Antiviral therapy reduces viral burden but does not prevent thymic involution in young cats infected with feline immunodeficiency virus.
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The thymus is a major target organ in human immunodeficiency virus type 1 (HIV-1)-infected children and feline immunodeficiency virus (FIV)-infected young cats (G. A. Dean and N. C. Pedersen, J. Virol. 72:9436-9440, 1998; J. L. Heeney, Immunol. Today 16:515-520, 1995; S. M. Schnittman et al., Proc. Natl. Acad. Sci. USA 87:7727-7731, 1990; T. A. Seemayer et al., Hum. Pathol. 15:469-474, 1984; H.-J. Shuurn et al., Am. J. Pathol. 134:1329-1338, 1989; J. C. Woo et al., J. Virol. 71:8632-8641, 1997; J. C. Woo et al., AIDS Res. Hum. Retrovir. 15:1377-1388, 1999). It is likely that the accelerated disease process in children and cats is due to infection of the thymus during the time when generation of naive T lymphocytes is needed for development of the mature immune system. Zidovudine (ZDV) monotherapy, which is used to prevent and treat perinatal HIV-1 infection (R. Sperling, Infect. Dis. Obstet. Gynecol. 6:197-203, 1998), previously had been shown to reduce viral burden in FIV-infected young cats (K. A. Hayes et al., J. Acquir. Immune Defic. Syndr. 6:127-134, 1993). The purpose of this study was to evaluate the effect of drug-induced reduction of viral burden in the thymus on virus-mediated thymic involution and peripheral blood CD4 decline using FIV-infected cats as a model for pediatric HIV-1 infection. Eight-week-old cats were randomly assigned to uninfected, saline-treated; uninfected, ZDV-treated; FIV-infected, saline-treated; and FIV-infected, ZDV-treated groups. Parameters measured included blood lymphocyte numbers, viral load in blood and thymic tissue, and thymic histopathology. While the viral burden was significantly reduced by ZDV monotherapy in peripheral blood lymphocytes, plasma, and thymus, thymic lesions were similar for the treated and untreated FIV-infected cats. Further, markedly lowering the viral burden did not increase blood CD4 lymphocyte numbers or prevent their decline. The data suggest that an inflammatory process continued in spite of reduced virus replication. These observations imply that reducing virus load and limiting thymic inflammation are separate factors that must be addressed when considering therapeutic strategies aimed at preserving thymic function. (+info)
Seroepidemiological survey of infection by feline leukemia virus and immunodeficiency virus in Madrid and correlation with some clinical aspects.
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A study of 180 healthy cats found that 15.6% were feline leukemia virus (FeLV) positive, 8.3% were feline immunodeficiency virus (FIV) positive, and 1.1% were FIV and FeLV positive, which corresponded to 30.4, 13.8, and 2.6, of 115 cats with FIV- and FeLV-related symptoms, respectively. Differences were seen in the sexes and ages of the populations studied. Anemia, leukopenia, and lymphopenia were the most frequent hematological abnormalities in infected cats. (+info)
Immunization of cats against feline immunodeficiency virus (FIV) infection by using minimalistic immunogenic defined gene expression vector vaccines expressing FIV gp140 alone or with feline interleukin-12 (IL-12), IL-16, or a CpG motif.
