Processing, fusogenicity, virion incorporation and CXCR4-binding activity of a feline immunodeficiency virus envelope glycoprotein lacking the two conserved N-glycosylation sites at the C-terminus of the V3 domain.

The process of feline immunodeficiency virus (FIV) entry into its target cells is initiated by the association of the surface (SU) subunit of the viral envelope glycoprotein (Env) with the cellular receptors CD134 and CXCR4. This event is followed by the fusion of the viral and cellular membranes, which is mediated by the transmembrane (TM) subunit of Env. We and others have previously demonstrated that the V3 domain of the SU subunit of Env is essential for CXCR4 binding. Of note, there are two contiguous and highly conserved potential N-glycosylation sites ((418)NST(420) and (422)NLT(424)) located at the C-terminal side of the V3 domain. We therefore decided to study the relevance for Env functions of these N-glycosylation motifs and found that disruption of both of them by introducing the N418Q/N422Q double amino acid substitution drastically impairs Env processing into the SU and TM subunits. Moreover, the simultaneous mutation of these N-glycosylation sites prevents Env incorporation into virions and Env-mediated cell-to-cell fusion. Notably, a recombinant soluble version of the SU glycoprotein carrying the double amino acid replacement N418Q/N422Q at the V3 C-terminal side binds to CXCR4 with an efficiency similar to that of wild-type SU.

Feline tetherin is characterized by a short N-terminal region and is counteracted by the feline immunodeficiency virus envelope glycoprotein.

Tetherin (BST2) is the host cell factor that blocks the particle release of some enveloped viruses. Two putative feline tetherin proteins differing at the level of the N-terminal coding region have recently been described and tested for their antiviral activity. By cloning and comparing the two reported feline tetherins (called here cBST2(504) and cBST2*) and generating specific derivative mutants, this study provides evidence that feline tetherin has a shorter intracytoplasmic domain than those of other known homologues. The minimal tetherin promoter was identified and assayed for its ability to drive tetherin expression in an alpha interferon-inducible manner. We also demonstrated that cBST2(504) is able to dimerize, is localized at the cellular membrane, and impairs human immunodeficiency virus type 1 (HIV-1) particle release, regardless of the presence of the Vpu antagonist accessory protein. While cBST2(504) failed to restrict wild-type feline immunodeficiency virus (FIV) egress, FIV mutants, bearing a frameshift at the level of the envelope-encoding region, were potently blocked. The transient expression of the FIV envelope glycoprotein was able to rescue mutant particle release from feline tetherin-positive cells but did not antagonize human BST2 activity. Moreover, cBST2(504) was capable of specifically immunoprecipitating the FIV envelope glycoprotein. Finally, cBST2(504) also exerted its function on HIV-2 ROD10 and on the simian immunodeficiency virus SIVmac239. Taken together, these results show that feline tetherin does indeed have a short N-terminal region and that the FIV envelope glycoprotein is the predominant factor counteracting tetherin restriction.

Identification of a Cullin5-ElonginB-ElonginC E3 complex in degradation of feline immunodeficiency virus Vif-mediated feline APOBEC3 proteins.

Various feline APOBEC3 (fA3) proteins exhibit broad antiviral activities against a wide range of viruses, such as feline immunodeficiency virus (FIV), feline foamy virus (FFV), and feline leukemia virus (FeLV), as well as those of other species. This activity can be counteracted by the FIV Vif protein, but the mechanism by which FIV Vif suppresses fA3s is unknown. In the present study, we demonstrated that FIV Vif could act via a proteasome-dependent pathway to overcome fA3s. FIV Vif interacted with feline cellular proteins Cullin5 (Cul5), ElonginB, and ElonginC to form an E3 complex to induce degradation of fA3s. Both the dominant-negative Cul5 mutant and a C-terminal hydrophilic replacement ElonginC mutant potently disrupted the FIV Vif activity against fA3s. Furthermore, we identified a BC-box motif in FIV Vif that was essential for the recruitment of E3 ubiquitin ligase and also required for FIV Vif-mediated degradation of fA3s. Moreover, despite the lack of either a Cul5-box or a HCCH zinc-binding motif, FIV Vif specifically selected Cul5. Therefore, FIV Vif may interact with Cul5 via a novel mechanism. These finding imply that SOCS proteins may possess distinct mechanisms to bind Cul5 during formation of the Elongin-Cullin-SOCS box complex.

