During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature and lymphoid tissue destruction correlate with disease progression. Here, we demonstrate that blockade of type 1 interferon (IFN-I) signaling using a type 1 interferon receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus (LCMV). IFN-I blockade both prior to and following establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T-cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization and virus persistence. Our results suggest therapies that target IFN-I may help control persistent virus infections.

By using a reverse genetics system that is based on the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV), we have identified the arenavirus small RING finger Z protein as the main driving force of virus budding. Both LCMV and Lassa fever virus (LFV) Z proteins exhibited self-budding activity, and both substituted efficiently for the late domain that is present in the Gag protein of Rous sarcoma virus. LCMV and LFV Z proteins contain proline-rich motifs that are characteristic of late domains. Mutations in the PPPY motif of LCMV Z severely impaired the formation of virus-like particles. LFV Z contains two different proline-rich motifs, PPPY and PTAP, which are separated by eight amino acids. Mutational analysis revealed that both motifs are required for efficient LFV Z-mediated budding. Both LCMV and LFV Z proteins recruited to the plasma membrane Tsg101, which is a component of the class E vacuolar protein sorting machinery that has been implicated in budding of HIV and Ebola virus. A renaviruses include Lassa fever virus (LFV) and the South American hemorrhagic fever (HF) viruses. These viruses cause severe human disease, and they pose a threat as agents of bioterrorism (1). The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is an important model with which to study both acute and persistent viral infection (2). In addition, LCMV provides an excellent system with which to study basic aspects of the molecular and cell biology of HF arenaviruses.LCMV is an enveloped virus, whose genome consists of two negative-sense, single-stranded RNA segments, called L (7.2 kb) and S (3.4 kb). Each segment uses an ambisense coding organization to direct the synthesis of two gene products in opposite orientation, and each is separated by an intergenic region (3) The S RNA encodes the nucleoprotein (NP), and the two surface virion glycoproteins (GPs), GP-1 and GP-2, which are derived by proteolytic cleavage of a precursor polypeptide, GP-C (4). GP-1 and GP-2 form the spikes on the virion envelope and mediate cell entry by interaction with the host cell surface receptor (5). The L RNA directs the synthesis of the virus RNA-dependent RNA polymerase (L protein), and a small RING finger protein called Z (11 kDa) (6). The NP associates with the viral genomic RNA species and L to form the viral ribonucleoprotein (RNP) core that is competent in transcription and RNA replication, and constitutes the minimal infectious unit (7). The role of Z in the virus life cycle is poorly understood, and homologues of Z are not found in other negativestrand (NS) RNA viruses. Z is a structural component of the virus (8), and in infected cells, Z has been reported to interact with several cellular factors, including promyelocytic leukemia protein (9), and the eukaryotic translation initiation factor 4E, the latter of which has been proposed to repress CAP-dependent translation (10, 11). In addition, early studies suggested a role of Z in viral transcriptional regulation (12).We have developed a reverse genetic system f...

Among cells of the immune system, CD11c+ and DEC-205+ splenic dendritic cells primarily express the cellular receptor (α-dystroglycan [α-DG]) for lymphocytic choriomeningitis virus (LCMV). By selection, strains and variants of LCMV that bind α-DG with high affinity are associated with virus replication in the white pulp, show preferential replication in a majority of CD11c+ and DEC-205+ cells, cause immunosuppression, and establish a persistent infection. In contrast, viral strains and variants that bind with low affinity to α-DG are associated with viral replication in the red pulp, display minimal replication in CD11c+ and DEC-205+ cells, and generate a robust anti-LCMV cytotoxic T lymphocyte response that clears the virus infection. Differences in binding affinities can be mapped to a single amino acid change in the viral glycoprotein 1 ligand that binds to α-DG. These findings indicate that receptor–virus interaction on dendritic cells in vivo can be an essential step in the initiation of virus-induced immunosuppression and viral persistence.