Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers

The mechanisms by which gammaherpesviruses maintain latency are unclear. Here we used a murine gammaherpesvirus model to show that previously uninfected B cells in immunocompetent mice can acquire virus during latency. In vivo depletion of T cells allowed viral reactivation, as measured by increased viral loads, but not enhanced transfer of virus to new cells. In the absence of both immune T cells and antibody following the transfer of latently infected cells into naïve animals, there was robust infection of new B cells. These data confirm that both T cells and antibody contribute to the control of gammaherpesvirus latency, reactivation, and spread.The hallmark of herpesvirus (HV) infections is the establishment of latency, a lifelong condition characterized by persistent viral genome maintenance and restricted, low-level viral gene expression. The ability to reactivate from latency, reenter the lytic life cycle, and generate infectious virions is responsible for many of the secondary pathological consequences of HV infections, including autoimmunity, cancer, immunoproliferative disorders, recrudescent skin lesions, and transplant rejection (15,19). An unresolved issue in the field of herpesvirology is how latent infections are maintained in the host over time. In the case of alphaherpesvirus (␣HV) latency, the viral genomes reside in nonreplicating cells such as neurons, and so latency is likely propagated by the mere survival of latently infected cells, with periodic de novo infections following reactivation events. ␤HV and ␥HV infections are different, as they establish latency in immune system cells, which, unlike neurons, not only can proliferate but also can express high levels of major histocompatibility complex (MHC) class I and are targets for T cell immunity. Since long-term latency persists even in the presence of functional virus-specific immunity, it is crucial to understand how viral latency is propagated in an immunocompetent host in order to develop rational strategies to control ␥HV infections.Mechanisms for ␥HV latency persistence include viral immune evasion strategies; proliferation of latently infected B cells, in which latent viral episomes are replicated and transferred to the daughter cells; direct cell-to-cell transfer of infectious virus to naïve cells, in the absence of cell-free virus; and asymptomatic shedding of lytic virus, leading to the infection of new B cells. There is evidence in the literature for each of these mechanisms. For example, Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) protein is associated with driving the proliferation of infected B cells (8). Furthermore, it has been shown that efficient EBV infection of epithelial cell lines requires cell-to-cell contact with virally infected cells in cocultures (3, 10), a process that is refractory to inhibition by blocking antibodies (Abs), suggesting that cell-free virus is not required for infection (22). In one study, long-term valacyclovir treatment did not affect the number of EBV DNA copies per B cell but did red...

supporting

confidence: 49%

De Novo Infection of B Cells during Murine Gammaherpesvirus 68 Latency

Freeman

Burkum

Yager

et al. 2011

“…In vivo, MHV68 chronic infection is attenuated in H2AX-deficient mice (44). Because gammaherpesvirus reactivation is important for the maintenance of the infected cell reservoir in vivo (19,30), it is possible that MHV68 usurps DDR components to facilitate its reactivation from latency. This possibility is corroborated by the finding that MHV68 orf36, a protein kinase necessary and sufficient to activate the DDR in the context of lytic infection, is required for optimal MHV68 latency and reactivation (42,44).…”

Section: Implications For A-t and Other Ddr-linked Diseasesmentioning

confidence: 99%

Ataxia Telangiectasia Mutated Kinase Controls Chronic Gammaherpesvirus Infection

Kulinski

Leonardo

Mounce

et al. 2012

Gammaherpesviruses, such as Epstein-Barr virus (EBV), are ubiquitous cancer-associated pathogens that interact with DNA damage response, a tumor suppressor network. Chronic gammaherpesvirus infection and pathogenesis in a DNA damage response-insufficient host are poorly understood. Ataxia-telangiectasia (A-T) is associated with insufficiency of ataxia-telangiectasia mutated (ATM), a critical DNA damage response kinase. A-T patients display a pattern of anti-EBV antibodies suggestive of poorly controlled EBV replication; however, parameters of chronic EBV infection and pathogenesis in the A-T population remain unclear. Here we demonstrate that chronic gammaherpesvirus infection is poorly controlled in an animal model of A-T. Intriguingly, in spite of a global increase in T cell activation and numbers in wild-type (wt) and ATM-deficient mice in response to mouse gammaherpesvirus 68 (MHV68) infection, the generation of an MHV68-specific immune response was altered in the absence of ATM. Our finding that ATM expression is necessary for an optimal adaptive immune response against gammaherpesvirus unveils an important connection between DNA damage response and immune control of chronic gammaherpesvirus infection, a connection that is likely to impact viral pathogenesis in an ATM-insufficient host.

“…Lytic infection kills the host cell; however, it also allows horizontal spread of EBV from cell to cell and may increase the pool of latently infected B cells from which transformed cells arise. Chronic acyclovir therapy in patients treated for herpes simplex virus reactivation also decreases EBV viral loads (14), suggesting that horizontal EBV transmission may be required to replenish the reservoir of latently infected cells. Consistent with a tumorigenic role for lytic infection, prophylactic treatment of transplant patients with antiviral drugs that inhibit lytic replication may reduce EBV-associated lymphomas (6,10).…”

mentioning

confidence: 99%

A New Model of Epstein-Barr Virus Infection Reveals an Important Role for Early Lytic Viral Protein Expression in the Development of Lymphomas

Dong

Hegde²,

Young³

et al. 2011

242

277

Epstein-Barr virus (EBV) infects cells in latent or lytic forms, but the role of lytic infection in EBV- DLBCL). Animals infected with the control virus developed tumors more frequently than Z-KO virus-infected animals. Specific immune responses against EBV-infected B cellswere generated in mice infected with either the control virus or the Z-KO virus. In both cases, forms of viral latency (type I and type IIB) were observed that are less immunogenic than the highly transforming form (type III) commonly found in tumors of immunocompromised hosts, suggesting that immune pressure contributed to the outcome of the infection. These results point to an important role for lytic EBV infection in the development of B cell lymphomas in the context of an active host immune response.