Didanosine causes sensory neuropathy in an HIV/AIDS animal model: impaired mitochondrial and neurotrophic factor gene expression.

Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developed ex vivo and in vivo models of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons. We investigated neuronal morphology, neurobehavioural testing, viral load, mitochondrial and neurotrophic factor gene expression after ddI treatment of FIV-infected and uninfected animals or dorsal root ganglia (DRG) cultures. ddI caused concentration-dependent neuronal injury in cultured feline DRGs (P < 0.05), together with reduced viral replication and diminished expression of mitochondrial cytochrome C oxidase subunit I gene (mtCOX I) and the neurotrophin, brain-derived neurotrophic factor (BDNF). Indeed, BDNF treatment reversed neuronal injury caused by FIV infection in the presence or absence of ddI exposure (P < 0.05). In vivo FIV infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddI treatment. Epidermal density of nerve endings was reduced after FIV infection (P < 0.05), especially with ddI treatment. Although viral replication in blood was suppressed in ddI-treated animals (P < 0.05), ddI had a limited effect on viral abundance in DRGs of the same animals. ddI decreased mtCOX I expression in DRG neurons of FIV-infected animals (P < 0.05). BDNF expression was downregulated by ddI in DRG Schwann cells following FIV infection. Thus, ddI treatment during FIV infection resulted in additive pathogenic effects contributing to the development of ATN, which was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in DRGs, highlighting the convergent pathogenic effects that antiretroviral drugs might have in patients with HIV infection.

Oxidative stress during acute FIV infection in cats.

Oxidative stress is thought to contribute to the pathogenesis of HIV infection in humans. For example, CD4(+) T cells are particularly affected in HIV patients and oxidative stress may also contribute to impairment of neutrophil function in HIV/AIDS patients. Since cats infected with FIV develop many of the same immunological abnormalites as HIV-infected humans, we investigated effects of acute FIV infection on oxidative stress in cats. Cats were infected with a pathogenic strain of FIV and viral load, changes in neutrophil number, total blood glutathione, malondiadehye, antioxidant enzyme concentrations, and reduced glutathione (GSH) concentration in leukocytes were measured sequentially during the first 16 weeks of infection. We found that superoxide dismutase and glutathione peroxidase concentrations in whole blood increased significantly during acute FIV infection. In addition, neutrophil numbers increased significantly during this time period, though their intracellular GSH concentrations did not change. In contrast, the numbers of CD4(+) T cells decreased significantly and their intracellular GSH concentration increased significantly, while intracellular GSH concentrations were unchanged in CD8(+) T cells. However, by 16 weeks of infection, many of the abnormalities in oxidative balance had stabilized or returned to pre-inoculation values. These results suggest that acute infection with FIV causes oxidative stress in cats and that CD4(+) T cells appear to be preferentially affected. Further studies are required to determine whether early treatment with anti-oxidants may help ameliorate the decline in CD4(+) T cell number and function associated with acute FIV infection in cats.

Expression of CD134 and CXCR4 mRNA in term placentas from FIV-infected and control cats.

