RNA transfer by Epstein-Barr virus triggers early events that regulate cell fate and promote immune evasion

More than 90% of the worldwide population is infected with Epstein
Barr virus (EBV). In general, the infection remains asymptomatic
and the virus persists for life in latently infected B cells.
During this state, viral activity is reduced to the maintenance of
the viral genome such that EBV-infected cells are not efficiently
recognized by the immune system. However, the first days of primary
infection are characterized by a period of lytic gene expression
that contributes to successful virus establishment (Kalla et al.,
2010). The abundant expression of “foreign” protein renders the
infected cell prone to immune recognition and requires viral
counter-measures to evade immune responses. The first part of this
work focuses on the importance of two immune evasins of EBV during
this early phase of infection: BCRF1 and BNLF2a, encoding the viral
homologue of the anti-inflammatory cytokine IL-10 and a unique
inhibitor of epitope loading on MHC I molecules, respectively. To
study their impact on immune responses to freshly infected B cells,
I generated recombinant EBV mutants, which are deficient in
expressing either BCRF1 or BNLF2a or both. I observed significant
immunological consequences during the first days of infection, but,
unexpectedly, the MHC I surface pattern of infected B cells was not
affected. Deficiency in BNLF2a expression in infected cells
resulted in a drastically increased response of EBV-specific CD8+ T
cells. BCRF1 did not participate in this effect, but instead
severely impaired the cytokine response to viral infection and
protected infected cells from elimination by NK/NKT cells. Thus,
both immune evasins have important functions during the early phase
of infection and are instrumental for the establishment of latency.
Their balanced activity illustrates the perfect adaptation of the
virus to the host’s immune system. The second part of this work
builds upon my initial observation that viral transcripts are
present in the infected cell almost instantly following virus
entry. I found that EBV particles represent the source of these
transcripts as I identified them to contain viral RNA which is
transferred to and expressed in the infected cell. I could further
demonstrate that these packaged transcripts exert important
biological functions in the infected cells by triggering the
initial viral transcription program or acting as immune modulators.
In sum, delivered RNAs apparently create a supportive environment
that promotes virus establishment in infected B cells. Thus,
despite EBV’s classification as a DNA virus, also packaged RNAs are
apparently essential for its infectious nature.