Background: There are many viruses that result in persistent infections affecting
millions of people worldwide. Although our immune system deploys different strategies
to eliminate them, many times they prove unsuccessful and call for a better understanding
of the host-virus interplay. One important weapon of the immune system
is CD8+ T cells which identify infected cells and limit the spread of infection using
different effector mechanisms.
Aim: The aim of this study is two-fold; the investigation of 1) the impact of immunogenetic
factors such as HLA class I molecules and Killer cell immunoglobulin-like
receptors (KIRs) on CD8+ T cell responses and 2) the efficiency of lytic and non-lytic
CD8+ T cell responses and how they shape viral escape dynamics.
Methods: The methods used to address the aims include statistical models, high-throughput
sequence analysis, ordinary differential equation models and agent-based
models.
Results: We find that HLA class I molecules explain a small percentage of the heterogeneity
observed in the outcome of HCV, HTLV-1 and HIV infections. However,
we show that an inhibitory KIR, namely KIR2DL2, can enhance both protective and
detrimental HLA class I-restricted anti-viral immunity, for both HCV and HTLV-1 infections
and in a manner compatible with the modulation of CD8+ T cell downstream
responses. Furthermore, for HIV/SIV infection, we show that the CD8+ T cell control
of the infection can be consistent with a non-lytic mechanism. Additionally, we find
that lytic CD8+ T cell responses are more efficient than non-lytic responses which can
lead to slower and less frequent viral escape explained by spatial factors.
Conclusions: We conclude that KIRs can play an important role in shaping HLA
class-I mediated immunity and suggest that this occurs in synergy with CD8+ T cells
whose lytic and non-lytic effector functions can differ in efficiency and lead to variable
viral escape rates.