Feline immunodeficiency virus (FIV) causes a natural infection of domestic cats that resembles HIV-1 in pathogenesis and disease progression. Feline AIDS is characterized by depression of the CD4+ T cell population and fatal opportunistic infections. Maternal-fetal transmission of FIV readily occurs under experimental conditions, resulting in infected viable kittens and resorbed or arrested fetal tissues. Although both FIV and HIV use the chemokine receptor CXCR4 as a co-receptor, FIV does not utilize CD4 as the primary receptor. Rather, CD134 (OX40), a T cell activation antigen and co-stimulatory molecule, is the primary receptor for FIV. We hypothesized that placental expression of CD134 and CXCR4 may render the placenta vulnerable to FIV infection, possibly facilitating efficient vertical transmission of FIV, and impact pregnancy outcome. The purpose of this project was to quantify the relative expression of CD134 and CXCR4 mRNA from the term placentas of three groups of cats: uninfected queens producing viable offspring, experimentally-infected queens producing only viable offspring, and experimentally-infected queens producing viable offspring among mostly non-viable fetuses. Total RNA was extracted from term placental tissues from all groups of cats. Real-time one-step reverse transcriptase-PCR was used to measure gene expression. The FIV receptors CD134 and CXCR4 were expressed in all late term feline placental tissues. Placentas from FIV-infected queens producing litters of only viable offspring expressed more CD134 and CXCR4 mRNA than those from uninfected queens, suggesting that infection may cause upregulation of the receptors. On the other hand, placentas from FIV-infected cats with non-successful pregnancies expressed similar levels of CD134 mRNA and slightly less CXCR4 mRNA than those from uninfected queens. Thus, it appears that cells expressing these receptors may play a role in pregnancy maintenance.

Effects of an oral superoxide dismutase enzyme supplementation on indices of oxidative stress, proviral load, and CD4:CD8 ratios in asymptomatic FIV-infected cats.

This study was designed to test the effect of antioxidant supplementation on feline immunodeficiency virus (FIV)-infected felines. Six acutely FIV-infected cats (> or =16 weeks post-inoculation) were given a propriety oral superoxide dismutase (SOD) supplement (Oxstrin; Nutramax Laboratories) for 30 days. Following supplementation, the erythrocyte SOD enzyme concentration was significantly greater in the supplemented FIV-infected group than the uninfected control group or the unsupplemented FIV-infected group. The CD4+ to CD8+ ratio increased significantly (0.66-0.88) in the SOD supplemented FIV-infected cats but not in the unsupplemented FIV-infected cats. Proviral load and reduced glutathione (GSH) levels in leukocyte cell types did not change significantly following supplementation. Antioxidant supplementation resulted in an increase in SOD levels, confirming the oral bioavailability of the compound in FIV-infected cats. This result warrants further investigation with trials of antioxidant therapy in FIV-infected cats that are showing clinical manifestations of their disease, as well as in other feline patients where oxidative stress likely contributes to disease pathogenesis, such as diabetes mellitus and chronic renal failure.

Altered tryptophan metabolism in FIV-positive cats.

BACKGROUND: Feline immunodeficiency virus (FIV) is analogous to human immunodeficiency virus, the causative agent of human acquired immunodeficiency syndrome (AIDS). In AIDS patients, a progressive reduction in serum tryptophan concentration occurs because of activation of an inducible tryptophan degradation pathway mediated by elevated lamda-interferon production. HYPOTHESIS: Cats infected with FIV have increased tryptophan catabolism evidenced by reduced circulating concentrations of tryptophan and increased concentrations of the tryptophan catabolite kynurenine. ANIMALS: Convenience sample of 235 cats submitted for diagnostic FIV serology (115 FIV-negative and 120 FIV-positive cats). METHODS: Retrospective, cross-sectional study. Serum was assayed for tryptophan and kynurenine using a high performance liquid chromatography assay with fluorescence and ultraviolet detection, respectively. RESULTS: Tryptophan and kynurenine concentrations were log-normally distributed. Geometric mean concentrations were: tryptophan: FIV-positive 30.6 microM (95% CI: 26.8 34.8 microM), FIV-negative 48.9 [microM (95% CI: 43.6-54.9 microM) (P < .001); kynurenine: FIV-positive 22.7 microM (95% CI: 25.5-10.9 microM), FIV-negative 9.9 microM (95% CI: 20.3-9.03 microM) (P < .001). The ratio of kynurenine to tryptophan was: FIV-positive 4.93 (95% CI: 5.62-4.32), FIV-negative 1.34 (95% CI: 1.53 1.17) (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Serum tryptophan concentration was significantly lower and serum kynurenine concentration was significantly higher in FIV-positive cats. The kynurenine: tryptophan ratio was >3-fold higher in FIV-positive animals, indicating increased tryptophan catabolism in this group. Dietary or pharmacologic intervention to support serum tryptophan concentrations has been shown to be clinically useful in humans with AIDS and might be applicable to cats with FIV infection.

