Evaluation of leukocyte ratios as survival prognostic markers in feline retrovirus infections.

The utility of neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) as prognostic markers in Feline Leukemia Virus (FeLV) and Feline Immunodeficiency Virus (FIV) infections has not yet been investigated. The aim of this study was to investigate these leukocyte ratios in retrovirus-positive cats and to evaluate their prognostic value for survival. This retrospective case-control study included 142 cats, 75 FIV-Antibodies (Ab)-positive, 52 FeLV-Antigen (Ag)-positive, and 15 FIV-Ab+FeLV-Ag-positive, and a control population of 142 retrovirus-negative age-, sex-, and lifestyle-matched cats. Signalment, complete blood count at the time of serological testing, and outcome were recorded. Leukocyte ratios were compared within the same case-control population, among the three retrovirus-seropositive populations, and were related to survival time. No significant difference was found in NLR, MLR, or PLR between FIV-Ab-positive and FIV-Ab+FeLV-Ag-positive cats and their cross-matched controls. In the FeLV-Ag-positive population, MLR was significantly lower than in the control population (0.05 and 0.14, respectively, P=0.0008). No ratio discriminated among the three infectious states. No ratio was significantly different between survivors and non-survivors in the population of FIV-Ab-positive cats. MLR at diagnosis was significantly higher in FeLV-Ag-positive cats that died 1-3 years after diagnosis than in FeLV-Ag-positive cats still alive at 3 years (P=0.0284). None of the three ratios could predict retroviruses-positive cats that would survive to the end of the study. Overall the results indicate that NLR, MLR, and PLR are not significantly different among retrovirus statuses evaluated and had a very limited prognostic value for the survival time in retrovirus-positive cats.

Insights into the genetic diversity, recombination, and systemic infections with evidence of intracellular maturation of hepadnavirus in cats.

Hepatitis B virus (HBV) is a human pathogen of global concern, while a high diversity of viruses related to HBV have been discovered in other animals during the last decade. Recently, the novel mammalian hepadnavirus, tentatively named domestic cat hepadnavirus (DCH), was detected in an immunocompromised cat. Herein, a collection of 209 cat sera and 15 hepato-diseased cats were screened for DCH using PCR, resulting in 12.4% and 20% positivity in the tested sera and necropsied cats, respectively. Among the DCH-positive sera, a significantly high level of co-detection with retroviral infection was found, with the highest proportion being co-detection with feline immunodeficiency virus (FIV). Full-length genome characterization of DCH revealed the genetic diversity between the nine Thai DCH sequences obtained, and that they phylogenetically formed three distinct monophyletic clades. A putative DCH recombinant strain was found, suggesting a possible role of recombination in DCH evolution. Additionally, quantitative PCR was used to determine the viral copy number in various organs of the DCH-moribund cats, while the pathological findings were compared to the viral localization in hepatocytes, adjacent to areas of hepatic fibrosis, by immunohistochemical (IHC) and western blot analysis. In addition to the liver, positive-DCH immunoreactivity was found in various other organs, including kidneys, lung, heart, intestine, brain, and lymph nodes, providing evidence of systemic infection. Ultrastructure of infected cells revealed electron-dense particles in the nucleus and cytoplasm of hepatocytes, bronchial epithelial cells, and fibroblasts. We propose the intracellular development mechanism of this virus. Although the definitive roles of pathogenicity of DCH remains undetermined, a contributory role of the virus associated with systemic diseases is possible.

Lack of protection against feline immunodeficiency virus infection among domestic cats in New Zealand vaccinated with the Fel-O-Vax® FIV vaccine.

