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1 Laboratory of Genomic Diversity, Basic Research Program, SAIC Frederick, National Cancer Institute, Frederick, Maryland 21702, USA
2 National Cancer Institute–Frederick, Frederick, Maryland 21702, USA
3 Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA
4 White Oak Conservation Center, Yulee, Florida 32097, USA
5 Department of Ecology, Evolution and Behavior, University of Minnesota, St. Paul, Minnesota 55108, USA
6 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA
8 Corresponding author (email: slattery{at}mail.ncifcrf.gov)
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Phylogenetic studies of the gag and pol genes from FIV in natural populations of pumas in North and South America and African lions in eastern and southern Africa and env regions from FIV-Fca sampled from domestic cats worldwide depict unique patterns of virus-host co-evolution. In pumas, FIV-Pco forms distinct divergent evolutionary lineages that are distributed throughout this species range (Carpenter et al., 1996; Biek et al., 2003). In lions, FIV-Ple is endemic to populations within east and south Africa and forms at least three different evolutionary clades with high levels of genetic differences (Brown et al., 1994; Troyer et al., 2004, 2005). Genetic analyses of FIV-Ple within a large out-bred population of lions in the Serengeti region of Tanzania revealed >90% prevalence with 43% of the individuals multiply infected with at least two subtypes (Brown et al., 1994; Troyer et al., 2004). In domestic cats, FIV-Fca subtype classification is made using the more variable env region rather than the pol or gag analyzed in FIV from other species. Even using the env region, FIV-Fca has lower levels of intersubtype divergence than FIV-Pco and FIV-Ple (Carpenter et al., 1998). Further, three of the five recognized subtypes or clades of FIV-Fca are composed of closely related strains from cats dwelling on different continents (Carpenter et al., 1998). Thus, the low genetic diversity and demonstrable pathogenicity of FIV in domestic cats suggest that this species acquired FIV relatively recently, whereas FIV-Pco and FIV-Ple descend from an earlier species experience with endemic virus and became attenuated as a natural outcome of a longer period of virus-host coevolution (Carpenter and O’Brien, 1995; Carpenter et al., 1996, 1998).
Under this scenario, FIV-Fca, FIV-Ple, and FIV-Pco would be expected to elicit different clinicopathologic abnormalities in their respective host species. However, evaluation of such parameters using a systematic approach in lions and pumas has been impeded by logistical difficulties and infrequent opportunities associated with sample collection in the wild, adequate preservation of samples in field conditions, and lack of reagents or reagent validation to measure blood cell responses for exotic felids accurately. Consequently, only one previously published study has reported lymphocyte subset alterations in five captive FIV-Ple seropositive lions (Bull et al., 2003) Additionally, the high seroprevalence rate of some free-ranging populations (up to 100%) (Brown et al., 1994; Carpenter and O’Brien, 1995; Biek et al., 2003; Troyer et al., 2004) may affect statistical analyses of seropositive versus seronegative groups.
Analysis of domestic cats infected with FIV-Fca, on the other hand, has been more intensively studied. Domestic cats infected with FIV-Fca experience profound changes in T-cell subsets concurrent with clinical immune deficiency. Like HIV in humans, the continued deterioration of the host immune system in FIV-positive domestic cats is correlated with the reduction in circulating CD4+ lymphocytes (Ackley et al., 1990; Novotney et al., 1990). In the initial acute phase, the CD4+/CD8+ ratio is lowered as a consequence by both the reduction of CD4+ T-cells and the marked expansion of CD8+ T-cells (Willett et al., 1993). However, subtype and/or strain-specific effects on the host circulating lymphocyte kinetics, which parallels the degree of immunosuppression or virulence, are observed in domestic cats infected with a less virulent strain of FIV characterized by low viral load (Hosie et al., 2002). Experimental infection of domestic cats with FIV-Pco or FIV-Ple results in apathogenic but productive infection (VandeWoude et al., 1997a, b, 2003; Terwee et al., 2005), which strengthens the hypothesis that nondomestic cat FIVs are host-adapted or perhaps less virulent lentiviruses.
