly, they arrived at
different conclusions. In a 2007 study, “cats were mucosally challenged with 10(2)-10(6) feline
immunodeficiency virus (FIV)-infected T cells. Although high-dose exposure (10(4)-10(6) T
cells) resulted in progressive infection [italics added], no evidence of infection was seen in 5 of
6 cats exposed to 10(2) or 10(3) T cells. However, after ex vivo CD8(+) T cell depletion and
phorbol myristate acetate treatment, FIV could be reactivated in tissues from 4 cats” [Assogba].
The fact that FIV could be reactivated from the tissue of the low-dose cats shows that a small
amount of inoculum can establish an infection, but at a level which suggests a protracted
expression of actual disease. A 2010 study “found that irrespective of mucosally administered
viral dose, FIV infection was induced in all cats. However, viremia was present in only half of
the cats, and viral dose was unrelated to the development of viremia [italics added]. Importantly,
regardless of viral dose, all cats experienced significant losses of intestinal CD4+ LPL and CD8+
intraepithelial lymphocytes (IEL)” [Howard]. Again, one can’t be certain of long-term
implications, but seemingly contradictory findings regarding retroviruses are all too common.
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References
Assogba BD, Leavell S, Porter K, Burkhard MJ. Mucosal administration of low-dose cell-associated feline
immunodeficiency virus promotes viral latency. J Infect Dis. 2007 Apr 15;195(8):1184-8.
http://www.ncbi.nlm.nih.gov/pubmed/17357056?
Diehl LJ, Mathiason-Dubard CK, O'Neil LL, Obert LA, Hoover EA. Induction of accelerated feline
immunodeficiency virus disease by acute-phase virus passage. J Virol. 1995 Oct;69(10):6149-57.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC189512/pdf/696149.pdf
Goto Y, Nishimura Y, Baba K, Mizuno T, Endo Y, Masuda K, Ohno K, and Tsujimoto H. Association of Plasma
Viral RNA Load with Prognosis in Cats Naturally Infected with Feline Immunodeficiency Virus. J Virol, October
2002, Vol. 76, No. 19, 10079-10083.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC136479/?
Hokanson RM, TerWee J, Choi IS, Coates J, Dean H, Reddy DN, Wolf AM, Collisson EW. Dose response studies
of acute feline immunodeficiency virus PPR strain infection in cats. Vet Microbiol. 2000 Oct 20;76(4):311-27.
Howard KE, Reckling SK, Egan EA, Dean GA. Acute mucosal pathogenesis of feline immunodeficiency virus is
independent of viral dose in vaginally infected cats. Retrovirology. 2010 Jan 19;7(1):2.
http://www.ncbi.nlm.nih.gov/pubmed/20085648?
Moraillon A, Barré-Sinoussi F, Parodi A, Moraillon R, Dauguet C. In vitro properties and experimental pathogenic
effect of three strains of feline immunodeficiency viruses (FIV) isolated from cats with terminal disease. Vet
Microbiol. 1992 Apr;31(1):41-54.
http://www.ncbi.nlm.nih.gov/pubmed/1377438?
O'Neil LL, Burkhard MJ, Hoover EA. Frequent perinatal transmission of feline immunodeficiency virus by
chronically infected cats. J Virol. 1996 May;70(5):2894-901.
http://www.ncbi.nlm.nih.gov/pubmed/8627764?
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5. Concurrent Illnesses
While it is clear that FIV infected cats suffer more severely from infection with a number of
common viruses, bacteria, and parasites, and generally mount a slower and less efficient immune
response to them, it is somewhat less clear whether infections with these secondary organisms,
particularly those that tend to be chronic, alter the immune status of FIV+ cats for the worse. A
number of short-term studies have examined FIV in relation to other pathogens with results that
are sometimes speculative and occasionally contradictory. In most cases, verdicts necessarily
involve predicting long-term impact on the basis of short-term results. Clearly co-infection with
feline leukemia virus (FeLV), because of its high pathogenic potential and shared immune-degrading character, has a profound detrimental impact on the immune competence of cats with
FIV. Numerous sources echo Neils Pedersen’s 1990 observation: “Preexistent feline leukemia
virus (FeLV) infection greatly potentiated the severity of the transient primary and chronic
secondary stages of feline immunodeficiency virus (FIV) infection” [Pedersen]. Studies of the
common upper respiratory viruses feline herpesvirus (FHV-1) and calicivirus (FCV), on the other
hand, have pretty consistently failed to find that co-infection with either has a lasting detrimental
effect on the immunity of FIV+ cats. A 1992 study found capacity for long-term antibody (IgG)
response unaffected [Reubel/Barlough]. A related study returned the same verdict for calicivirus.
