Research Article: BST-2 controls T cell proliferation and exhaustion by shaping the early distribution of a persistent viral infection

Date Published: July 20, 2018

Publisher: Public Library of Science

Author(s): Shuzo Urata, Elizabeth Kenyon, Debasis Nayak, Beatrice Cubitt, Yohei Kurosaki, Jiro Yasuda, Juan C. de la Torre, Dorian B. McGavern, E. John Wherry.


The interferon inducible protein, BST-2 (or, tetherin), plays an important role in the innate antiviral defense system by inhibiting the release of many enveloped viruses. Consequently, viruses have evolved strategies to counteract the anti-viral activity of this protein. While the mechanisms by which BST-2 prevents viral dissemination have been defined, less is known about how this protein shapes the early viral distribution and immunological defense against pathogens during the establishment of persistence. Using the lymphocytic choriomeningitis virus (LCMV) model of infection, we sought insights into how the in vitro antiviral activity of this protein compared to the immunological defense mounted in vivo. We observed that BST-2 modestly reduced production of virion particles from cultured cells, which was associated with the ability of BST-2 to interfere with the virus budding process mediated by the LCMV Z protein. Moreover, LCMV does not encode a BST-2 antagonist, and viral propagation was not significantly restricted in cells that constitutively expressed BST-2. In contrast to this very modest effect in cultured cells, BST-2 played a crucial role in controlling LCMV in vivo. In BST-2 deficient mice, a persistent strain of LCMV was no longer confined to the splenic marginal zone at early times post-infection, which resulted in an altered distribution of LCMV-specific T cells, reduced T cell proliferation / function, delayed viral control in the serum, and persistence in the brain. These data demonstrate that BST-2 is important in shaping the anatomical distribution and adaptive immune response against a persistent viral infection in vivo.

Partial Text

Arenaviruses are enveloped viruses with a bi-segmented, negative strand RNA genome and a life cycle restricted to the cell cytoplasm [1]. Each genome segment uses an ambisense coding strategy to direct the expression of two proteins in opposite orientation and separated by a non-coding intergenic region. The large segment encodes for the RNA-dependent-RNA-polymerase (L) and the matrix protein (Z) that mediates viral assembly and budding [2–4]. The small segment (S; 3.5 kb) encodes the glycoprotein (GP) precursor, GPC, and the viral nucleoprotein (NP). GPC is co-translationally cleaved by signal peptidase to produce a stable 58 amino acid Stable Signal Peptide (SSP) and GPC that is post-translationally processed by the cellular Site 1 Protease to yield the two mature virion glycoproteins (GP1 and GP2) that together with SSP form the GP complex involved in receptor binding and virus cell entry. GP1 mediates virion attachment to the cell surface followed by cell entry via receptor-mediated endocytosis, whereas GP2 is responsible for the pH-dependent fusion event in the acidic environment of the endosome to complete the virus cell entry process and release of virus ribonucleoprotein into the cell cytoplasm to initiate transcription and replication of the viral genome [1]. The L polymerase and NP are the minimal trans-acting factors required for virus RNA replication and gene transcription [5], whereas production of infectious particles also requires GP and Z [2].

Innate immunity is the first line of host defense against viral infections. Accordingly, to facilitate the completion of a successful infection many viruses encode molecules that counteract different components of the host innate immune response. Arenavirus NP has been shown to interfere with both induction of IFN-I [49–52] and activation of NF-kB, a critical player in the host inflammatory response to infection [53, 54]. Likewise, we have documented that the IFN-I inducible BST-2 interferes with LASV Z/GPC-induced VLP production [22]. Similar to that described for HIV-1 [22, 25], BST-2 appears to retain LASV VLP on the cell surface. Consistent with this observation, BST-2 was reported to inhibit production of LASV infectious progeny [55]. However, whether these findings are unique to LASV or generally applicable to arenaviruses, remains unknown. In this study, we investigated the contribution of BST-2 to the antiviral defense mounted against the prototypic arenavirus, LCMV.