We examined changes in T-cell lymphocytes in response to FIV infection in a cohort of both captive and free-ranging populations of lions and pumas and found significant changes in circulating lymphocyte T-cell subsets associated with FIV infection. These findings may have significant implications for management of FIV-positive endangered feline species and for the health of individual animals.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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The FIV-positive and -negative individuals were sampled from pumas in North America and African lions from the Serengeti National Park in Tanzania and Kruger National Park in South Africa (Table 1
). All pumas and free-ranging African lions were captured, anesthetized, examined, and bled as part of ongoing field studies (Roelke et al., 1993; Roelke-Parker et al., 1996). The puma sample consisted of 10 uninfected individuals (1–9 yr-old) and six FIV-Pco–infected animals (5–12 yr-old); five were captive, and 11 were free-ranging, all originating from the same population in southern Florida, USA. Twelve FIV-Ple–infected lions (2–12 yr-old) and five zoo-bred captive naive lions of unknown ages with no record of ancestral geographic origin were sampled. All seropositive lions were free-ranging in either Kruger National Park, South Africa, or Serengeti National Park, Tanzania. Captive lions were bled during routine yearly physical examinations.
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Peripheral whole blood collected from both captive and free-ranging animals was processed within 48 hr. Whole blood collected with EDTA was used for an absolute white blood cell count (WBC), determined by the Unopipette® counting system and hemocytometer, and an absolute lymphocyte count, determined by staining blood films with a modified Wright-Giemsa stain. To process samples for lymphocyte analyses, peripheral blood mononuclear cells (PBMCs) were separated from whole anticoagulated blood collected by using Histopaque-1077 (Sigma, St. Louis, Missouri, USA) and viably frozen. Five milliliters of whole blood was overlaid on 5 ml histopaque and spun at 400 x G for 30 min. The PBMC layer was removed, washed in phosphate buffered saline (PBS), and spun at 250 x G for 10 min at least twice. Cell pellets were gently suspended in 90% fetal calf serum with 10% dimethyl sulfoxide (DMSO) and viably frozen, in aliquots of 107 cells/ml/cryotube, at a rate of 1 C/min and stored in liquid nitrogen.
Serum samples were simultaneously collected and screened for antibodies to both FIV-Pco and FIV-Ple antigens. Western blot analysis for FIV-reacting antibodies was performed as previously described (Diehl et al., 1995; Vande-Woude et al., 1997a, b; Troyer et al., 2005). Tissue culture supernatant containing either virus strain grown on 3201 T-cells was concentrated by ultracentrifugation. Protein content was determined, and viral antigen was subjected to polyacrylamide electrophoresis and transferred to nylon membranes. Diluted serum was reacted with membrane strips, and bound antibody detected by horse radish peroxidase-labeled secondary antibodies. To ensure FIV antibody detection, FIV-Fca antigen was used in separate tests in addition to FIV-Pco for pumas and FIV-Ple for lions. Positive and negative sera served as controls for comparison to unknown samples.
Immunofluorescence flow cytometry
Viably frozen PBMCs were quickly thawed at 37 C, washed in PBS, counted, and resuspended in a buffer solution of PBS. The PBMCs (1x106) were combined in separate tubes with monoclonal antibodies that recognize the following: feline CD4+ (Fel7 clone CD4; Klotz and Cooper, 1986; Ackley et al., 1990); feline CD8+ (FT2 clone fCD8-Beta; Klotz and Cooper, 1986); and feline Pan-T+ cell CD5 equivalent (clone f43; Ackley and Cooper, 1992). The T-cell profiles were generated by double labeling with CD5+/CD4+, CD5+/CD8+, or CD4+/CD8+ and quantified by two-color immunofluorescence flow cytometry (IFC) using Becten-Dickenson FACscan and Cell Quest software. A dot-plot of side and forward scatter was used to construct a live lymphocyte gate of 5,000–10,000 cells per assay. The absolute number of T-cells was determined by multiplying the fraction of respective CD4+, CD8+, and CD5+ subpopulations times the number of lymphocytes/ml within the original sample. The CD5– cells, within the gated lymphocyte fraction, were considered primarily B cells, though it is possible that this fraction could also contain small proportions of monocytic cells. No conversion values were available for lions sampled from Kruger Park (Ple 133, 134, 135, 138). The potential bias introduced by using viably frozen PBMC versus those from fresh blood for IFC was addressed by setting the gates to exclude nonspecific binding and thus compensate for background staining due to cell death. Moreover, IFC analysis provided comparable results whether performed on frozen or fresh PBMC in our experience (Vande-Woude, unpublished data) as well as that of others (Bull et al., 2003).