“Acute FCV infection did not significantly alter the CD4+/CD8+ T lymphocyte ratio in FIV
infected compared to non-FIV infected cats. The ongoing humoral (IgG) response to FIV was not
affected by the FCV infection. There was no significant change in the proportion of FIV infected
peripheral blood mononuclear cells during 8 subsequent weeks after FCV challenge as
determined by polymerase chain reaction” [Reubel/George]. A 1995 study of FHV found that
while a virus with a laboratory-engineered deletion of a binding ligand could stimulate FIV
production when bound to the on-switch (LTR) of the viral genes integrated into a feline cell, the
actual wildtype virus inhibits the FIV LTR [Kawaguchi]. A 1996 study of Bartonella henselae
(the catscratch fever virus) in FIV+ cats found, “The incidence of lymph node swelling was
lower in only FIV antibody-positive cats (3.0%), but higher in B. henselae antibody-positive cats
(13.6%) and significantly higher in both B. henselae and FIV antibody-positive cats (42.9%)
compared with the incidence of lymph node swelling in cats which were negative for both
antibodies (5.5%)” [Ueno]. Since B. henselae DNA has been demonstrated to survive so-called
therapeutic “clearance” of the virus, an ongoing detrimental effect on the efficiency of the
lymphatic system cannot be discounted. All three pathogens, it should be noted, have been
implicated as chronic antigen stimulants of immune activity in gingivostomatitis (and in the case
of herpes and calici recurrent upper respiratory infections), which is generally found to be more
severe and more refractory to treatment in FIV+ cats.
The relationship of FIV infection to life-threatening parasitic diseases has been a subject of
ongoing interest. Opinion is divided on whether FIV+ cats are more liable to infection by or
suffer disproportionately from hemobartonella /M. haemofelis (See the “FIV and Hemobartonella” page), although one source pointedly cites reactivation of acute disease from a latent carrier as a result of immune suppression as a possibility [Just]. While a 2006 study found no differences in blood chemistry between FIV- and FIV+ cats infected with FIV [Tasker], the
subject of a possible long-term degradation of immunity by co-infection hasn’t been addressed in
detail. Toxoplasmosis and FIV coinfection have received a good deal of attention. There is broad
agreement that toxoplasmosis represents a more significant threat to FIV+ than to FIV- cats. (See
the “FIV and Toxoplasmosis” page.) A 1992 study went further and pointedly credited T gondii
with chronically degrading immune competence in FIV+ cats, finding it “likely to cause a more
rapid disease progression than that from infection with FIV alone” [Lin]. A1996 study
[Lappin/George], again comparing blood chemistries of FIV- and FIV+ cats reported,
Both groups of cats developed significant decreases in neutrophil counts following primary inoculation with
T. gondii; FIV-infected cats that were neutropenic prior to inoculation with T. gondii developed the most
profound decreases in neutrophil numbers. Both FIV-naive and FIV-infected cats became lymphopenic
during acute T. gondii infection; however, only FIV-naive cats developed lymphocytosis in the recovery
stage. FIV-infected cats had lower total CD4+ and higher total CD8+ T-lymphocyte counts than FIV-naive
cats prior to inoculation with T. gondii, but changes in these lymphocyte subsets were similar between
groups of cats during the first several weeks after inoculation. Toxoplasma gondii infection had neither an
ameliorating nor enhancing effect on T-lymphocyte subset abnormalities in FIV-infected cats during acute
or chronic infection. Both groups of cats developed comparable levels of T. gondii-specific IgM and IgG
antibodies and T. gondii antigen-specific lymphocyte blastogenic responses following primary inoculation.
Both groups of cats were fed T. gondii tissue cysts 66 wk following primary exposure and both groups were
solidly immune as evidenced by a lack of oocyst shedding and only minor changes in IgM but not IgG
antibodies.
