Cellular Restriction Factors of Feline Immunodeficiency Virus

Lentiviruses are known for their narrow cell- and species-tropisms, which are determined by cellular proteins whose absence or presence either support viral replication (dependency factors, cofactors) or inhibit viral replication (restriction factors). Similar to Human immunodeficiency virus type 1 (HIV-1), the cat lentivirus Feline immunodeficiency virus (FIV) is sensitive to recently discovered cellular restriction factors from non-host species that are able to stop viruses from replicating. Of particular importance are the cellular proteins APOBEC3, TRIM5α and tetherin/BST-2. In general, lentiviruses counteract or escape their species’ own variant of the restriction factor, but are targeted by the orthologous proteins of distantly related species. Most of the knowledge regarding lentiviral restriction factors has been obtained in the HIV-1 system; however, much less is known about their effects on other lentiviruses. We describe here the molecular mechanisms that explain how FIV maintains its replication in feline cells, but is largely prevented from cross-species infections by cellular restriction factors

Functions, structure, and read-through alternative splicing of feline APOBEC3 genes

APOBEC3 (A3, Apolipoprotein B mRNA-editing catalytic polypeptide 3) genes in the genome of domestic cat (Felis catus) were identified and characterize

INHIBITION OF NON-PRIMATE LENTIVIRUSES BY APOBEC3 CYTIDINE DEAMINASE

APOBEC3 (apolipoprotein B mRNA editing catalytic polypeptide 3 [A3]) proteins are an element of the intrinsic immunity of modern mammalia against retroviruses. The evolution of the A3 genes is characterized by an adaptive selection and a taxon-specific expansion and/or extinction. All A3 genes consist either of one zinc (Z)-coordinating domain (Z1, Z2 or Z3) or two Z-domains (Z2-Z1, Z2-Z2, Z2-Z3). While humans carry seven A3 genes, Equus caballus carries six and Felis catus four A3 genes. The genome of Equus caballus carries two Z1, two Z2-Z2, one Z2 and one Z3 A3 gene. Some of the equine A3 are able to restrict the Equine infectious anaemia virus (EIAV). Equine macrophages, which are the natural target cells for EIAV, express only a limited repertoire of the A3 genes. In addition, the transcriptional level of the anti-EIAV A3 mRNAs was significantly lower in macrophages than in equine peripheral blood mononuclear cells. Equine A3 proteins hyper-mutated EIAV genomes supporting their predicted function. In contrast to all other extant lentiviruses, EIAV does not encode a vif gene. Other EIAV-specific genes as dUTPase and S2, whose relevance for the viral replication in previous studies was only insufficiently characterized, did not influence the inhibitory effect of the equine A3 proteins. Thus, EIAV does not have an antagonist against its species-own A3 proteins. These findings indicate that lentiviral replication can occur independent from a vif gene, which likely developed later in the evolution of the lentiviruses. Felis catus and of other Felidae encode A3 genes of the type Z2 and Z3. Beside one-domain molecules, also two-domain encoding read-through transcripts with two Vif interaction sites were detectable, that restricted different feline retroviruses. FIV (Feline immunodeficiency virus) encodes a Vif protein that counteracts the inhibitory effect of the feline A3 proteins. Despite a high genetic diversity in felid A3 genes, no strong resistance could be shown against the neutralizing activity of Vif of the domestic cat FIV. Non-feline A3 proteins restricted FIV independently of Vif, which proves that the interaction between A3 and Vif proteins is species-specific and thus limits interspecies virus transmission. Species-specificity was also demonstrated for the interaction of feline A3 and the Vif protein of HIV-1. Feline cells that expressed human entry receptors were permissive for the transduction with a HIV-1 reporter virus but the virus was not able to spread in these cells. HIV replication in feline cells is strongly inhibited by the feline A3 proteins. In order to overcome this restriction, the vif gene of HIV-1 was replaced by vifFIV. This chimeric HIV-1 showed spreading replication in feline cells expressing human receptors. Altogether, these findings implicate the importance of a novel animal model for HIV-1 based on Felis catus

Auswirkungen institutioneller Rahmenbedingungen auf das Bildungsstreben der Eltern und die Bedeutung der Lehrerempfehlung

Ziel dieses Beitrages ist es, anhand eines Vergleichs von Bayern und Hessen, Unterschiede zu ermitteln, die sich aus den bundeslandspezifischen Regelungen des Sekundarschulübergangs ergeben. Zunächst zeigen Absolventenprognosen der Länder, dass das offenere System Hessens wesentlich mehr Absolventen den Erwerb eines höheren Abschlusses ermöglicht, als das rigidere System Bayerns. In einem nächsten Schritt werden die Faktoren betrachtet, welche nach Bundesland unterschiedlich Einfluss auf die Übertrittsentscheidung nehmen - die Empfehlung durch die Grundschullehrkraft und die elterliche Bildungsaspiration: In Hessen sind sowohl die Schulempfehlungen der Grundschullehrer/innen als auch die schullaufbahnbezogenen Erfolgserwartungen der Eltern auf eine höhere Bildung ausgerichtet und angesichts der Prognosen auch erfolgversprechend. In dem starreren System Bayerns ist in letzter Instanz die Grundschulempfehlung ausschlaggebend. Neben der erwartbar geringeren Zahl an Abiturienten und dem deutlich erhöhten Anteil an Abgängern mit Hauptschulabschluss bzw. Qualifiziertem Hauptschulabschluss, liegen auch die elterlichen Erfolgserwartungen deutlich unter denen der hessischen Eltern. Ferner zeigt sich in Bezug auf den Bildungshintergrund der Eltern eine erhebliche Ungleichheit; sowohl hinsichtlich der Abschlusserwartungen (und dabei verstärkt für Hessen), als auch in den Lehrerempfehlungen in beiden Bundesländern. (DIPF/Orig.)This article examines the effect of varying school placement policies after primary school in two German federal states, Bavaria and Hesse. At first, federal projections of school leavers revealed that the more open educational system in Hesse will lead to a higher proportion of students with higher educational degrees (like Abitur) compared to the more rigid Bavarian system. Secondly we take a look at state specific differences regarding the factors behind the transitional decision: Parental aspirations and the recommendation of the elementary school teacher. In Hesse, recommendations and parental schooltrack expectancy are focused on higher education and reflect the higher federal projections. In Bavaria the recommendation of the elementary school teacher is binding for the parents; thus, beside the lower projected number of graduates with Abitur and the higher number of graduates with lower secondary education (like Hauptschule), the expectancy of Bavarian parents is also lower. Finally we found strong evidence for social inequality regarding teacher recommendations in both states and for parental aspirations predominantly in Hesse. (DIPF/Orig.