Infections with feline immunodeficiency virus (FIV) are common in New Zealand, although the impact of those infections on the health status of the cats remains unclear. Although many cats are vaccinated yearly with a commercial FIV vaccine containing FIV subtypes A and D, the effectiveness of this vaccine in protection against infection with field FIVs is unclear, as a high proportion of New Zealand viruses belong to subtype C. The objective of the study was to compare the frequency of FIV infection among adult FIV-vaccinated and FIV-unvaccinated domestic cats with access to outdoors. Buccal swabs were collected by the participating veterinarians and tested for the presence of FIV provirus by quantitative PCR. Overall, 26/185 (14.0 %) samples were positive for FIV, including 7/82 (8.5 %) samples from FIV-unvaccinated and 19/103 (18.4 %) from FIV-vaccinated cats. There was no protective effect of vaccination on FIV infection among sampled cats (p = 0.05). Partial sequences of the FIV envelope gene from five New Zealand viruses were analysed by the maximum likelihood method. All clustered with other New Zealand FIV sequences from subtypes A (n = 2), C (n = 2) or putative recombinant viruses (n = 1). While the FIV vaccination did not prevent FIV infection among sampled cats, it may have had an impact on transmissibility of the virus or on disease progression. As neither was addressed in the current study, further research is needed to fully assess the potential benefits of FIV vaccination. Considering the frequency of FIV infection in FIV-vaccinated cats, FIV infection status should be monitored not only before the first vaccination, but before each yearly booster.

A phylogenetic study of Feline Immunodeficiency Virus (FIV) among domestic cats in Turkey.

Feline Immunodeficiency Virus (FIV) is the most prominent retrovirus in cats. Molecular studies on FIV are of great importance to enable further studies, for example, understanding the pathogenesis and developing improved vaccines. We aimed to elucidate the molecular status of FIV and provide a detailed characterization of FIV in Turkey because at present there is very limited information available in the literature. We also evaluated a potential link between clinical symptoms and FIV subtypes according to results obtained from molecular tests. Whole blood was collected from 200 client-owned domestic cats and molecular diagnosis and characterization was performed. The env, gag and vif gene regions were amplified and sequenced for phylogenetic analysis. We obtained specific amplicons based on bothenvand gag for FIV in 21 cats; only 2 of the 21 positive samples could also be characterized based on the vif gene region. Separate clusters were identified according to previously determined genotyping strategies; however, they were observed in FIV subtype B. The molecular findings of some individual cats were evaluated in conjunction with their clinical symptoms in an attempt to determine potential relationships between the genetic characteristics of FIV and symptoms of disease. As a result, overexpression of the vif gene could be important in leading to serious clinical symptoms. Our results emphasize the necessity of considering FIV in diagnosis and performing the neccesary diagnostics to confirm or rule out FIV infection. The molecular dynamics of FIV should be periodically updated by further analyses to establish a successful prevention strategy.

An RNA-Directed Gene Editing Strategy for Attenuating the Infectious Potential of Feline Immunodeficiency Virus-Infected Cells: A Proof of Concept.

Modern antiretroviral therapy for immunodeficiency viruses, although remarkably effective in controlling viral transcription, and overt virus-associated morbidity, has failed to absolutely eradicate retroviruses from their infected hosts as a result of proviral integration in long-lived reservoir cells. Immunodeficiency virus-infected patients are therefore consigned to lifelong antiviral therapy as a means to control viremia, viral transmission, and infection-associated morbidity. Unfortunately, lifelong antiviral therapies can be difficult for patients to continuously maintain and may be associated with therapy-specific morbidities. Patient advocates have argued for new methods to achieve retroviral eradication. As a proof-of-concept study, a lentivirus-delivered RNA-directed gene editing strategy was utilized in a series of in vitro experiments in an attempt to attenuate the feline immunodeficiency virus (FIV) proviral load, viral transcription, and production of infectious virions. We found that a feline T lymphocyte cell line (MCH5-4) treated with an FIV-specific clustered regularly interspersed short palindromic repeats (CRISPR)-associated protein 9 (Cas9) gene editing tool resulted in a reduction of cell-free viral RNA relative to control cells. Decreased infectious potential was demonstrated in a two-step FIV infection study-naïve MCH5-4 cells infected with cell-free FIV harvested from FIV-infected and CRISPR lentivirus-treated cells had less integrated proviral DNA than control cells. This study represents the initial steps towards the development of an effective method of proviral eradication in an immunodeficiency virus-infected host.

