Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

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The human γ-herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, infect >90% of the population worldwide, and latent infection is associated with numerous malignancies. Rational vaccination and therapeutic strategies require an understanding of virus-host interactions during the initial asymptomatic infection. Primary EBV infection is associated with virus replication at epithelial sites and entry into the circulating B lymphocyte pool. The virus exploits the life cycle of the B cell and latency is maintained long term in resting memory B cells. In this study, using a murine γ-herpesvirus model, we demonstrate an early dominance of latent virus at the site of infection, with lung B cells harboring virus almost immediately after infection. These data reinforce the central role of the B cell not only in the later phase of infection, but early in the initial infection. Early inhibition of lytic replication does not impact the progression of the latent infection, and latency is established in lymphoid tissues following infection with a replication-deficient mutant virus. These data demonstrate that lytic viral replication is not a requirement for γ-herpesvirus latency in vivo and suggest that viral latency can be disseminated by cellular proliferation. These observations emphasize that prophylactic vaccination strategies must target latent γ-herpesvirus at the site of infection.

Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Early Establishment of γ-Herpesvirus Latency: Implications for Immune Control

Flaño

Jia

Moore

et al. 2005

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“…Despite this very low level of viral latency, splenic dendritic cells but not B cells are capable of presenting viral lyticphase epitopes to ␥HV68-specific CD8 ϩ T cell hybridomas. This finding is unexpected as germinal center and memory B cells constitute the major viral reservoir during long-term latency (65,66). It suggests that dendritic cells cross-present lytic-phase viral Ags during ␥HV persistence and supports the existence of continuous viral reactivation during the latency phase of infection (38,67,68).…”

Section: Discussionmentioning

confidence: 87%

Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence

Cush¹,

Anderson²,

Ravneberg³

et al. 2007

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During infection with viruses that establish latency, the immune system needs to maintain lifelong control of the infectious agent in the presence of persistent Ag. By using a γ-herpesvirus (γHV) infection model, we demonstrate that a small number of virus-specific central-memory CD8+ T cells develop early during infection, and that virus-specific CD8+ T cells maintain functional and protective capacities during chronic infection despite low-level Ag persistence. During the primary immune response, we show generation of CD8+ memory T cell precursors expressing lymphoid homing molecules (CCR7, L-selectin) and homeostatic cytokine receptors (IL-7α, IL-2/IL-15β). During long-term persistent infection, central-memory cells constitute 20–50% of the virus-specific CD8+ T cell population and maintain the expression of L-selectin, CCR7, and IL-7R molecules. Functional analyses demonstrate that during viral persistence: 1) CD8+ T cells maintain TCR affinity for peptide/MHC complexes, 2) the functional avidity of CD8+ T cells measured as the capacity to produce IFN-γ is preserved intact, and 3) virus-specific CD8+ T cells have in vivo killing capacity. Next, we demonstrate that at 8 mo post-virus inoculation, long-term CD8+ T cells are capable of mediating a protective recall response against the establishment of γHV68 splenic latency. These observations provide evidence that functional CD8+ memory T cells can be generated and maintained during low-load γHV68 persistence.

“…For example, both ␥HV68 and EBV induce B cell activation, but they do it in different ways. EBV accomplishes this directly through the expression of several viral genes, including latent membrane protein 1, LMP2a, and EBV-encoded nuclear Ag 2 (64 -68), whereas ␥HV68-driven B cell activation appears to rely on normal Ag and CD4 T cell signaling mechanisms (7,45,69,70). However, despite using a different mechanism for B cell activation, ␥HV68 latency fits the original model proposed for EBV (14) that the virus exploits the life cycle of the B cell, in that latency is preferentially established in highly activated, germinal center B cells, allowing the virus to gain access to the long-lived memory B cell compartment.…”

Section: Discussionmentioning

confidence: 99%

“…As has been described for EBV, memory B cells are a preferential reservoir of long-term ␥HV68 latency (6,8,16). Genetically manipulated mouse strains with defects in B cell activation and memory B cell development thus provide valuable models for studying ␥HV68 latency (7,17).…”

Section: T He Oncogenic Human Gammaherpesviruses Ebv Andmentioning

confidence: 94%

Perturbation of B Cell Activation in SLAM-Associated Protein-Deficient Mice Is Associated with Changes in Gammaherpesvirus Latency Reservoirs

Kim

Burkum

Cookenham

et al. 2007

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Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP)) interactions with SLAM family proteins play important roles in immune function. SAP-deficient mice have defective B cell function, including impairment of germinal center formation, production of class-switched Ig, and development of memory B cells. B cells are the major reservoir of latency for both EBV and the homologous murine gammaherpesvirus, gammaherpesvirus 68. There is a strong association between the B cell life cycle and viral latency in that the virus preferentially establishes latency in activated germinal center B cells, which provides access to memory B cells, a major reservoir of long-term latency. In the current studies, we have analyzed the establishment and maintenance of γHV68 latency in wild-type and SAP-deficient mice. The results show that, despite SAP-associated defects in germinal center and memory B cell formation, latency was established and maintained in memory B cells at comparable frequencies to wild-type mice, although the paucity of memory B cells translated into a 10-fold reduction in latent load. Furthermore, there were defects in normal latency reservoirs within the germinal center cells and IgD+“naive” B cells in SAP-deficient mice, showing a profound effect of the SAP mutation on latency reservoirs.