Evolutionary Principles in Viral Epitopes - Mathematical Methods and Models in Biomedicine - page 62

with herpesvirus leads to life-long latent infection with periodic reactivation of the
virus. A limited set of viral genes that enable the virus to replicate are expressed
during latent infection phase of gamma herpesviruses, while in the alpha subfamily,
there are no latent proteins, but there are latent RNA transcripts [ 23 ]. Latency of
the beta subfamily is less understood and appears to rely in host gene control and
host differentiation signals. The production of the virus depends on another cascade
that classifies the viral genes into three major groups according to their respective
expression pattern; immediate-early (IE), early and late. The immediate early (IE)
genes encode proteins that are expressed first and are regulatory in nature. These
proteins control the expression of viral and cellular genes and are critical in the
determination whether the infection will be abortive or productive [ 15 ].
We hypothesized that the destruction of the virus during latent or early productive
infection would prevent further virus infection and dissemination. We expected to
observe reduced exposure of viral proteins expressed during the latent phase of the
infection. We investigated the epitope density in proteins expressed in each viral life
cycle stage. Here, we focus on: herpes simplex virus type 1 (HSV1-HHV1), human
cytomegalovirus (HCMV-HHV5), Epstein-Barr virus (EBV-HHV) and the Kaposi's
sarcoma-associated herpesvirus (KSHV-HHV8).
We have first looked for all latent proteins. The KSHV genome encodes over 90
proteins. Eighty-two of these proteins were classified into three groups (latent, IE
and lytic) based on their expression phase [ 15 ]. We expected the SIR score of the
latent proteins to be lower than all others. The 77 EBV proteins were also divided
into IE, latent and lytic proteins [ 45 ]. In the HSV1 there are only latent transcripts,
and no viral proteins are expressed. HCMV also has latent proteins, but a list of such
proteins was not found. The HCMV genes were divided into lytic and IE genes.
The SIR score of the latent proteins in both KSHV and EBV was indeed
significantly lower than the SIR score for all proteins, while lytic proteins have a
higher SIR score (Fig. 4 ).
If the lower SIR score is indeed a measure of immune-induced selection pressure
to reduce the number of epitopes, other immune evasion mechanisms may be used
in these high-risk proteins. One such mechanism could be self-mimicry. In other
words, one would expect that the fraction of epitopes similar to self to be also higher
in the latent group. This was indeed the case for both EBV and KSHV (Fig. 5 ).
The escape from the immune system is thus obtained using both a reduction in the
number of epitopes and mimicry. The number of immunogenic epitopes is however
still not reduced to zero. The remaining epitopes may either evoke no immune
response or develop alternative evasion mechanisms, such as MHC downregulation,
or interference with the cleavage process [ 1 , 2 ]. Obviously, some epitopes are left,
since many of the low SIR score proteins are actually very immunogenic. The low
SIR score is not evidence of low immunogenecity, but of the fact that the virus
attempts to hide the epitopes of this specific protein. In fact, it may actually be the
opposite. The proteins that the virus would try to hide may be the most immunogenic
proteins.
Virions are also not present in the earliest phase of infection, during the
expression of immediate early (IE) genes. The IE proteins are expressed during the