The incidence of aggressive behavior in cats naturally infected with Feline Immunodeficiency Virus (FIV) and its interaction with FIV disease progression.

A study was undertaken to determine the possible interaction between aggressive behavior and Feline immunodeficiency virus (FIV) disease progression based on semi­quantitative viral load levels and health status in naturally FIV­infected cats. FIV status was determined in ninety­six owned and stray cats, using nested polymerase chain reaction (PCR). Aggressive tendencies were assessed based on observation and the cats' demeanor as determined by the owners and shelter caretakers. Results showed that forty­seven cats (49%) were PCR­positive for FIV infection and all aggressive cats were FIV­positive (100%). FIV infection was significantly linked to extreme aggressive tendencies and the extremely aggressive FIV­infected cats were more likely to have an unhealthy status compared to the non­aggressive individuals (p = 0.022). There was also a significant difference (p = 0.012) in the mean Cycle threshold (Ct) values between the aggressive and non­aggressive FIV­infected cats and also between the unhealthy FIV­infected cats with extreme aggressive tendencies and the healthy FIV­infected individuals without aggression (p = 0.001). Accordingly, results indicated that parameters associated with FIV disease progression are directly linked to aggression. The possible impact of FIV on the behavioral pattern of naturally infected cats should not be underestimated. However, there is an urgent need to conduct more experiments to support the assumptions about the possible exacerbation of aggression tendencies in naturally FIV­infected cats following the direct effect of FIV through the course of the infection.

Effects of Regulatory T Cell Depletion on NK Cell Responses against Listeria monocytogenes in Feline Immunodeficiency Virus Infected Cats.

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance, preventing autoimmune diseases and restraining chronic inflammatory diseases. Evidence suggests Treg cells and NK cells have important roles in feline immunodeficiency virus (FIV) pathogenesis; however, in vivo studies investigating the interplay between these two cell populations are lacking. We previously described innate immune defects in FIV-infected cats characterized by cytokine deficits and impaired natural killer cell (NK) and NK T cell (NKT) functions. In this study, we investigated whether in vivo Treg depletion by treatment with an anti-feline CD25 monoclonal antibody would improve the innate immune response against subcutaneous challenge with Listeria monocytogenes (Lm). Treg depletion resulted in an increased overall number of cells in Lm-draining lymph nodes and increased proliferation of NK and NKT cells in FIV-infected cats. Treg depletion did not normalize expression of perforin or granzyme A by NK and NKT cells, nor did Treg depletion result in improved clearance of Lm. Thus, despite the quantitative improvements in the NK and NKT cell responses to Lm, there was no functional improvement in the early control of Lm. CD1a+ dendritic cell percentages in the lymph nodes of FIV-infected cats were lower than in specific-pathogen-free control cats and failed to upregulate CD80 even when Treg were depleted. Taken together, Treg depletion failed to improve the innate immune response of FIV-infected cats against Lm and this may be due to dendritic cell dysfunction.

Immunopathologic Effects of Prednisolone and Cyclosporine A on Feline Immunodeficiency Virus Replication and Persistence.

