Hantaviral mechanisms driving HLA class I antigen presentation require both RIG-I and TRIF.

Hantaviruses are emerging human pathogens. They induce an unusually strong antiviral response of human HLA class I (HLA-I) restricted CD8⁺ T cells that may contribute to tissue damage and hantavirus-associated disease. In this study, we analyzed possible hantaviral mechanisms that enhance the HLA-I antigen presentation machinery.

Incoming RNA virus nucleocapsids containing a 5'-triphosphorylated genome activate RIG-I and antiviral signaling.

Host defense to RNA viruses depends on rapid intracellular recognition of viral RNA by two cytoplasmic RNA helicases: RIG-I and MDA5. RNA transfection experiments indicate that RIG-I responds to naked double-stranded RNAs (dsRNAs) with a triphosphorylated 5' (5'ppp) terminus. However, the identity of the RIG-I stimulating viral structures in an authentic infection context remains unresolved.

Dobrava-Belgrade hantavirus from Germany shows receptor usage and innate immunity induction consistent with the pathogenicity of the virus in humans.

Background: Dobrava-Belgrade virus (DOBV) is a European hantavirus causing hemorrhagic fever with renal syndrome (HFRS) in humans with fatality rates of up to 12%. DOBV-associated clinical cases typically occur also in the northern part of Germany where the virus is carried by the striped field mouse (Apodemus agrarius). However, the causative agent responsible for human illness has not been previously isolated.

Modulation of innate immune responses by hantaviruses.

Hantavirus infection can cause hantavirus cardiopulmonary syndrome or hemorrhagic fever with renal syndrome depending on the virus species involved. The determinants for the virus species specific virulence in humans are unclear. Successful infection is a conditio sine qua non for the virulence of a virus and it is well-known that the innate interferon (IFN) system generally plays a decisive role to prevent establishment of an infection.

Genetic reassortment between high-virulent and low-virulent Dobrava-Belgrade virus strains.

The tri-segmented RNA genome of hantaviruses facilitates genetic reassortment by segment swapping when cells are co-infected with different virus strains. We found efficient in vitro reassortment between members of two different genetic lineages of the Dobrava-Belgrade virus species, the weakly virulent DOBV-Aa and highly virulent DOBV-Af. In all reassortants, S and L segments originated from the same parental strain, and only the M segment was exchanged.

Generation and characterization of genetic reassortants between Puumala and Prospect Hill hantavirus in vitro.

Hantaviruses belong to the family Bunyaviridae characterized by tri-segmented RNA genomes. Depending on the hantavirus species, infection can lead to hantavirus cardiopulmonary or haemorrhagic fever with renal syndrome. In vitro studies suggest that pathogenic hantaviruses evade induction of innate antiviral responses, and this ability might determine the virulence in humans.

Infection of in vivo differentiated human mast cells with hantaviruses.

Increased vascular permeability is a key feature of the pathological symptoms caused by hantaviruses. Here, we analysed the interaction between hantaviruses and mast cells, which regulate vascular homeostasis. In highly purified human skin mast cells increasing amounts of Hantaan (HTNV) and, to a lower extent, Prospect Hill (PHV) virions were produced.

Defective particles can lead to underestimated antibody titers in virus neutralization tests.

Objective: Stocks of RNA viruses often contain divergent mixtures of infectious and defective particles (DPs). Since the surface of both particles share the same immunoreactivity, differing ratios of these particles in stocks used for virus neutralization tests might alter the results. Here the impact of such off-target effects were measured.

Hantaan virus triggers TLR3-dependent innate immune responses.

Immediately after viral infection, innate responses including expression of IFN-alpha/beta and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-alpha/beta and ISGs in response to an infection is often decisive for virulence. Interestingly, in primary endothelial cells ISGs are induced later by hantaviruses pathogenic to humans than those considered to be nonpathogenic or of low virulence.

Hantavirus-induced immunity in rodent reservoirs and humans.

Hantaviruses are predominantly rodent-borne pathogens, although recently novel shrew-associated hantaviruses were found. Within natural reservoir hosts, hantairuses do not cause obvious pathogenetic effects; transmission to humans, however, can lead to hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome, depending on the virus species involved. This review is focussed on the recent knowledge on hantavirus-induced immune responses in rodent reservoirs and humans and their impact on susceptibility, transmission, and outcome of hantavirus infections.

MxA-independent inhibition of Hantaan virus replication induced by type I and type II interferon in vitro.

Interferons (IFN) induce an antiviral state against Hantaan virus (HTNV) but the mechanisms responsible for inhibition are unclear. The IFN-inducible MxA is discussed to be important for control of infections with hantaviruses. To characterize the role of endogenous MxA, the inhibition of HTNV induced by type I and type II IFNs was compared in Vero and A549 cells.

A novel method for cloning of non-cytolytic viruses.

Hantaviruses are rodent-borne pathogens with a segmented single-stranded RNA genome of negative polarity. Spontaneous occurrence of variants with genetic heterogeneity have been observed both in vivo and in vitro. The objective of this study was to establish a method for the cloning of genetically homogenous hantaviruses which can be used for subsequent functional studies.

Functional characterization of the interaction between human La and hepatitis B virus RNA.

The La protein is a multifunctional RNA-binding protein and has also been suggested to be involved in the stabilization of hepatitis B virus (HBV) RNA. Here we demonstrate that antibodies against the human La protein specifically precipitate HBV RNA from HBV ribonucleoprotein-containing mammalian cell extracts, providing evidence for the association between human La and HBV RNA. Moreover, we report that the turnover of HBV RNA depends on structural features and less on the primary sequence of the La-binding site on the viral RNA.

Molecular characterization of the human La protein.hepatitis B virus RNA.B interaction in vitro.

The La protein was recently identified as a host factor potentially involved in the cytokine-induced post-transcriptional down-regulation of hepatitis B virus (HBV) RNA. The La binding site was mapped to a predicted stem-loop structure within a region shared by all HBV RNAs, and it was concluded that the La protein might be an HBV RNA-stabilizing factor. To characterize the RNA binding mediated by the different RNA recognition motifs (RRMs) of the human La protein, several La deletion mutants were produced and analyzed for HBV RNA binding ability.

Antiviral activity of interferon-alpha against hepatitis B virus can be studied in non-hepatic cells and Is independent of MxA.

It is well established that interferon-alpha can induce non-cytotoxic intracellular suppression of hepatitis B virus replication, but the mechanisms involved are unclear. Cell culture studies to characterize these mechanisms are restricted, in part because hepatitis B virus replicates almost exclusively in liver-derived cells. To overcome this limitation we used a cytomegalovirus promoter-controlled hepatitis B virus expression system, which leads to intracellular viral replication even in non-hepatic cell lines.