Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Abstract

A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed.

Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68

“…The primary cellular compartment for MHV68 latency in secondary lymphoid tissues is B cells. As for EBV, naïve follicular B cells are thought to be the initial target, with the virus driving infected cells through GC reactions into long-lived memory B cells (reviewed in 38 ) ( Supplemental Figure 1 ). Consistent with this, during latency establishment, the virus genome is detectable in naïve follicular B2 B cells (sIgD + ), GC B cells (GL7 + /CD95 + ), and isotype-switched memory B cells (reviewed in 13 , 39 ).…”

“…High-throughput sequencing of the immunoglobulin genes indicates that infected B cells participate in the germinal center (GC), with evidence of somatic hypermutation and isotype class switching ( 38 , 148 , 149 ). There is a striking occurrence of clonal expansion and recurrence of Ighv10-1 usage in infected GC B cells, with little clonal overlap of V genes in uninfected B cells of the same animal at the peak of splenic latency.…”

“…The origin of plasmablasts and the link between GC reactions and long-term latency in memory B cells are unknown. The potential for the selection and expansion of virus nonreactive and autoreactive pathological B cells is an important issue for the field (reviewed in 38 ).…”

Stress-Induced Epstein-Barr Virus Reactivation

“…Kaposi sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus capable of establishing latent infection in B cells [ 160 ]. Given that EBV also establishes latent infection in B cells, it is unsurprising that they interact during co-infection.…”

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

“…During the peak of latency, day 14-22 post infection, MHV68UNG protein is detected in a significant percentage of infected GC cells. Whether the MHV68UNG protein participates in or alters SHM or CSR is not known 24,25 .…”