β₁Integrin Expression Increases Susceptibility of Memory B Cells to Epstein-Barr Virus Infection

Abstract

Epstein-Barr virus (EBV) uses nasal mucosa-associated lymphoid tissue (NALT) as a portal of entry toEpstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that is transmitted via saliva and infects more than 90% of the world's population (21). Much of EBV's medical importance relates to its association with B-cell malignancies, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease (21). The oncogenic potential of EBV is clearly illustrated by its unique capability to transform B cells in vitro (21).In the current paradigm, EBV infects naïve B cells in tonsils in vivo (32). EBV is present mainly as a latent virus; upon infection, EBV expresses distinct patterns of its latency genes depending upon distinct B-cell differentiation stages, varying from expression of all 10 known EBV latency genes in naïve B cells to the complete absence of EBV mRNA expression in resting memory B cells. This has led to the model that EBV, by virtue of expression of its latency genes, provides cell survival signals in naïve B cells (32). In particular, recent data suggest that EBV expedites the antigen-driven somatic hypermutation and selection of B cells taking place in germinal centers (GC) (26). Chaganti et al. challenged the current paradigm by showing for patients with primary EBV infection that EBV avoids GC transit and directly infects memory B cells (6). This report is consistent with in vitro experiments showing that EBV is able to infect memory B cells (9, 10), in addition to the well-accepted susceptibility of naïve and GC B cells to EBV.Irrespective of which B-cell subset is the primary target of EBV, its propagation within the host is linked to proliferation of infected B cells, which deliver latent EBV to daughter cells, or, more rarely, to switching of EBV to lytic infection (21). The latter process can eventually be triggered by the differentiation of infected memory B cells into plasma cells and results in the release of virions that may subsequently infect new B cells (17). Importantly, transmission of EBV to naïve hosts is thought to occur via droplets loaded with virions (21). Thus, lytic replication of EBV takes place best in nasal mucosa-associated lymphoid tissue (NALT), which will release EBV into the saliva, generating infectious droplets. Therefore, the NALT is the point of EBV transmission, i.e., the portal of entry of EBV as well as a shedding organ for further transmission (21).The attachment of EBV to B cells is mediated by the direct interaction of EBV glycoprotein gp350/220 with cellular CD21, initiating receptor-mediated endocytosis. After binding to CD21, EBV gp42 can interact with host HLA class II molecules, leading to a conformational change in the viral glycoproteins and triggering fusion with the host cell membrane (12,28). Nevertheless, experimental data suggest that CD21 and HLA class II molecules are dispensable for the infection of B cells (14). Notably, in polarized oropharyngeal epithelial cells, which lack CD21, interactions between ␤1 int...

Epstein-Barr Virus Infection of Naïve B Cells In Vitro Frequently Selects Clones with Mutated Immunoglobulin Genotypes: Implications for Virus Biology

“…More recently, Dorner et al also reported that naïve (CD27 − ) and total memory (CD27 + ) B cells from tonsils were equally infectable in short-term assays, although subsequently naïve cells grew slightly quicker and gave slightly better LCL yields from limiting dilution seedings [48]. While naïve (CD27 − ) cells from peripheral blood resembled their tonsillar counterparts, they were more infectable than peripheral blood memory (CD27 + ) preparations; this could not be explained at the level of receptor (CD21)/co-receptor (HLAII) expression but was ascribed to heterogeneity among circulating memory cells in expression of another putative co-receptor, α5β1 integrin [49]. Comparisons with the present work are difficult because Dorner et al employed an unusual recombinant EBV strain (lacking one of the latent proteins, LMP2A) whose low titre preparations necessitated the use of spinoculation to achieve measurable rates of infection.…”

Integrin β1 Mediates Vaccinia Virus Entry through Activation of PI3K/Akt Signaling

“…Integrins are involved in the entry of many viruses (2,5,19,21,26,34,36,44,59,64) and bacteria (16,27,40). The pathogen-host interaction may promote the clustering of integrins and focal adhesion formation but subvert the downstream signaling network to modify membrane traffic and cytoskeletal dynamics to meet their own needs (1,17).…”

The Glycoprotein B Disintegrin-Like Domain Binds Beta 1 Integrin To Mediate Cytomegalovirus Entry

“…The coordination of growth factor receptor activation, integrin engagement, and virus entry is beginning to emerge as a common theme in herpesvirus entry (89). Furthermore, integrins have also been shown to be important for the entry of memory B cells and epithelial cells (18,27). While it is the BMRF2 and gH/gL glycoproteins that have been implicated in the integrin interactions mediating these EBV entry events, it remains possible that the gB disintegrin-like domain may also play a role in coordinating integrin engagement, growth factor signaling, and virus entry.…”