Evaluation of a novel nested PCR for the routine diagnosis of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV).

Laboratory diagnosis of feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) usually involves both viruses, as the clinical signs are similar and coinfection may occur. Serological methods may not represent an accurate diagnosis: maternal antibodies or cross-reactions may give false positive results to FIV, and false negative results may occur in latent FeLV status, or in certain FIV infection stages. A nested polymerase chain reaction (PCR) technique was designed to detect FeLV, FIV and feline endogenous retrovirus simultaneously. The detection of endogenous sequences was considered indicative of successful DNA extraction. The technique was used to diagnose FIV and FeLV in the blood cells of 179 cats. The kappa value with the serological data was 0.69 for FeLV and 0.87 for FIV. The joint detection of FeLV and FIV by this novel nested PCR is sensitive, specific, fast and convenient, and its applicability for clinical diagnosis is promising, as the direct evidence of the presence of the virus is more realistic than the indirect data provided by the serological detection.

Bold attitude makes male urban feral domestic cats more vulnerable to Feline Immunodeficiency Virus.

Individual differences in behaviour are a phenomenon that is more and more attracting the attention of scientists. Among the other reasons, behavioural individuality occurs because selection favours the adoption of different tactics by individuals. It is now widely recognized that within many vertebrate species, individuals vary along an axis the extremes of which are represented by individuals 'bold' and 'shy', sometimes called 'proactive' and 'reactive'. Here we present the case of feral domestic cats (Felis catus L.) living in group in the urban environment where showing bold attitudes is linked to the benefit of a high annual reproductive success but, on the other hand, to a high probability to be infected by the Feline Immunodeficiency Virus (FIV), a lethal disease caused by a retrovirus. In this species, natural selection has probably favoured proactive temperament in spite of the cost represented by getting the disease. In fact, proactive individuals, even if FIV positive, reproduce more than reactive individuals before the last stage of FIV-infection (AIDS) characterized by a loss of immunological defences and subsequent opportunistic infections. Evolutionary implications are discussed.

Placental immunopathology and pregnancy failure in the FIV-infected cat.

Placental HIV infections frequently result in infected babies or miscarriage. Aberrant placental cytokine expression during HIV infections may facilitate transplacental viral transmission or pregnancy perturbation. The feline immunodeficiency virus (FIV)-infected cat is a model for HIV infections due to similarities in biology and clinical disease. The purpose of this study was to evaluate placental immunomodulator expression and reproductive outcome using the FIV-infected cat model. Kittens were cesarean delivered from FIV-B-2542-infected and control queens near term; placental and fetal tissues were collected. Real-time RT-PCR was used to measure expression of representative placental Th1 cytokines, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma), a Th2 cytokine, IL-10, and chemokine receptor CXCR4. On average, control queens delivered 3.8 kittens/litter; 1 of 31 kittens (3.2%) was non-viable. FIV-infected queens produced 2.7 kittens/litter; 15 of 25 concepti (60%) were non-viable. FIV was detected in 14 of 15 placentas (93%) and 21 of 22 fetuses (95%) using PCR. Placental immunomodulator expression did not differ significantly when placentas from infected cats were compared to those of control cats. However, elevated expression of Th1 cytokines and increased Th1/Th2 ratios (IL-1beta/IL-10) occurred in placentas from resorptions. Therefore, increased placental Th1 cytokine expression was associated with pregnancy failure in the FIV-infected cat.