Statistical analysis
The total T-cell (CD5+) profile generated by IFC displayed the relative proportions of CD4+, CD8+, and CD4–CD8– subpopulations within the PBMC sample. These ratios were not independent because they were derived from the total CD5+ T-cells; therefore, we performed heterogeneity G-tests (Sokol and Rohlf, 1991). Each profile was tested against the expected profile from control naive animals to determine if the individual T-cell subset profile changed with FIV infection. Significance was determined by computation of a G-statistic that approximates a chi squared distribution.
For each IFC profile, the relative proportions of CD4+, CD8+, and CD4– CD8–CD5+ cells were converted into absolute numbers of cells based on the absolute cell count of lymphocytes. We evaluated the following absolute cell counts for each animal: WBC/ml, total lymphocytes/ml, total CD5– cells/ml, CD5+ T-cells/ml, CD4+/ml, CD8+/ml, and CD4–CD8–CD5+/ml. In addition, we examined two subsets, CD8+ßlow and CD8+ßhigh, identified by the antibody FT2 as it binds specifically to the beta chain of the CD8+ heterodimer molecule. Estimates of cell counts for each were computed by multiplying the relative proportion times the estimated CD8+ cells/ml count for each individual.
The distribution of each cell count variable was tested for normality using the Shapiro-Wilks’ W suitable for small sample sizes. The relative impact of FIV status on the cell count variables for each species was tested using analysis of variance (ANOVA) and paired t-tests of means (SAS, 2001).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Further, cell count data were used to test for changes in WBC/ml, total lymphocytes/ml, total CD5– cells/ml, CD5+ T-cells/ml, CD4+ cells/ml, CD8+ T-cells/ml, CD8ßhigh/ml, CD8ßlow/ml, and CD4–CD8–CD5+ cells/ml. Shapiro-Wilks’ W test indicated normal distributions for each of these cell count variables. Two of these variables, WBC/ml and CD8+ T-cells/ml, did not change with FIV status in either lions or pumas (Table 3; Figs. 1a, b).
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The IFC profiles of the relative proportions of CD4+, CD8+, and CD4–CD8– CD5+ cells within FIV-negative pumas were uniform among individuals (G-test, NS). The mean T-cell profile for pumas infected with FIV-Pco was 42:27:29 (percentage of CD4+, CD8+, and CD4– CD8–CD5+, respectively). Three of the six FIV-Pco–infected pumas (Pco-075, Pco-733, and Pco-736) had significant differences in IFC profiles (Table 2
), but the overall mean profile for positive animals was not significantly altered relative to negative controls (G-test, P=0.069).
Infection with FIV-Pco was correlated with an overall reduction in cell counts of total lymphocytes (t-test, P=0.03) that involved both CD5+ T-cells and CD5– lymphocyte subsets and was accompanied by a 50% reduction in CD4+ cells/ml relative to uninfected pumas (t-test, P=0.008) (Table 3 and Fig. 1a). No significant changes were observed in the CD8+ and CD4–CD8–CD5+ T-cell subsets relative to the negative controls (Tables 2 and 3). Further examination of the CD8+ T-cell subset revealed no change in CD8+ßlow cells, but a significant decline in mean CD8+ßhigh cells was detected with FIV-Pco infection (t-test, P= 0.008) (Table 3 and Fig. 2a, b).
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Homogeneous IFC profiles of uninfected lion controls had an average ratio of 60 : 22 : 18 for relative CD4+, CD8+, and CD4–CD8–CD5+ percentages. In contrast, IFC profiles for infected lions were more highly heterogeneous (G-test, P=9.0x10–9), and each had significant deviation from the mean profile (G-test, P=2.5x10–5) (Table 2).
