T–cell memory: lessons from Epstein–Barr virus infection in man

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: Discussionsupporting

confidence: 51%

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

Flaño

Jia

Moore

et al. 2005

“…This loss of function in the presence of persistent Ag follows a progression in the sequence of cytotoxicity, IL-2, TNF-␣, and IFN-␥ production, exhaustion, and deletion (20,21). However, these findings appear to be at odds with situations where viruses persist and CD8 ϩ T cell functions are not apparently compromised (22)(23)(24)(25), with reports of residual Ag presentation (26) or with a possible role for Ag in the maintenance of immunological memory (27). ␥-herpesviruses (␥HV) are characterized by the establishment of lifelong asymptomatic infection, the persistence in Ͼ90% of the human population, and the association with a large list of life-threatening conditions (28,29).…”

Section: The Contribution Of Memory Cd8contrasting

confidence: 48%

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

Cush¹,

Anderson²,

Ravneberg³

et al. 2007

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.

“…In The Netherlands, a cross-sectional serum study in 1991 had shown that 40% is EBVseropositive at 10 years of age increasing to 98% at 30 years, while CMV immunity is detected in ϳ30 and 50%, respectively (14). Infection with these viruses early in life is most often asymptomatic, while infection later in life is a self-limiting disease more often associated with clinical symptoms (12). On the other hand, chickenpox (varicella) is a common disease of childhood caused by primary infection with VZV, a highly contagious herpesvirus with attack rates of Ͼ85% in susceptible contacts in the temperate climate under 7 years of age (15)(16)(17).…”

Section: Frequencies Of Circulating Cytolytic Cd45ramentioning

confidence: 99%

“…Both EBV and CMV are herpesviruses that infect the vast majority of humans, following a bimodal pattern of infection with peaks during early childhood and late adolescence, being defined to a large extent by socioeconomic factors (12,13). In The Netherlands, a cross-sectional serum study in 1991 had shown that 40% is EBVseropositive at 10 years of age increasing to 98% at 30 years, while CMV immunity is detected in ϳ30 and 50%, respectively (14).…”

Section: Frequencies Of Circulating Cytolytic Cd45ramentioning

confidence: 99%

Frequencies of Circulating Cytolytic, CD45RA+CD27−, CD8+ T Lymphocytes Depend on Infection with CMV

Kuijpers

Vossen

Gent

et al. 2003

145

110

Viral infections may cause serious disease unless the adaptive immune system is able to clear the viral agents through its effector arms. Recent identification and functional characterization of subpopulations of human CD8+ T cells has set the stage to study the correlation between the appearance of particular subsets and common viral infections during childhood, i.e., EBV, CMV, varicella-zoster virus (VZV), and the attenuated measles-mumps-rubella (MMR) vaccine strains. In a cohort of 220 healthy children we analyzed lymphocytes and subpopulations of CD4+ and CD8+ T cells. The presence of the cytolytic CD45RA+CD27− subset of CD8+ T cells correlated with prior CMV infection as defined by seroconversion (p < 0.0001). The number of this CD8+ T cell subset remained stable during follow-up over 3 years in 40 children. The CD45RA+CD27− subset of CD8+ T cells first appeared during acute CMV infection and subsequently stabilized at an individual set-point defined by age and immunocompetence. The functional importance of these cells in CMV surveillance was reflected by their increased numbers in immunosuppressed pediatric kidney transplant patients. Preferential expansion of CD8+CD45RA+CD27− cytolytic T cells seems unique for CMV.