Feline immunodeficiency virus (FIV) induces opportunistic disease in chronically infected cats, and both prednisolone and cyclosporine A (CsA) are clinically used to treat complications such as lymphoma and stomatitis. However, the impact of these compounds on FIV infection are still unknown and understanding immunomodulatory effects on FIV replication and persistence is critical to guide safe and effective therapies. To determine the immunologic and virologic effects of prednisolone and CsA during FIV infection, FIV-positive cats were administered immunosuppressive doses of prednisolone (2 mg/kg) or CsA (5 mg/kg). Both prednisolone and CsA induced acute and transient increases in FIV DNA and RNA loads as detected by quantitative PCR. Changes in the proportion of lymphocyte immunophenotypes were also observed between FIV-infected and naïve cats treated with CsA and prednisolone, and both treatments caused acute increases in CD4+ lymphocytes that correlated with increased FIV RNA. CsA and prednisolone also produced alterations in cytokine expression that favored a shift toward a Th2 response. Pre-treatment with CsA slightly enhanced the efficacy of antiretroviral therapy but did not enhance clearance of FIV. Results highlight the potential for drug-induced perturbation of FIV infection and underscore the need for more information regarding immunopathologic consequences of therapeutic agents on concurrent viral infections.

Expression of APOBEC3 Lentiviral Restriction Factors in Cats.

Feline immunodeficiency virus (FIV) is a naturally occurring T-cell tropic lentiviral disease of felids with many similarities to HIV/AIDS in humans. Similar to primate lentiviral-host interactions, feline APOBEC3 (A3) has been shown to inhibit FIV infection in a host-specific manner and feline A3 degradation is mediated by FIV Vif. Further, infection of felids with non-native FIV strains results in restricted viral replication in both experimental and naturally occurring infections. However, the link between molecular A3-Vif interactions and A3 biological activity during FIV infection has not been well characterized. We thus examined expression of the feline A3 genes A3Z2, A3Z3 and A3Z2-Z3 during experimental infection of domestic cats with host-adapted domestic cat FIV (referred to as FIV) and non-adapted Puma concolor FIV (referred to as puma lentivirus, PLV). We determined A3 expression in different tissues and blood cells from uninfected, FIV-infected, PLV-infected and FIV/PLV co-infected cats; and in purified blood cell subpopulations from FIV-infected and uninfected cats. Additionally, we evaluated regulation of A3 expression by cytokines, mitogens, and FIV infection in cultured cells. In all feline cells and tissues studied, there was a striking difference in expression between the A3 genes which encode FIV inhibitors, with A3Z3 mRNA abundance exceeding that of A3Z2-Z3 by 300-fold or more. Interferon-alpha treatment of cat T cells resulted in upregulation of A3 expression, while treatment with interferon-gamma enhanced expression in cat cell lines. In cats, secondary lymphoid organs and peripheral blood mononuclear cells (PBMC) had the highest basal A3 expression levels and A3 genes were differentially expressed among blood T cells, B cells, and monocytes. Acute FIV and PLV infection of cats, and FIV infection of primary PBMC resulted in no detectable change in A3 expression with the exception of significantly elevated A3 expression in the thymus, the site of highest FIV replication. We conclude that cat A3 expression is regulated by cytokine treatment but, by and large, lentiviral infection did not appear to alter expression. Differences in A3 expression in different blood cell subsets did not appear to impact FIV viral replication kinetics within these cells. Furthermore, the relative abundance of A3Z3 mRNA compared to A3Z2-Z3 suggests that A3Z3 may be the major active anti-lentiviral APOBEC3 gene product in domestic cats.

Detection of feline immunodeficiency virus subtypes A and B circulating in the city of Buenos Aires.

Feline immunodeficiency virus (FIV), genus Lentivirus, is responsible for feline immunodeficiency syndrome in domestic cats. FIV has been classified into six subtypes: A, B, C, D, E and F, based on regions of the env gene as well as the gag gene. In Argentina, the circulation of subtypes B and E was reported more than two decades ago. The objective of this work was to study the FIV variants circulating presently in the city of Buenos Aires in naturally infected cats utilizing a nested PCR targeting the gag gene. A phylogenetic comparison with representative sequences of five previously published subtypes shows a clustering with subtypes A and B. This is the first report of FIV subtype A in Argentina.

[Contribution of animal models to HIV research]. / Apport des modèles animaux dans la recherche sur le VIH.