Measured cell counts indicated total lymphocytes did not vary with FIV-Ple infection as observed with FIV-Pco in pumas (Table 3 and Fig. 1b). Instead, infected lions had both a significant reduction in CD5+ T-cells (t-test, P=0.0025) and a dramatic 80% decline in CD4+ cells (t-test, P=0.0001) relative to controls (Fig. 1b). This CD4+ cell decline was observed without a significant increase in overall CD8+ levels. However, within the CD8+ subset, ßhigh cells declined precipitously with FIV-Ple infection to one-third the levels observed in controls (t-test, P=0.006) and was accompanied by an expansion of ßlow cells (t-test, P=0.03) (Fig. 2a, b). Further unique changes were observed including an increase in the cell counts of the CD4–CD8–CD5+ subset (t-test, P=0.05) and an increase in the CD5– lymphocytes (t-test, P=0.001), presumed to be mostly B cells, in infected lions relative to negative controls (Table 3 and Fig. 1b).
Alteration of the CD4+/CD8+ ratio with FIV infection
Both lions and pumas were examined for reduction of the CD4+/CD8+ ratio commonly observed in FIV-Fca infection of domestic cats. In lions, the CD4+/CD8+ ratio sharply declined from mean=2.95 (range of 2.23–5.04) in controls to mean=1.17 (range of 0.21–2.57) in FIV-Ple–infected individuals (Table 2). In contrast, the puma CD4+/CD8+ T-cell ratio was not significantly altered (Table 2) with values slightly less in pumas with FIV-Pco mean=1.73 (range of 0.91–2.57) compared with mean=1.93 (range of 1.37–2.92) in negative animals. The drop in CD4+ cells in positive pumas was accompanied by a proportional, albeit not significant, reduction in CD8+ cells (Fig. 1b) sufficient to maintain the CD4+/CD8+ ratio as unchanging with FIV-Pco status.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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The major alteration in the relative proportion and absolute cell count of CD4+, CD8+, and CD4–CD8– subsets in both seropositive lions and pumas was a reduction in CD4+ T-cells. In domestic cats infected with FIV-Fca, the CD4+/CD8+ ratio declines during the asymptomatic phase from two or more to less than one (English et al., 1994; Bendinelli et al., 1995;) because of CD4+ depletion concurrent with relative or absolute CD8+ increase. The magnitude of CD4+ depletion was profound in FIV-Ple lions and resulted in a sharp decline in the CD4+/CD8+ ratio. By contrast, the CD4+/CD8+ ratio was not significantly altered in pumas even though FIV-Pco infection was correlated with a 50% decline in CD4+ T-cells.
Additional differences between lions and pumas included alterations of total lymphocytes and CD5+ T-cells; neither of these changes paralleled the typical findings in domestic cats. For example, pumas infected with FIV-Pco had relative lymphopenia, indicated by the 41% lower total lymphocyte count, which was distributed equally between CD5+ and CD5– cell subsets. Although lymphopenia was not noted in seropositive lions (Fig. 1b), a significant decrease (48%) in CD5+ T-cells was accompanied by a compensatory increase in CD5– lymphocytes that masked this loss. Most studies have not recorded lymphopenia or pan-T-cell loss as a striking finding in domestic cat FIV infection. Therefore, assuming CD5– cells are predominantly B-cells, this increase would be a unique feature to FIV-Ple infection as B-cell lymphocyte kinetics in FIV-Fca infected cats have not been reported to be altered relative to naive controls (Ackley et al., 1990; Novotney et al., 1990).