The report is predictable in finding differences in the chemistries of the two groups and hopeful
in suggesting a lack of long-term impairment in the FIV+ group. It is also perplexing since the
primary author of the report had written elsewhere during the same period of the lively possibility
that “FIV-coinfected cats have . . . long-term activated infection . . ."[Lappin1] and ongoing
retardation of long-term antibody (IgG) response [Lappin2] as a result of their
immunosuppression. Lappin has noted elsewhere that “FIV infection on T. gondii-specific
infection humoral responses may vary depending on the duration of T. gondii infection, the
strains of T. gondii and FIV, as well as the degree of immuno-suppression induced by the FIV”
[Lappin/Dawe]. Possibly these variables explain the somewhat conflicting data.
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References
Just F, Pfister K. Frequency of h Wochenschr. aemoplasma infections of the domestic cat in Germany [Article in
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Kawaguchi Y, Maeda K, Pecoraro MR, Inoshima Y, Jang HK, Kohmoto M, Iwatsuki K, Ikeda Y, Shimojima M,
Tohya Y, et al. The feline herpesvirus type 1 ICP4 down-regulates feline immunodeficiency virus long terminal
repeat (LTR)-directed gene expression via the C/EBP site in the LTR. J Vet Med Sci. 1995 Dec;57(6):1129-31.
http://www.ncbi.nlm.nih.gov/pubmed/8720064?
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Therapy. XII Small Animal Practice. Philadelphia: Saunders, 1995:309 -14.
Lappin[2] MR. Feline toxoplasmosis: interpretation of diagnostic test results. Semin Vet Med Surg (Small Anim). 1996 Aug;11(3):154-60. http://www.ncbi.nlm.nih.gov/pubmed/8942211?.
Lappin MR, Dawe DL, Windl PA, Green CE, Prestwood AK. The effect of glucocorticoid administration on oocyst shedding, serology and cell-mediated immune responses of cats with recent/chronic
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Lappin MR, George JW, Pedersen NC, Barlough JE, Murphy CJ, Morse LS. Primary and secondary Toxoplasma
gondii infection in normal and feline immunodeficiency virus-infected cats. J Parasitol. 1996 Oct;82(5):733-42.
http://www.ncbi.nlm.nih.gov/pubmed/8885881?
Lin DS, Bowman DD, Jacobson RH. Immunological changes in cats with concurrent Toxoplasma gondii and feline
immunodeficiency virus infections. J Clin Microbiol. 1992 Jan;30(1):17-24.
http://www.ncbi.nlm.nih.gov/pubmed/1346403?
Pedersen NC, Torten M, Rideout B, Sparger E, Tonachini T, Luciw PA, Ackley C, Levy N, Yamamoto J. Feline
leukemia virus infection as a potentiating cofactor for the primary and secondary stages of experimentally induced
feline immunodeficiency virus infection. J Virol. 1990 Feb;64(2):598-606.
http://www.ncbi.nlm.nih.gov/pubmed/2153226?
Reubel GH, George JW, Barlough JE, Higgins J, Grant CK, Pedersen NC. Interaction of acute feline herpesvirus-1
and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats. Vet
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Reubel GH, George JW, Barlough JE, Higgins J, Grant CK, Pedersen NC. Interaction of acute feline herpesvirus-1
and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats. V
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Tasker S, Caney SM, Day MJ, Dean RS, Helps CR, Knowles TG, Lait PJ, Pinches MD, Gruffydd-Jones TJ. Effect
of chronic FIV infection, and efficacy of marbofloxacin treatment, on Mycoplasma haemofelis infection. Vet
Microbiol, 2006 Jul 27, np.
http://www.unboundmedicine.com/medline/ebm/record/16876338/abstract/Effect_of_chronic
_FIV_infection_and_efficacy_of_marbofloxacin_treatment_on_Mycoplasma_haemofelis_infection
Ueno H, Hohdatsu T, Muramatsu Y, Koyama H, Morita C. Does coinfection of Bartonella henselae and FIV induce clinical disorders in cats? Microbiol Immunol. 1996;40(9):617-20. http://www.ncbi.nlm.nih.gov/pubmed/8908605?