Even today, despite triple therapy, the epidemic of the human immunodeficiency virus (HIV) is a major public health problem. In this perspective, continuous research is essential for the development of curative and vaccinal approaches. Animal models contribute to the implementation of new therapeutic and preventive strategies. We present here the characteristics of major animal models of HIV, which are non-human primates (SIV or SHIV-infected macaques and natural hosts of SIV), as well as different humanized mouse models and their advances. We will also list how they have already allowed, and still allow today, to broaden our knowledge on the physiopathology of HIV infection, tissue distribution of the virus, viral reservoirs, immunological responses against the virus in the very early infection stages and at the tissue level, but also in the development of vaccine candidates (RhCMV, broad-spectrum antibodies, etc…) and clinical trials for a cure. The advantages and limitations of the different animal models will be described. While continuing research on alternative methods, refinement or reduction of the animal model, a good knowledge of the specificities of each animal model allows an adequate use in relation to the scientific questions addressed.

Variation in Intra-individual Lentiviral Evolution Rates: a Systematic Review of Human, Nonhuman Primate, and Felid Species.

Lentiviral replication mediated by reverse transcriptase is considered to be highly error prone, leading to a high intra-individual evolution rate that promotes evasion of neutralization and persistent infection. Understanding lentiviral intra-individual evolutionary dynamics on a comparative basis can therefore inform research strategies to aid in studies of pathogenesis, vaccine design, and therapeutic intervention. We conducted a systematic review of intra-individual evolution rates for three species groups of lentiviruses-feline immunodeficiency virus (FIV), simian immunodeficiency virus (SIV), and human immunodeficiency virus (HIV). Overall, intra-individual rate estimates differed by virus but not by host, gene, or viral strain. Lentiviral infections in spillover (nonadapted) hosts approximated infections in primary (adapted) hosts. Our review consistently documents that FIV evolution rates within individuals are significantly lower than the rates recorded for HIV and SIV. FIV intra-individual evolution rates were noted to be equivalent to FIV interindividual rates. These findings document inherent differences in the evolution of FIV relative to that of primate lentiviruses, which may signal intrinsic difference of reverse transcriptase between these viral species or different host-viral interactions. Analysis of lentiviral evolutionary selection pressures at the individual versus population level is valuable for understanding transmission dynamics and the emergence of virulent and avirulent strains and provides novel insight for approaches to interrupt lentiviral infections.IMPORTANCE To the best of our knowledge, this is the first study that compares intra-individual evolution rates for FIV, SIV, and HIV following systematic review of the literature. Our findings have important implications for informing research strategies in the field of intra-individual virus dynamics for lentiviruses. We observed that FIV evolves more slowly than HIV and SIV at the intra-individual level and found that mutation rates may differ by gene sequence length but not by host, gene, strain, an experimental setting relative to a natural setting, or spillover host infection relative to primary host infection.

Prevalence of and factors associated with feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) in cats of the state of Santa Catarina, Brazil.

A cross-sectional study was conducted in 274 cats for determination of FeLV antigenemia and FIV seropositivity and factors associated with those infections in cats presented at the Veterinary Hospital of the Santa Catarina State University - UDESC (Brazil). Apparent prevalence for sick cats at the hospital population was 28.41% (95%CI 21.88-34.94%) for FeLV, 7.65% (95%CI 3.71-11.50%) for FIV and 2.18% (95%CI 0.56-5.47%) for both viruses. For healthy cats, the apparent prevalence was 9.89% (95%CI 3.75-16.02%) for FeLV, 2.20% (95%CI 0.34-7.75%) for FIV by immunoassay (ELISA). Average age for FeLV- and FIV-positive individuals was 38.32 and 64.25 months, respectively. Behavior such as aggressiveness and sex (male) were both associated with increased odds of result positivity test for FeLV and FIV; older animals were also associated with FIV test results. A very small proportion of the animals were vaccinated against FeLV and none against FIV. Most of the animals were adopted from shelters or rescued from streets, living with multiple cats that had access to outdoors. The high prevalence of FeLV suggests a need for better control strategies against this disease.