Glycan moiety modifications of feline alpha1-acid glycoprotein in retrovirus (FIV, FeLV) affected cats.

alpha1-Acid glycoprotein (AGP) is considered one of the major acute phase proteins in cats. In humans, AGP is a heavily glycosylated protein that undergoes several modifications of its glycan moiety during acute and chronic inflammatory pathologies. In this paper we present the feline AGPs (fAGP) glycan moiety modifications in the course of two prevalent feline diseases, the FIV (feline immunodeficiency virus) dependent feline acquired viral immunodeficiency and the feline leukemia virus (FeLV) associated lymphoma. The glycan moiety of fAGP was investigated by means of the binding of its oligosaccharides residues with specific lectins. Four lectins were used: Sambucus nigra agglutinin I and Maackia amurensis agglutinin lectins were used to detect sialic acid residues, Aleuria aurantia lectin was used to detect L-fucose residues and Concanavalin A was used to evaluate the degree of branching. It was found that fAGP undergoes several post-translational modifications of its glycan pattern: in particular the degree of sialylation is increased in FeLV-positive cats diagnosed with lymphoma, while FeLV-positive that did not presented any specific clinical signs cats do not present any increase of expression of sialic acid on the surface. Furthermore, FIV induced a modification of the glycan moiety of fAGP, which however varied widely among individuals. In order to determine the number and the position of oligosaccharide chains, the cDNA sequence of fAGP was also determined. The translation of the mature fAGP coding sequence gave rise to a sequence of 183 residues, with five potential N-glycosylation sites, but also with seven potential phosphorylation sites.

Neuron loss and axon reorganization in the dentate gyrus of cats infected with the feline immunodeficiency virus.

The pathophysiological bases of cognitive, motor, and behavioral abnormalities in patients infected with the human immunodeficiency virus (HIV-1) remain largely unknown. To test the possibility that changes in hippocampal neuronal structure may contribute to these neurologic abnormalities, we examined the brains of cats infected with the feline immunodeficiency virus (FIV), an animal model of HIV-1 infection. We evaluated the dentate gyrus by using Timm's staining to estimate the extent of granule cell axon reorganization and by using Nissl staining, immunocytochemistry, and the optical fractionator method to estimate changes in the number of different neuronal subtypes. FIV-infected cats had abnormally high amounts of Timm's staining in the inner molecular layer and granule cell layer and loss of Nissl-stained, somatostatin-immunoreactive, and parvalbumin-immunoreactive neurons in the hilus. An inverse correlation existed between hilar neuron numbers and extent of aberrant Timm's staining. Increased Timm's staining and hilar neuron loss occurred throughout the septotemporal axis of the hippocampus. This type of neuronal loss and synaptic reorganization may provide an anatomic basis for some of the neurologic symptoms found in FIV-infected cats and HIV-infected humans.

Feline immunodeficiency virus causes increased glutamate levels and neuronal loss in brain.

Feline immunodeficiency virus, like human immunodeficiency virus type 1, is a retrolentivirus causing neurological disease and immune suppression. Primary neurological complications, including human immunodeficiency virus encephalopathy and peripheral neuropathy, and neuropathological changes, including gliosis, neuronal injury and multinucleated giant cells, have been described for human immunodeficiency virus type 1 infection. Excitatory amino acids have been implicated as a basis for human immunodeficiency virus encephalopathy and the accompanying neuronal injury. Here, we test our hypothesis that feline immunodeficiency virus infection results in glial activation accompanied by enhanced glutamatergic activity, causing neuronal loss. Neurological signs observed in naturally and experimentally infected animals included ataxia, aggressivity and reduced motor activity. Neuropathological changes included gliosis, perivascular cuffing and neuronal dropout in the brains of both experimentally and naturally infected animals, but not in uninfected animals. Feline immunodeficiency virus antigen and genome were detected in the brains of all experimentally and naturally infected animals. Proton nuclear magnetic resonance spectroscopy revealed significantly increased glutamate levels in the feline immunodeficiency virus-infected animals. In contrast, glutamate decarboxylase levels in GABAergic neurons were reduced in feline immunodeficiency virus-infected animals. These findings provide direct in vivo evidence for enhanced glutamate levels in conjunction with neuronal loss, supporting the hypothesis of glutamate-mediated neurotoxicity as a major mechanism in the neuropathogenesis of retrolentiviral infections.

Partial characterization and tissue distribution of the feline mu opiate receptor.