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6. Immune Background
Some aspects of disease progression are explainable only in terms of the native immune
resources that individual cats have to draw on as a start point. In one study of 226 FIV-infected
cats, 143 (63%) were found to express antibodies to the primary binding receptor on the surface
of target cells (CD134) required by FIV for attachment. “[A]nalyses revealed that the
anti-CD134 antibodies bound to a cryptic epitope [molecular region] on the receptor that was
only exposed when SU [the surface protein of the viral envelope] bound to CD134. Anti-CD134
binding caused displacement of SU from the surface of the cell and inhibition of infection. The
presence of antibodies to CD134 correlated with lower virus loads and a better overall health
status in FIV+ cats. . . . The findings are consistent with a role for antireceptor antibodies in
protection from virus spread and disease progression” [Grant]. Why would some cats generate
antibodies while others don’t? One can only assume that the native immune characteristics of
the cats differ in some regard. It is well established that how well a given cat copes with the
initial acute stage of FIV infection has ramifications into the indefinite future. Particularly
important is the effectiveness of the cell-mediated immune response via the CD8+ effector cells
(CTLs, or cytotoxic T- lymphocytes) that lyse infected cells and produce soluble factors that
inactivate virus. One study investigating the relationship between CD8+ T cell’s anti-FIV
activity and FIV proviral DNA ( integrated into cells) reported, “The anti-FIV activity and the
proviral DNA load were correlated, and the number of proviral DNA copies was high in cats
with decreased anti-FIV activity. Particularly, no anti-FIV activity was detected in the cats staged
as having an acquired immunodeficiency syndrome (AIDS)-related complex or AIDS, and the
number of proviral DNA copies was obviously increased compared to those in the cats in the
asymptomatic stage. These results suggest that decreased anti-FIV activity destroys the control of
in vivo FIV replication, which leads to an increased proviral DNA load with the progression of
the clinical stage of disease” [Hodatsu]. Why do some cats display a stronger CTL response to
the same virus when other factors in disease progression of the sort already noted are discounted?
Intrinsic immune factors seem at least part of the likely explanation.
An estimated 5% to 10% of people who are infected by HIV (called “elite controllers”) are able to naturally suppress viral replication and never develop AIDS symptoms. HIV research has established that various individual genetic peculiarities play a role in retarding disease progression. These are referred to as “restriction genes.” These factors vary from one long-term non-progressor to another. No single factor accounts for all instances of delayed progression. A recent (2008) study of the function of mitochondria (the cellular energy machines) in AIDS progression sought to determine whether variations in mitochondrial DNA (passed down through the female lineage) were owing to AIDS restriction genes. Researchers reported, “The associations found in our
study appear to support a functional explanation by which mtDNA variation among haplogroups”
influence “ATP [energy] production, ROS [oxidative stress] generation, and apoptosis
[spontaneous cell death] . . . correlated to AIDS disease progression” [Hendrickson]. A
haplogroup is a group of similar people that share a common ancestor with a single genetic
nucleotide mutation. In other people, certain combinations of so-called histocompatibility antigens seem to preclude progression. Some have white blood cells that produce a combination of chemicals called beta-chemokines, identified by Gallo in 1995, that inhibit viral replication [Maugh]. Another genetically conferred advantage relates to inheritance of particular Class I HLA genes that control antigen peptide-presenting receptors on cell surfaces. “It has been known for more than a decade that certain HLA genes make receptors that seem particularly adept at presenting HIV peptides to CD8 T cells [inviting destruction], and that possessing these HLA genes greatly increases the chances of becoming an elite controller. Conversely, some other HLA genes are associated with high HIV viral loads and rapid disease progression”[International]. A better known instance of such “lucky” genes involves the HIV co-receptor CCR5 (or CKCR5), which is necessary for viral fusion with and penetration of the cell membrane of certain target cells. A famous 1996 study reported the following. “An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 [DNA sequence] deletion[s] . . . occurred
exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion . . . was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in [those with the] CKR5 deletion. The CKR5 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a
dominant phenotype of delaying progression to AIDS among infected individuals” [Grant].
Eventually, it became clear that the small number of people who inherited this deletion error
from both parents were functionally immune to HIV infection.
