How to prevent viremia rebound? Evidence from a PRRSv data-supported model of immune response Natacha Go1,2,3*, Suzanne Touzeau

Context: Understanding what determines the between-host variability in
infection dynamics is a key issue to better control the infection spread. In
particular, pathogen clearance is desirable over rebounds for the health of the
infected individual and its contact group. In this context, the Porcine Respiratory
and Reproductive Syndrome virus (PRRSv) is of particular interest. Numerous
studies have shown that pigs similarly infected with this highly ubiquitous virus
elicit diverse response proles. Whilst some manage to clear the virus within a
few weeks, others experience prolonged infection with a rebound. Despite much
speculation, the underlying mechanisms responsible for this undesirable rebound
phenomenon remain unclear.
Methods: We aimed at identifying immune mechanisms that can reproduce and
explain the rebound patterns observed in PRRSv infection using a mathematical
modelling approach of the within-host dynamics. As diverse mechanisms were
found to in
uence PRRSv infection, we established a model that details the
major mechanisms and their regulations at the between-cell scale. We developed
an ABC-like optimisation method to t our model to an extensive set of
experimental data, consisting of non-rebounder and rebounder viremia proles.
Results: We compared, between both proles, the estimated parameter values,
the resulting immune dynamics and the ecacy of the underlying immune
mechanisms. Exploring the in
uence of these mechanisms, we showed that
rebound was promoted by high apoptosis, high cell infection and low cytolysis by
Cytotoxic T Lymphocytes, while increasing neutralisation was very ecient to
prevent rebounds.
Insights: Our paper provides an original model of the immune response and an
appropriate systematic tting method, whose interest extends beyond PRRS
infection. It gives the rst mechanistic explanation for emergence of rebounds
during PRRSv infection. Moreover, results suggest that vaccines or genetic
selection promoting strong neutralising and cytolytic responses, ideally associated with low apoptotic activity and cell permissiveness, would prevent rebound.