Reduction in CD4+ cells in lions and pumas was not accompanied by an absolute increase of CD8+ cells as observed in domestic cats. During the acute and asymptomatic phases of FIV infection, CD8+ T-cells are both cytotoxic and virus-suppressive in domestic cats (Prince et al., 1991; English et al., 1994). In particular, the heterodimer CD8+ molecule exhibits changes in the composite 
and ß chains correlated with time course of viral infection, antiviral activity, and pathogenesis of disease (Shimojima et al., 1998). The CD8+ subset changes in lions and pumas in this study were based on the FT-2 antibody that binds exclusively to the ß chain of the heterodimer. Previous studies of the CD8+ ß chain in the asymptomatic phase of FIV infection in domestic cats showed depletion of CD8+ßhigh cells and the appearance and expansion of CD8+ßlow T cells, which secrete a soluble factor inhibitory for in vitro FIV infection (Bucci et al., 1998a, b; Shimojima et al., 1998; Gebhard et al., 1999). This simultaneous expansion of CD8+ßlow T-cell subsets offsets a decrease in total CD5+ T-cells with FIV-Fca infection (Willett et al., 1993). In this study, lions and pumas resembled domestic cats by having a significant depletion of CD8+ßhigh cells and a reduction of CD5+ cells, but only lions had a concomitant expansion of CD8+ßlow cells. A similar result in a study of five seropositive captive lions with an expanded CD8+ßlow subset relative to naive animals (Bull et al., 2003) suggests this is a signature of FIV-Ple infection. Results from FIV-Pco–infected pumas demonstrated a decline in lymphocytes in general, and CD4+ cells in particular, which was not offset by expansion of any subset presented here. Rather, a substantial number of CD8+ßlow cells are present in pumas irrespective of FIV status. Perhaps these cells are part of an immune response to another unspecified pathogen, or this may reflect the outcome of coevolution of virus and host that has resulted in a "standing army" within the species as a whole.
The changes in CD4+ subpopulations in lions and to a lesser extent in pumas in response to FIV infection provide strong support for T-cell dyscrasia as observed with domestic cats. Yet other lymphocyte changes specific to lions and pumas suggest that additional immune responses occur in both species, and perhaps clues reside within an uncharacterized T-cell population present within the CD4– CD8– subset. Although pumas showed no change in CD4–CD8– cell counts with FIV-Pco infection, FIV positive lions had a significant increase relative to controls. Thus, the more muted immune response of pumas consisting of general lymphopenia and reduction of CD4+ cells not accompanied by a change in the CD4+/CD8+ ratio suggests FIV-Pco causes less T-cell perturbation in pumas than FIV-Ple in lions. The FIV-Ple elicits a dramatic decline in CD4+ cells, yet lions may be in the process of coadapting to the virus, as suggested by the unique combination of increased CD5– cells, expansion of the CD8+ßlow subset, and increased numbers of CD4–CD8– cells.
Alternatively, extreme changes in CD4+ levels in lions also may be influenced by other determinants such as length of FIV infection or other microbial infections, as well as relative binding affinities of monoclonal antibodies originally developed for domestic cat T-cell antigens. The highly heterogeneous IFC profiles observed among individual wild seropositive lions relative to the more uniform profiles of control lions in zoos might reflect stress differences between captive and free-ranging populations. The fact that FIV status increases with age, and is seen with high seroprevalence in many free-ranging populations of lions (Brown et al., 1994; Troyer et al., 2004), also makes it difficult to determine how age and environmental conditions may have contributed to our findings. We were unable to assess the effect of age in this study because of insufficient replicates per age class and unknown ages for some of both positive and negative lions, leading to a prohibitively small sample for statistical analysis.
Overall, this immunological survey of naturally FIV-infected animals may serve as an indictor of the susceptibility of both captive and wild populations to emerging disease. Outbreaks of opportunistic infections, each with varying degrees of pathogenicity, have been documented in non-domestic species of cat. In lions, a canine distemper virus (CDV) outbreak caused significant mortality in free-ranging FIV-infected African lions of the Serengeti ecosystem in 1994 (Roelke-Parker et al., 1996) although other CDV outbreaks in the same seropositive populations had negligible mortality (Packer et al., 1999). In pumas, a recent outbreak of feline leukemia virus has been linked with, but no causality yet established for, the deaths of a small number of seropositive Florida panthers (M. Cunningham, unpubl. data). The precise role of FIV in regulating immune response to such opportunistic infection remains unknown, yet the T-cell changes observed in FIV-infected lions and pumas in this study suggest that further investigation is warranted and that it would be prudent to discourage the translocation of seropositive animals into naive populations.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONLITERATURE CITED |
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Received for publication 13 October 2004.
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