Whether cats possess restriction genes that affect aspects of FIV infection is unknown , but given the number of genetic peculiarities affecting dynamics of host-virus interaction so far catalogued in HIV research, it seems highly likely that as yet undefined restriction genes play some role in the immune background of individual cats. Even more likely is that the dissemination of such genes among the many species of wild felines helps to explain why they handle FIV infection better than domestic cats do–since FIV existed in wild
populations long before the existence of felis domesticus, and there has been plenty of time for
natural selection to establish favorable genetic variations in entire species groups. An intriguing instance is provided by the APOBEC3 (A3) series of genes. Reports one source, “Our data support a complex evolutionary history of expansion, divergence, selection and individual extinction of antiviral A3 genes that parallels the early evolution of Placentalia, becoming more intricate in taxa in which the arms race between host and retroviruses is harsher.” FIV VIF protein in domestic cats negates the anti-FIV effects of A3 proteins that are effective in larger wild felids. Evidently, “FIV infecting F. catus has evolved the potential to escape A3-mediated restriction of its host since the divergence of both felide lineages” [Munk].
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References
Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, Goedert JR, Buchbinder SP, Vittinghoff
E, Gomperts E, Donfield S, Vlahov D, Kaslow R, Saah J, Rinaldo C, Detels R, O'Brien SJ. Genetic Restriction of
HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural Gene. . . Science 27
September 1996: Vol. 273. no. 5283, pp. 1856 - 1862. http://www.ncbi.nlm.nih.gov/pubmed/8791590?
Grant CK, Fink EA, Sundstrom M, Torbett BE,and John H. Elder JH. Improved health and survival of
FIV-infected cats is associated with the presence of autoantibodies to the primary receptor, CD134. PNAS.
November 24, 2009; 106(47): 19980–19985. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775039/?
Hendrickson SL, Hutcheson HB, Ruiz-Pesini E, Poole JC, Lautenberger J, Sezgin E, Kingsley L, Goedert JJ,
Vlahov D, Donfield S, Wallace DC, and O’Brien SJ. Mitochondrial DNA Haplogroups influence AIDS Progression.
AIDS. 2008 November 30; 22(18): 2429–2439. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699618/
Hohdatsu T, Nakanishi T, Saito I, Koyama H. Ability of CD8+ T cell anti-feline immunodeficiency virus (FIV)
activity and FIV proviral DNA load in mononuclear cells in FIV-infected cats. J Vet Med Sci. 2005
Jan;67(1):129-31. http://www.jstage.jst.go.jp/article/jvms/67/1/129/_pdf.
Maugh II T. Anti-HIV Find Is Revealed--and Quickly Disputed Science: A family of proteins blocks replication of the virus, researchers say. Others fault the study's methods and conclusion. The Nation. September 27, 2002. http://articles.latimes.com/2002/sep/27/science/sci-hiv27
Munk C, Beck T, Zielonka J, Hotz-Wagenblatt A, Chareza S, Battenberg M, Thielebein J, Cichutek K, Bravo IG, O'Brien SJ, Lochelt M, Yuhki N. Functions, structure, and read-through alternative splicing of feline APOBEC3 genes. Genome Biol. 2008;9(3):R48. http://www.ncbi.nlm.nih.gov/pubmed/18315870
The International HIV Controllers Study, Science Express November 4, 2010 10.1126/science.1195271.
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7. Environmental Circumstances
There is no direct research to speak of documenting the relationship between the life a cat has
lived and FIV disease expression– only a lot of anecdotal testimony and some applied reasoning
based on animal and human studies of stress and HIV disease progression. Many people who
have acquired their FIV+ cats as rescued strays in poor health, nursed them patiently back to
health, and then given them a secure indoor environment in which to live out their days are
surprised at how healthy they remain. Cats are remarkably resilient creatures. Some of those
rescues, unfortunately, don’t remain healthy. If the life they led as strays played a role in their
decline, what might some of the relevant factors be? Lack of medical care and exposure to the
elements and to other diseases–a possible accelerant already discussed–are obvious candidates.