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Four groups of cats, each containing four animals, were immunized at 0, 3, and 6 weeks with minimalistic immunogenic defined gene expression vector (MIDGE) vaccines containing the gene(s) for feline immunodeficiency virus (FIV) gp140, FIV gp140 and feline interleukin-12 (IL-12), FIV gp140 and feline IL-16, or FIV gp140 and a CpG motif. MIDGEs were coated onto gold beads and injected intradermally with a gene gun. A fifth group of four cats were immunized in an identical manner but with blank gold beads. All cats were challenge exposed to virulent FIV 4 weeks following the final immunization, and the course of infection was monitored. The two groups of cats immunized with the FIV gp140 gene alone or with blank gold particles became highly viremic and seroconverted as early as 4 weeks after infection. In contrast, three of four cats immunized with FIV gp140 in combination with feline IL-12 failed to become viremic or seropositive, as has been shown elsewhere (F. S. Boretti, C. M. Leutenegger, C. Mislin, et al., AIDS 14:1749-1757, 2000). Here we show the effect of IL-12 when used as an adjuvant on the viral RNA and DNA load and on the cytokine profile. In addition, the two groups of cats immunized either with gp140 and IL-16 or with gp140 and the CpG had greatly reduced viremia. Protection correlated weakly with cytotoxic T-lymphocyte activity and increased cytokine transcription of IL-12, gamma interferon, and IL-10 by peripheral blood mononuclear cells in the postchallenge period. This study extends the data on IL-12 and provides new results on CpG motifs and IL-16 used as adjuvants in the FIV cat model. (+info)
Relationship of lymphoid lesions to disease course in mucosal feline immunodeficiency virus type C infection.
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Feline immunodeficiency virus (FIV) infection typically has a prolonged and variable disease course in cats, which can limit its usefulness as a model for human immunodeficiency virus infection. A clade C FIV isolate (FIV-C) has been associated with high viral burdens and rapidly progressive disease in cats. FIV-C was transmissible via oral-nasal, vaginal, or rectal mucosal exposure, and infection resulted in one of three disease courses: rapid, conventional/slow, or regressive. The severity of the pathologic changes paralleled the disease course. Thymic depletion was an early lesion and was correlated with detection of FIV RNA in thymocytes by in situ hybridization. The major changes in thymic cell populations were depletion of p55+/S100+ dendritic cells, CD3- cells, CD4+/CD8- cells, and CD4+/CD8+ cells and increases in apoptosis, CD45R+ B cells, and lymphoid follicles. In contrast to thymic depletion, peripheral lymphoid tissues often were hyperplastic. Mucosally transmitted FIV-C is thymotropic and induces a spectrum of lymphoid lesions and disease mirroring that seen with the human and simian immunodeficiency virus infections. (+info)
Immunogenicity of an anti-clade B feline immunodeficiency fixed-cell virus vaccine in field cats.
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Attempts at vaccine development for feline immunodeficiency virus (FIV) have been extensive, both because this is a significant health problem for cats and because FIV may be a useful vaccine model for human immunodeficiency virus. To date, only modest success, producing only short-term protection, has been achieved for vaccine trials in controlled laboratory settings. It is unclear how relevant such experiments are to prevention of natural infection. The current study used a vaccine that employs cell-associated FIV-M2 strain fixed with paraformaldehyde. Subject cats were in a private shelter where FIV was endemic, a prevalence of 29 to 58% over an 8-year observation period. Cats roamed freely from the shelter through the surrounding countryside but returned for food and shelter. After ensuring that cats were FIV negative, they were immunized using six doses of vaccine over a 16-month period and observed for 28 months after the initiation of immunization. Twenty-six cats (12 immunized and 14 nonimmunized controls) were monitored for a minimum of 22 months. Immunized cats did not experience significant adverse effects from immunization and developed both antibodies and cellular immunity to FIV, although individual responses varied greatly. At the conclusion of the study, 0 of 12 immunized cats had evidence of FIV infection, while 5 of 14 control cats were infected. Thus, the vaccine was safe and immunogenic and did not transmit infection. Furthermore, vaccinated cats did not develop FIV infection in a limited clinical trial over an extended time period. Thus, the data suggest that a fixed, FIV-infected cell vaccine has potential for preventing natural FIV infection in free-roaming cats. (+info)
Expression of CXCR4 in the brain of feline immunodeficiency virus infected cat.
