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. In addition, this review incorporates a discussion on the potential role of direct cell-virus interactions in the pathogenesis of hantavirus infections in humans. Finally, questions for further research efforts on the immune responses in potential hantavirus reservoir hosts and humans are summarized.

Summary 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 (ds) RNAs with a triphosphorylated 5′ (5′ppp) terminus. However, identity of the RIG-I stimulating viral structures in an authentic infection context remains unresolved. We show that incoming viral nucleocapsids containing a 5′ppp dsRNA “panhandle” structure trigger antiviral signaling that commences with RIG-I, is mediated through the adaptor protein MAVS, and terminates with transcription factor IRF-3. Independent of mammalian cofactors or viral polymerase activity, RIG-I bound to viral nucleocapsids, underwent a conformational switch, and homo-oligomerized. Enzymatic probing and super-resolution microscopy suggest that RIG-I interacts with the panhandle structure of the viral nucleocapsids. These results define cytoplasmic entry of nucleocapsids as the proximal RIG-I-sensitive step during infection, and establish viral nucleocapsids with a 5′ppp dsRNA panhandle as a RIG-I activator.

Immediately after viral infection, innate responses including expression of IFN-α/β and IFN-stimulated genes (ISGs) are elicited ubiquitously by recruitment of specific pathogen recognition receptors. The velocity to induce IFN-α/β 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. Here we demonstrate that pathogenic Hantaan (HTNV) and putatively nonpathogenic Prospect Hill hantavirus (PHV) differentially activate innate responses in the established cell lines A549 and HuH7. STAT1α phosphorylation was detectable 3 h after PHV inoculation but not within the first 2 days after HTNV inoculation. The velocity to induce the ISGs MxA and ISG15 correlated inversely with amounts of virus produced. Moreover, expression of the inflammatory chemokine CCL5 was also induced differentially. Both hantaviruses induced innate responses via TRAF3 (TNF receptor-associated factor 3), and TLR3 was required for HTNV-induced expression of MxA, but not for the MxA induction triggered by PHV. Infection of RIG-I-deficient HuH7.5 cells revealed that RIG-I (retinoic acid receptor I) was not necessary for induction of innate responses by PHV. Taken together, these data suggest that HTNV and PHV elicit different signaling cascades that converge via TRAF3. Early induction of antiviral responses might contribute to efficient elimination of PHV. Subsequent to clearance of the infection, innate responses most likely cease; vice versa, retarded induction of antiviral responses could lead to increased HTNV replication and dissemination, which might cause a prolonged inflammatory response and might contribute to the in vivo virulence.

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. The data demonstrate that the first RRM is not required for binding, whereas the RNP-1 and RNP-2 consensus sequences of the RRM-2 and RRM-3 are separately required for binding, indicating a cooperative function of these two RRMs. Furthermore, the results suggest that multimeric La disassembles into monomeric La upon binding of HBV RNA.B. By gel retardation assay the affinity of the wild type human La⅐HBV RNA.B interaction was determined in the nanomolar range, comparable to the affinity determined for the mouse La⅐HBV RNA.B interaction. This study identified small regions within the human La protein mediating the binding of HBV RNA. Hence, these binding sites might represent targets for novel antiviral strategies based on the disruption of the human La⅐HBV RNA interaction, thereby leading to HBV RNA degradation.The human La protein is a 47-kDa phosphoprotein predominantly localized in the nucleus. It was first discovered as an autoantigen recognized by antibodies present in sera of patients suffering from systemic lupus erythematosus and Sjögren's syndrome (1, 2). The La protein is a member of a large group of RNA-binding proteins containing RNA recognition motifs (RRM) 1 (3-8) and is implicated in several steps of RNA metabolism. Among the different La proteins identified in a variety of organisms, the N-terminal part is highly conserved (9). La was shown to co-immunoprecipitate with a number of small RNA molecules (10). A role for La in the termination of RNA polymerase III transcription has been described. It was shown that La interacts with RNA polymerase III transcripts such as pre-tRNA by binding to a small stretch of uridines at the 3Ј-end common to these transcripts and might be necessary for proper processing of these precursors (11-17). In addition, La is known to interact with a variety of viral and other cellular . La is also suggested to be involved in the capindependent translation initiation of several viruses, including polio virus and hepatitis C virus (19,(27)(28)(29), and more recently evidence is growing that La stabilizes various RNAs, such as histone and hepatitis C and B virus RNA (22,23,25,30,31). At this time point it is not clear yet how La fulfills all of these different functions, however, assuming that this protein acts as a RNA chaperone, thereby stabilizing RNA structures, a function in these varied processes might be envisaged.The human La protein contains three RNA recognition motifs (RRM) involved in the binding of RNAs (9), although t...

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