Poor nutrition is another. Chronic retroviral infections are known to induce a dearth of vital
nutrients and internally manufactured substances that are necessary to efficient immune
functioning, effects of which can only be magnified by what might be lacking in diet. One HIV
study [Guenter] reported,
This investigation retrospectively studied relationships between survival in human immunodeficiency
virus-seropositive outpatients receiving recent therapies (n = 77) and two markers of nutritional status,
serum albumin and percent of usual body weight. Subjects were observed for an average of 186 +/- 8 days;
19% died within the study period. Kaplan-Meier curves and Cox regressions showed that older subjects
who had lower CD4 counts, lower albumin levels, or had lost more weight demonstrated poorer survival.
Albumin levels and weight loss were related to CD4 counts. The relative risk of death for subjects with low
albumin levels (<3.5 g/dl) was 3.6 times greater (p < 0.021, with 95% confidence limits [95%CL] of
1.2-10.9) than that for subjects with normal albumin levels (>=3.5 g/dl), even after controlling for age and
CD4 counts. Similarly, after controlling for CD4 counts and age, subjects whose baseline body weights
were <90% of their usual weight had a greater relative death risk (8.3 times greater, p < 0.002, 95% CL
2.3-34.1) than those who had lost less. Survivors and nonsurvivors who had similar CD4 counts differed
significantly in albumin levels (p < 0.05). Thus, nutritional status influences survival independent of CD4
counts.
Another reported that deficiency of vitamin A or vitamin B12 in people with HIV was associated
with a decline in CD4+ cell count while normalization of vitamin A, vitamin B12 and zinc was
associated with higher CD4+ cell counts. Low B12 significantly predicted accelerated HIV-1
disease progression determined by CD4 cell count and AIDS index . Researchers concluded,
“These data suggest that micronutrient deficiencies are associated with HIV-1 disease
progression and raise the possibility that normalization might increase symptom-free survival”
[Baum]. The stress of a hard-scrabble existence is probably yet another risk factor for disease
progression. There is ample research in human medicine of the relationship between stress and
compromised immune function. Stress causes cortisol production, and glucocorticoids depress
immune function. Just as glucocorticoids are routinely used in the laboratory to activate latent
pathogens, stress is widely known to, for instance, induce flares of a variety of herpes viruses.
One source [Reiche] describes the biochemistry of stress this way:
The persistent activation of the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary
axes in chronic stress response and in depression impairs the immune response. . . . At the cellular level,
stressed and depressed patients had overall leukocytosis, high concentrations of circulating neutrophils,
reduced mitogen-stimulated lymphocyte proliferation and neutrophil phagocytosis. At the molecular level,
high levels of serum basal cortisol, acute phase proteins, specific antibodies against herpes simplex virus
type 1 and Epstein Barr virus, plasma concentration of interleukins IL-1, IL-6, and TNF-a, and a shift in the
balance of Th1 and Th2 immune response were observed. Both stress and depression were associated with
the decreased cytotoxic T-cell and natural killer cell activities affecting the processes of the immune
surveillance of tumours, and the events that modulate the development and the accumulation of somatic
mutations and genomic instability. DNA damage, growth and angiogenic factors, proteases, matrix
metalloproteinases, and reactive oxygen species were also related to the chronic stress response and
depression.
Cats with retroviral infections require all of the immune forces they can muster. Effects such as
these can only lay the groundwork for decline.
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References
Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE,
Hennekens, Charles H. Micronutrients and HIV-1 disease progression. JAIDS September 1995, Volume 9, Issue 9,
pp: F7-984,985-1101.
http://journals.lww.com/aidsonline/Abstract/1995/09000/Micronutrients_and_HIV_1_disease_progression.10.aspx
Guenter P, Muurahainen N, Simons G, Kosok A, Cohan GR Rudenstein R, Turner JL. Relationships Among
Nutritional Status, Disease Progression, and Survival in HIV Infection. JAIDS October 1993, Volume 6, Issue 10,
pp: 1073-1177.
http://journals.lww.com/jaids/Abstract/1993/10000/Relationships_Among_Nutritional_Status,_Disease.8.aspx
Reiche EMV, Morimoto HK and Vargas SM. Stress and depression-induced immune dysfunction: Implications for
the development and progression of cancer. International Review of Psychiatry 2005, Vol. 17, No. 6, Pages
515-527.
http://informahealthcare.com/doi/abs/10.1080/02646830500382102
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