Differences in tropism and pH dependence for glycoproteins from the Clade B1 arenaviruses: Implications for receptor usage and pathogenicity

Abstract

The Clade B lineage of the New World arenaviruses contains four viruses capable of causing severe hemorrhagic fevers in humans. Within this group, the B1 sub-lineage contains the pathogenic viruses Junin (JUNV) and Machupo (MACV), as well as the non-pathogenic Tacaribe virus (TCRV). In order to elucidate differences that may determine pathogenicity, we studied the entry pathways directed by the glycoproteins (GPs) from these related B1 viruses, using pseudotyped retroviral vectors and GP1 immunoadhesin constructs. Our data revealed variations in the efficiency with which different cell types could be transduced by B1 vectors, and this correlated with the ability of the immunoadhesins to bind to those cells. Interestingly, the tropism directed by the TCRV GP proved to be distinct from that of JUNV and MACV, in particular on lymphocyte cell lines. In addition, the GPs showed variations in their sensitivity to an inhibitor of endosome acidification, with the TCRV GP again being the outlier. Together these data suggest that more than one entry pathway can be used by these closely related viruses and that the ability to cause human disease may be highly dependent on receptor usage.

Substitutions in the Glycoprotein (GP) of the Candid#1 Vaccine Strain of Junin Virus Increase Dependence on Human Transferrin Receptor 1 for Entry and Destabilize the Metastable Conformation of GP

“…Either possibility could have a profound effect on the tropism and infectivity of the virus and could contribute to attenuation. We therefore analyzed the requirement for a low-pH trigger by transducing cells with GP vectors in the absence or presence of the lysosomotropic agent NH 4 Cl, as previously described (32). We found that entry directed by both XJ and Cd1 GPs remained sensitive to inhibition by NH 4 Cl but that the Cd1 GP was significantly less affected by the block to endosomal acidification than the XJ GP (P ϭ 0.0068) (Fig.…”

“…1B). GP1 binds to host cell surface receptors (32,33) and is noncovalently associated with the GP2 subunit, which contains a fusion peptide and transmembrane anchor (9,22,24,43). The SSP remains associated with the GP1-GP2 complex (44) and is required for transport of GP to the cell surface (2,18) and for activation of fusion (42).…”

Receptor determinants of zoonotic transmission of New World hemorrhagic fever arenaviruses

“…TfR1 up-regulation on immune cells activated in response to infection may accelerate viral replication in these cells and may in part explain the higher lethality of New World hemorrhagic fevers compared with Lassa fever. Several studies also indicate that additional or alternative receptors for clade B viruses exist (38)(39)(40)(41). For example, the nonpathogenic clade B viruses Amapari and Tacaribe use a receptor on human cells distinct from TfR1 and ␣-dystroglycan (38,41).…”

Nonhuman Transferrin Receptor 1 Is an Efficient Cell Entry Receptor for Ocozocoautla de Espinosa Virus

“…1A) and HeLa (Fig. 1B) cells efficiently (10,16,21,22). Although not as efficiently as MACV and LASV pseudotypes, OCEV pseudotypes entered Vero E6 cells at levels comparable to those of TCRV, indicating that the OCEV GPC is functional.…”

“…In 1967, a VHF epidemic occurred in Chiapas To identify OCEV's cell entry determinants, we first evaluated whether the OCEV genome encodes a functional GPC. Retroviruses pseudotyped with arenavirus glycoproteins have been used successfully to characterize arenavirus cell entry determinants (10,13,15,16,(21)(22)(23)(24). We therefore produced enhanced green fluorescent protein (eGFP)-expressing Moloney murine leukemia virus (MoMLV) pseudotyped with control (TCRV, MACV, or LASV) GPC (15,16,25) or OCEV GPC (synthesized by DNA2.0 based on GenBank accession number JN897398) and evaluated transduction efficiencies in cells obtained from ATCC.…”