Running Loose or Getting Lost: How HIV-1 Counters and Capitalizes on APOBEC3-Induced Mutagenesis through Its Vif Protein

Human immunodeficiency virus-1 (HIV-1) dynamics reflect an intricate balance within the viruses’ host. The virus relies on host replication factors, but must escape or counter its host’s antiviral restriction factors. The interaction between the HIV-1 protein Vif and many cellular restriction factors from the APOBEC3 protein family is a prominent example of this evolutionary arms race. The viral infectivity factor (Vif) protein largely neutralizes APOBEC3 proteins, which can induce in vivo hypermutations in HIV-1 to the extent of lethal mutagenesis, and ensures the production of viable virus particles. HIV-1 also uses the APOBEC3-Vif interaction to modulate its own mutation rate in harsh or variable environments, and it is a model of adaptation in a coevolutionary setting. Both experimental evidence and the substantiation of the underlying dynamics through coevolutionary models are presented as complementary views of a coevolutionary arms race

Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids▿

To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Δvif FIV, felid A3Z2s did not show any antiviral activity against Δvif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether VifFIV can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1.VifFIV was constructed. This HIV-1.VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases ▿ †

The mammalian APOBEC3 (A3) proteins comprise a multigene family of cytidine deaminases that act as potent inhibitors of retroviruses and retrotransposons. The A3 locus on the chromosome 28 of the horse genome contains multiple A3 genes: two copies of A3Z1, five copies of A3Z2, and a single copy of A3Z3, indicating a complex evolution of multiple gene duplications. We have cloned and analyzed for expression the different equine A3 genes and examined as well the subcellular distribution of the corresponding proteins. Additionally, we have tested the functional antiretroviral activity of the equine and of several of the human and nonprimate A3 proteins against the Equine infectious anemia virus (EIAV), the Simian immunodeficiency virus (SIV), and the Adeno-associated virus type 2 (AAV-2). Hematopoietic cells of horses express at least five different A3s: A3Z1b, A3Z2a-Z2b, A3Z2c-Z2d, A3Z2e, and A3Z3, whereas circulating macrophages, the natural target of EIAV, express only part of the A3 repertoire. The five A3Z2 tandem copies arose after three consecutive, recent duplication events in the horse lineage, after the split between Equidae and Carnivora. The duplicated genes show different antiviral activities against different viruses: equine A3Z3 and A3Z2c-Z2d are potent inhibitors of EIAV while equine A3Z1b, A3Z2a-Z2b, A3Z2e showed only weak anti-EIAV activity. Equine A3Z1b and A3Z3 restricted AAV and all equine A3s, except A3Z1b, inhibited SIV. We hypothesize that the horse A3 genes are undergoing a process of subfunctionalization in their respective viral specificities, which might provide the evolutionary advantage for keeping five copies of the original gene

Multiple Restrictions of Human Immunodeficiency Virus Type 1 in Feline Cells▿

The productive replication of human immunodeficiency virus type 1 (HIV-1) occurs exclusively in defined cells of human or chimpanzee origin, explaining why heterologous animal models for HIV replication, pathogenesis, vaccination, and therapy are not available. This lack of an animal model for HIV-1 studies prompted us to examine the susceptibility of feline cells in order to evaluate the cat (Felis catus) as an animal model for studying HIV-1. Here, we report that feline cell lines harbor multiple restrictions with respect to HIV-1 replication. The feline CD4 receptor does not permit virus infection. Feline T-cell lines MYA-1 and FeT-1C showed postentry restrictions resulting in low HIV-1 luciferase reporter activity and low expression of viral Gag-Pol proteins when pseudotyped vectors were used. Feline fibroblastic CrFK and KE-R cells, expressing human CD4 and CCR5, were very permissive for viral entry and HIV-long terminal repeat-driven expression but failed to support spreading infection. KE-R cells displayed a profound block with respect to release of HIV-1 particles. In contrast, CrFK cells allowed very efficient particle production; however, the CrFK cell-derived HIV-1 particles had low specific infectivity. We subsequently identified feline apolipoprotein B-editing catalytic polypeptide 3 (feAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity. CrFK cells express at least three different APOBEC3s: APOBEC3C, APOBEC3H, and APOBEC3CH. While the feAPOBEC3C did not significantly inhibit HIV-1, the feAPOBEC3H and feAPOBEC3CH induced G to A hypermutations of the viral cDNA and reduced the infectivity ∼10- to ∼40-fold