T cells modulate Epstein-Barr virus latency phenotypes during infection of humanized mice

J Virol. 2014 Mar;88(6):3235-45. doi: 10.1128/JVI.02885-13. Epub 2014 Jan 3.

Abstract

Human B cells, the main target of Epstein-Barr virus (EBV), can display several types of latent viral protein expression, denoted 0, I, IIa, IIb, or III. Of these, only type III expression induces proliferation of cells in vitro. These latency types are present at specific stages of infection and are also characteristic of different tumor types, but their generation is not fully understood. In this study, we analyzed the role of T cells in the regulation of EBV viral latency by using humanized NOD/SCID/IL2Rγ(-/-) mice. Several spleens presented macroscopic tumors 4 weeks after infection. Explanted spleen B cells from some of the EBV-infected mice proliferated in vitro, but this was usually lowered when cyclosporine was added to the cultures. This suggested that the in vitro growth of EBV-infected B cells required T cell help; thus, cells other than type III cells were also present in the spleens. Quantitative PCR analysis of promoter activities specific for the different EBV latency types confirmed that in addition to type III cells, type IIa and type I cells were present in the spleen. The relative usage of the viral promoter specific for I and IIa latency types (Q promoter) was higher in CD8(+) cell-depleted mice, and it was absent from CD4(+) cell-depleted mice. These results indicate that CD4(+) T cells are necessary for the generation/maintenance of cells with latency I/IIa in the humanized mice. CD4(+) T cells contributed to this process through their CD40L expression.

Importance: At primary infection with EBV, the infected B cells are proliferating and express viral proteins that have transforming potential. However, when the acute infection is resolved, in healthy individuals EBV is carried by a small fraction of B cells that express a restricted number of viral proteins unable to induce proliferation. Understanding the details of this transition is of fundamental importance. We studied this question in humanized mice by manipulating their different T cell compartments before and during infection with EBV. Our results indicate that CD4(+) T cells are responsible for the switch to a nonproliferating EBV program during primary infection with EBV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / virology
  • Herpesvirus 4, Human / genetics
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Promoter Regions, Genetic
  • T-Lymphocytes / immunology*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Latency*

Substances

  • Viral Proteins