Heroin abuse is a common route of acquiring HIV-1 infection. However, the effects of opiates on lentivirus disease progression are not well understood. Feline immunodeficiency virus is recognized as a good animal model for HIV-1, but characterization of the opiate receptor system in cats is lacking. Here we report the partial sequencing of the feline mu opiate receptor (MOR) and demonstrate a homology of 92 and 93% to the published human MOR sequences. Additionally, MOR transcripts were detected in the feline brain and tonsil but not in the spleen. Also, specific receptor ligand interactions were observed using microphysiometry.

Expression of apoptosis-related gene mRNAs in feline T-cells infected with feline immunodeficiency virus (FIV).

In the present study, full length of feline bax, bcl-2, bcl-xL and caspase 3 genes were sequenced and the expression of these mRNAs were also investigated in FIV-infected lymphocytes. The full length cDNA sequence of bax (646 bp), bcl-2 (1423 bp), bcl-xL (1163 bp) and caspase 3 genes (1208 bp) contained a single open reading frame of 579 bp coding 193 amino acids, 708 bp coding 236 amino acids, 702 bp coding 234 amino acids and 834 bp coding 278 amino acids, respectively. Number of apoptotic Kumi-1 cells gradually increased after FIV infection and approximately 70% were apoptotic and 30% were viable in the cells infected with FIV after 8-day incubation, though approximately 80% were non-apoptotic and 20% were dead in non-infected cells. The expression of bcl-2 mRNA in lymphocytes of established cell line was increased by FIV. The amounts of mRNAs of bax, caspase 3 and bcl-xL in FIV-infected cells were not different from those in uninfected control cells.

Constitutive expression of types 1 and 2 cytokines by alveolar macrophages from feline immunodeficiency virus-infected cats.

Evidence suggests that feline immunodeficiency virus (FIV), causes pulmonary immunodeficiency. The overall objective of this study was to explore FIV-induced alterations in cell counts and cytokine gene expression in the pulmonary compartment during the acute stage infection. Bronchoalveolar lavage (BAL) cells were collected from FIV-infected and control cats at 0, 4, 10, and 16 weeks post-FIV infection for phenotype and cytokine analysis. The major change in BAL cellular populations following FIV-infection was the development of a neutrophilia. Total BAL cell counts and relative numbers of alveolar macrophages (AM), eosinophils, and lymphocytes remained similar in both groups. The RT-qcPCR analyses of AM purified from BAL showed constitutive expression of TNFalpha, IL6 and IL10 mRNAs that peaked during the acute stage of infection then declined. The TNFalpha and IL6 bioactive protein secretion showed a similar response. In contrast, IFNgamma expression increased progressively with time after infection and paralleled a progressive increase in FIV-gag mRNA in AM. The IL12 p40 expression also differed from the other cytokines in that there was a progressive decrease in the number of cats with AM IL12 expression following FIV infection. Infection of AM in vitro with FIV also caused an increase in TNFalpha and IL6 mRNA and bioactive protein suggesting that the increased cytokine response by AM following infection of cats with FIV is an intrinsic characteristic of FIV-infected AM. In summary, pulmonary immune changes seen in FIV-infected cats are similar to those seen in HIV-infected human patients.

Tumor necrosis factor-alpha responses are depressed and interleukin-6 responses unaltered in feline immunodeficiency virus infected cats.

Feline immunodeficiency virus (FIV), a lentivirus similar to HIV, causes an acquired immunodeficiency syndrome in cats. Similar to human immunodeficiency virus (HIV), the pathogenesis of FIV is associated with dysregulation of the cytokine network. While alterations in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) expression have been reported in HIV-infected patients, changes attributable to HIV and those caused by cofactors such as secondary infections cannot always be readily distinguished. This study evaluated the effect of FIV infection on TNF-alpha and IL-6 production in cats not exposed to other potential cofactors such as secondary infections. TNF-alpha and IL-6 activities were evaluated in bronchoalveolar lavage (BAL) cells from FIV-infected and uninfected specific pathogen free (SPF) cats. Supernatants from lipopolysaccharide (LPS)-stimulated BAL cells from uninfected SPF cats had high levels of TNF-alpha and IL-6 activity, while stimulated BAL cell supernatants from FIV-infected SPF cats had significantly lower levels of TNF-alpha but unaltered IL-6 activity. Similarly, Con A/phorbol myristate acetate (PMA) stimulated non-adherent (NA-) peripheral blood mononuclear cells (PBMC) from FIV infected cats synthesized less TNF-alpha than similarly treated NA-PBMC from uninfected cats. Feline immunodeficiency virus could be recovered from the culture supernatants of BAL cells from infected cats by co-cultivation with susceptible lymphocytes. In situ hybridization identified FIV mRNA in a small fraction of alveolar macrophages in the BAL cell cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

16alpha-Bromo-epiandrosterone therapy modulates experimental feline immunodeficiency virus viremia: initial enhancement leading to long-term suppression.