Structural basis of antiviral activity of peptides from MPER of FIV gp36.

Feline immunodeficiency virus (FIV) is a naturally occurring Lentivirus causing acquired immunodeficiency syndrome in felines. It is considered a useful non-primate model to study HIV infection, and to test anti-HIV vaccine. Similarly to HIV, FIV enters cells via a mechanism involving a surface glycoprotein named gp36. C8 is a short synthetic peptide corresponding to the residues 770WEDWVGWI777 of gp36 membrane proximal external region (MPER). It elicits antiviral activity by inhibiting the fusion of the FIV and host cell membrane. C8 is endowed with evident membrane binding property, inducing alteration of the phospholipid bilayer and membrane fusion. The presence and the position of tryptophan residues in C8 are important for antiviral activity: the C8 derivative C6a, obtained by truncating the N-terminal 770WE771 residues, exhibits conserved antiviral activity, while the C8 derivative C6b, derived from the truncation of the C-terminal 776WI777, is nearly inactive. To elucidate the structural factors that induce the different activity profiles of C6a and C6b, in spite of their similarity, we investigated the structural behaviour of the two peptides in membrane mimicking environments. Conformational data on the short peptides C6a and C6b, matched to those of their parent peptide C8, allow describing a pharmacophore model of antiviral fusion inhibitors. This includes the essential structural motifs to design new simplified molecules overcoming the pharmacokinetic and high cost limitations affecting the antiviral entry inhibitors that currently are in therapy.

Enrichment Preferences of FIV-Infected and Uninfected Laboratory-Housed Cats.

Environmental enrichment is critical for alleviating stress in laboratory felines. However, there is a paucity of information about suitable enrichment for cats. This study aimed to determine preferred enrichment options of individually-housed, castrated male domestic short hair cats (Felis catus) used in a longitudinal study of the effects of chronic feline immunodeficiency virus (FIV) infection, and to determine if the FIV status of the cats affected enrichment preferences. Preference testing was performed with two types of grooming brushes, three different interactive play options, including a laser, ball, and petting interaction with a familiar investigator, and two types of toenail conditioning objects. We found that cats elected to be brushed, preferred social interaction and play with the laser to the ball, and preferred to scratch on an inclined-box toenail conditioning object compared to a horizontal, circular toenail conditioning object. There were individual preferences for enrichment opportunities. There were no differences in preferences between FIV-infected and sham-infected cats. These enrichment preferences may be used to advise laboratory animal facilities and researchers about how to best accommodate the behavioral needs of laboratory cats.

HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model.

Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca2+ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca2+ activity using intracellular Ca2+ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca2+ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca2+ by the activation of the endoplasmic reticulum (ER)-associated Ca2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95's stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca2+ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca2+ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca2+ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.

Clinical features, fungal load, coinfections, histological skin changes, and itraconazole treatment response of cats with sporotrichosis caused by Sporothrix brasiliensis.

Zoonotic sporotrichosis caused by the fungus Sporothrix brasiliensis is usually severe in cats. This study investigated the associations between clinical features, fungal load, coinfections, histological skin changes, and response to itraconazole in cats with sporotrichosis caused by S. brasiliensis. Fifty-two cats with skin lesions and a definitive diagnosis of sporotrichosis were treated with itraconazole for a maximum period of 36 weeks. The animals were submitted to clinical examination and two subsequent collections of samples from the same skin lesion for fungal diagnosis and histopathology, as well as serology for feline immunodeficiency (FIV) and leukaemia (FeLV) viruses. Thirty-seven (71%) cats were clinically cured. Nasal mucosa lesions and respiratory signs were associated with treatment failure. Cats coinfected with FIV/FeLV (n = 12) had a lower neutrophil count in the lesion. A high fungal load in skin lesions was linked to young age and treatment failure, as well as to a longer time of wound healing, poorly formed granulomas and fewer neutrophils, macrophages and lymphocytes in these lesions. These results indicate that itraconazole is effective, but nasal mucosal involvement, respiratory signs and high fungal loads in skin lesions are predictors of treatment failure that will assist in the development of better treatment protocols for cats.