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Advances in understanding the mechanisms of human immunodeficiency virus (HIV)-1 entry have revealed that the cell surface CD4 expression alone is insufficient and needs an additional molecule on its surface for the viral entry. These are G-protein coupled seven transmembrane (7-TM) family molecules (chemokine receptor) and amongst them one is CXCR4. Feline homologue of CXCR4 acting as a co-receptor for feline immunodeficiency virus (FIV) entry is already reported for the Crandle feline kidney cells strain (CrFK) of FIV. An experiment was carried out to search the expression of CXCR4 retrospectively in FIV (CrFK) infected cat brain tissues using immunohistochemically in the formalin fixed paraffin sections against 12G5, a mouse monoclonal antibody to CXCR4. We observed the expression of this receptor in feline neurons, astrocytes and in some vascular endothelial cells. The study of expression of CXCR4 in the brain, which is one of the many chemokine receptors in the central nervous system, may provide further insight into the interactions between brain cells, pathogens, and the immune system, and help understand the pathogenesis of HIV dementia. (+info)
Phenotypic and functional characteristics of FIV infection in the bone marrow stroma.
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Human (HIV) and feline (FIV) immunodeficiency virus has been reported to infect bone marrow (BM) and stroma, followed by a loss in normal hematopoiesis. However, the magnitude and nature of HIV and FIV pathogenesis of the BM/stromal network are still unclear. In the current studies, pathogenesis of stromal cells was evaluated using the FIV model. Fourteen specific-pathogen-free cats inoculated with the four different strains (FIV(UK8), FIV(Bang), FIV(Shi), or FIV(Pet)) were monitored for FIV infection in the peripheral blood mononuclear cells (PBMC), BM cells, and stromal cells. All inoculated cats became positive for FIV in the PBMC by 7 weeks p.i. and 13 of 14 cats had FIV in the BM cells by 7-13 weeks p.i. FIV was detected in macrophages and stromal fibroblasts from FIV(UK8)-, FIV(Bang)-, and FIV(Shi)-infected cats but not from FIV(Pet)-infected cats and only transiently in cells from FIV(Shi)-infected cats. The ability of the supernatants from FIV-infected stromal cells to sustain the growth of uninfected BM cells was decreased 35-46% when compared to the supernatants from uninfected stromal cells. These results suggest that the FIV infection of the stroma alters normal hematopoietic function(s) and that the infected stromal cells can also serve as a reservoir for FIV infection. (+info)
Thymic lesions in cats infected with a pathogenic molecular clone or an ORF-A/2-deficient molecular clone of feline immunodeficiency virus.
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Previous studies using feline immunodeficiency virus (FIV) molecular clones lacking the putative transactivator gene (ORF-A/2) failed to address the issue of thymus pathogenesis or investigate the levels of viral replication in separate lymphoid compartments (Y. Inoshima, et al., J. Virol. 70:8518-8526, 1996; E. E. Sparger, et al., Virology 205:546-553, 1994). Using a highly pathogenic molecular clone of FIV, JSY3, and an ORF-A/2-deficient mutant, JSY3DeltaORF-A/2, we compared viral replication and the extent of thymic dysfunction as measured by the formation of lymphoid follicles and alteration of the thymocyte subsets. Viral replication was reduced in JSY3DeltaORF-A/2-infected cats as measured by lymphocyte coculture, immunohistochemistry, and quantitative PCR. Cell-associated viral load measured by lymphocyte coculture varied in a tissue-dependent manner with replication highest in lymphocytes isolated from the thymus, lower in those from the peripheral blood, and lowest in those from lymph node. Thymic proviral load and the number of viral p24 Gag-positive cells within the thymus detected by immunohistochemistry were also reduced. In addition, the onset of a reduced peripheral blood CD4/CD8 ratio was delayed in JSY3DeltaORF-A/2-infected cats. The formation and extent of thymic lymphoid follicular hyperplasia were similar in JSY3 and JSY3DeltaORF-A/2-infected cats as measured by anticytokeratin immunohistochemistry and flow cytometry for percent pan T-negative, immunoglobulin G-positive cells within the thymus. In contrast, comparison of thymocyte subpopulations demonstrated a reduced expansion of single-positive CD4(-) CD8(+) thymocytes in JSY3DeltaORF-A/2-infected cats. Level of viral replication, therefore, may not correlate with the formation of thymic lymphoid follicles but may correlate with the expansion of the single-positive CD4(-) CD8(+) thymocyte subpopulation. (+info)