16alpha-Bromo-epiandrosterone (epiBr), a synthetic derivative of the natural hormone dehyroepiandrosterone (DHEA), was evaluated for its effects on feline immunodeficiency virus (FIV) infection in experimental cats. The rationale for this study was based on the ability of DHEA to significantly reduce the mortality to viral infections in mice. DHEA and epiBr also have demonstrable in vitro anti-viral activity for both HIV-1 and FIV. Preliminary pharmacokinetic studies in cats demonstrated that subcutaneously injected epiBr was rapidly absorbed, completely metabolized, and nontoxic. Metabolites were excreted in both urine and feces, with the latter having the most complex pattern of breakdown products. Cats were then divided into four groups; two groups were infected with FIV and two uninfected. Two groups, one infected and one uninfected were treated on 5 consecutive days of weeks 0, 4, 8, 12 and 16 with epiBr. The remaining two groups were mock treated with the drug vehicle alone. Treatment started 1 week prior to infection and extended for 4 weeks after infection. Cats were observed for 20 weeks post-FIV infection. Infected cats had identical decreases in blood neutrophil and lymphocyte counts following, regardless of whether they were treated with epiBr or vehicle alone. The CD4/CD8 T-cell ratio was decreased following FIV exposure, but was significantly more decreased for the epiBr treated animals from week 2 post-infection onward. CD4+ T cells were decreased in FIV-infected cats treated with epiBr compared to their untreated cohort, while CD8+ T cells tended to be higher in treated animals. FIV infected cats that were treated with epiBr had over one-log higher virus loads at week 2 post-infection than non-epiBr treated cohorts. In spite of this enhanced initial viremia, the subsequent levels of virus in the blood were significantly lower in epiBr treated versus untreated animals. EpiBr treated cats had significantly higher FIV-p24 antibody responses than control cats receiving vehicle alone, although primary and secondary antibody responses to a T-cell dependent non-FIV antigen, keyhole limpet hemocyanin (KLH), were unaffected. EpiBr treatment significantly decreased the expected FIV-induced suppression of IL-12 p40 mRNA levels in peripheral blood mononuclear cells (PBMCs) observed at weeks 4, 5, 8, 9 and 16 post-infection, but had no influence on FIV-induced changes in IL-4, IL-6, IL-10, IFN-gamma, MIP-1alpha and RANTES.

Interleukin-1beta production in periradicular lesions in a human immunodeficiency virus/acquired immune deficiency syndrome model compared with a noninfected host.

This study elucidates the role of interleukin-1 (IL-1) in developing periradicular lesions in immunocompetent and immunocompromised (human immunodeficiency virus/acquired immune deficiency syndrome) hosts. Eight cats were immunosuppressed with steroids before infection with feline immunodeficiency virus (FIV). Eight uninoculated cats served as controls. Periradicular lesions were induced around the canine teeth. At 1 and 4 wk periradicular exudate was sampled via the root canals. IL-1beta levels were measured with ELISA. Data were analyzed using the Mann-Whitney U test and the Wilcoxon signed rank test. Statistically significant differences existed in cytokine levels between the FIV and non-FIV groups (p < 0.001). Cytokines were below detectable levels in the FIV group. A significant decrease in IL-1beta levels at 4 wk compared with 1 wk occurred in the non-FIV group (p < 0.05). In conclusion decreased IL-1beta production was obtained in the FIV group. In the non-FIV group decreases in IL-1beta levels were encountered at the chronic stage of the periradicular lesion compared with the acute stage.