Evolutionary Principles in Viral Epitopes - Mathematical Methods and Models in Biomedicine - page 64

initial infection, having mainly regulatory functions (although they are also required
for genome replication). As in the case of the latent proteins, one would expect the
SIR score of the IE proteins to be low. We defined the IE proteins for the HSV1,
E B V, H C M V a n d K S H V.
The SIR score of the IE proteins was indeed significantly lower than the SIR
score of all proteins in the virus, which in turn was lower than the SIR score of lytic
proteins (Fig. 4 p 6). Similarly, the fraction of epitopes similar to self was

higher within the IE proteins than in all other epitopes (on average). The SIR score
of IE proteins and their similarity to self was intermediate between the latent and all
other lytic proteins, although for KSHV there was no statistical difference between
the similarity to self of latent and IE proteins. In the early phase of infection, when
the stealth of the infection and viral population growth may be critical, it is probably
important (from the virus point of view) to reduce the host detection, but not as much
as in the latent phase. In contrast with latent proteins, the IE proteins are expressed
for a short period, since they are downregulated by the early proteins. Thus, even if
they are partially presented to the immune system, CTLs have a limited time to use
the IE epitopes in order to destroy the virally infected cells.

< 1 . e −

3.4 HIV: A Second Example of the Same Principle

As in the herpes case, beyond the total reduced number of epitopes, we can see in
HIV a non-uniform epitope density distribution among proteins. We separated the
HIV-1-M(B) CTL epitope repertoire into its nine genetic components and computed
the appropriate SIR score for each protein. Within the nine HIV proteins, a clear and
logical hierarchy of the SIR score emerges. Regulatory proteins (Tat and Rev) have
very few epitopes left already at the HIV ancestral sequence. Their SIR score is
close to the basal level induced by the errors inherent to the prediction algorithms.
The “late” virion associated proteins (Gag, Pol and Env) are found at the top of
the list. Accessory proteins also have an intermediate SIR score (Fig. 6 ). This is in
good agreement with the observed critical role of Tat specific CTL in stopping the
acute infection stage [ 27 ] and with the differential total variability of the HIV genes
[ 3 , 7 ]. Epitopes from proteins that are produced during the first stages of the HIV
gene replication after cell entry, such as the regulatory proteins Rev and Tat, are
exposed early to CTLs within the cell. Their detection by CTLs can lead to cellular
destruction, long before new virions are produced.
Epitopes originating from Gag and Env proteins are presented to CTLs only later
in the infection. The detection of such epitopes may not critically impair HIV, as
some virions may have the time to bud before the cell is destroyed. The same trend
was observed using the sub-Saharan allele frequency (Fig. 6 ). One can actually
observe similar results at the single allele level when looking at frequent HLA
alleles (that are probably highly sampled in the non-serotyped population) (data
now shown).