Absence of A3Z3-Related Hypermutations in the env and vif Proviral Genes in FIV Naturally Infected Cats.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) proteins comprise an important family of restriction factors that produce hypermutations on proviral DNA and are able to limit virus replication. Vif, an accessory protein present in almost all lentiviruses, counteracts the antiviral A3 activity. Seven haplotypes of APOBEC3Z3 (A3Z3) were described in domestic cats (hap I⁻VII), and in-vitro studies have demonstrated that these proteins reduce infectivity of vif-defective feline immunodeficiency virus (FIV). Moreover, hap V is resistant to vif-mediated degradation. However, studies on the effect of A3Z3 in FIV-infected cats have not been developed. Here, the correlation between APOBEC A3Z3 haplotypes in domestic cats and the frequency of hypermutations in the FIV vif and env genes were assessed in a retrospective cohort study with 30 blood samples collected between 2012 and 2016 from naturally FIV-infected cats in Brazil. The vif and env sequences were analyzed and displayed low or undetectable levels of hypermutations, and could not be associated with any specific A3Z3 haplotype.

A Novel Hepadnavirus Identified in an Immunocompromised Domestic Cat in Australia.

High-throughput transcriptome sequencing allows for the unbiased detection of viruses in host tissues. The application of this technique to immunosuppressed animals facilitates the detection of viruses that might otherwise be excluded or contained in immunocompetent individuals. To identify potential viral pathogens infecting domestic cats we performed high-throughput transcriptome sequencing of tissues from cats infected with feline immunodeficiency virus (FIV). A novel member of the Hepadnaviridae, tentatively named domestic cat hepadnavirus, was discovered in a lymphoma sample and its complete 3187 bp genome characterized. Phylogenetic analysis placed the domestic cat hepadnavirus as a divergent member of mammalian orthohepadnaviruses that exhibits no close relationship to any other virus. DNA extracted from whole blood from pet cats was positive for the novel hepadnavirus by PCR in 6 of 60 (10%) FIV-infected cats and 2 of 63 (3.2%) FIV-uninfected cats. The higher prevalence of hepadnavirus viraemia detected in FIV-infected cats mirrors that seen in human immunodeficiency virus-infected humans coinfected with hepatitis B virus. In summary, we report the first hepadnavirus infection in a carnivore and the first in a companion animal. The natural history, epidemiology and pathogenic potential of domestic cat hepadnavirus merits additional investigation.

Applications of the FIV Model to Study HIV Pathogenesis.

Feline immunodeficiency virus (FIV) is a naturally-occurring retrovirus that infects domestic and non-domestic feline species, producing progressive immune depletion that results in an acquired immunodeficiency syndrome (AIDS). Much has been learned about FIV since it was first described in 1987, particularly in regard to its application as a model to study the closely related lentivirus, human immunodeficiency virus (HIV). In particular, FIV and HIV share remarkable structure and sequence organization, utilize parallel modes of receptor-mediated entry, and result in a similar spectrum of immunodeficiency-related diseases due to analogous modes of immune dysfunction. This review summarizes current knowledge of FIV infection kinetics and the mechanisms of immune dysfunction in relation to opportunistic disease, specifically in regard to studying HIV pathogenesis. Furthermore, we present data that highlight changes in the oral microbiota and oral immune system during FIV infection, and outline the potential for the feline model of oral AIDS manifestations to elucidate pathogenic mechanisms of HIV-induced oral disease. Finally, we discuss advances in molecular biology, vaccine development, neurologic dysfunction, and the ability to apply pharmacologic interventions and sophisticated imaging technologies to study experimental and naturally occurring FIV, which provide an excellent, but often overlooked, resource for advancing therapies and the management of HIV/AIDS.