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.
Highlights
Epstein–Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) are two of the seven oncogenic viruses associated with human cancers
In a latent cell culture system or in a KSHV neoplasia, there exists a subpopulation of KSHV-infected cells that either undergo full lytic reactivation or express a low level of genes ascribed to the lytic cycle such as K1 and vIL6 [113]
Due to the autoimmune properties of the human IGHV4-34 gene segment, B cells expressing them are excluded from germinal center (GC) and memory B cell compartments and the levels are low in sera of healthy individuals [194,195]
Summary
Epstein–Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) are two of the seven oncogenic viruses associated with human cancers. GHVs of humans, Epstein–Barr virus (EBV, HHV-4) and Kaposi sarcoma herpesvirus (KSHV, HHV-8), in addition to the small animal model pathogen, the B lymphotropic murine gammaherpesvirus 68. KSHV infection of PLWH drives four independent, and sometimes concomitant disease manifestations: Kaposi sarcoma (KS), an endothelial cell-derived neoplasia of the skin and viscera; primary effusion lymphoma (PEL); a subset of multicentric Castleman disease (MCD); and KS inflammatory cytokine syndrome (KICS) [20]. As a member of the rhadinovirus arm of the GHV subfamily, MHV68 is genetically closer to KSHV, but shares with EBV and KSHV the properties of driving primary B cell proliferation and lymphoma development in the host [26]. Dynamic Molecular Events as the B Cell Traverses Compartments of the Germinal Center
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