Paradoxically, flaviviruses such as West Nile (WNV) and others, directly induce increased expression of MHC-I, as well as MHC-II, and several adhesion molecules involved in immune recognition by CTL. This increased expression results in a marked increase in the efficiency of recognition and killing of infected cells by WNV-specific CTL ([
3,
4]), because although the affinity of individual T cell receptor (TcR)-MHC-virus peptide interaction is unchanged, the multiple intermolecular interactions increases the avidity of interaction of virus-specific CTL with the infected cell. This increased avidity also enables the functional interaction with MHC
h
i
, infected cells by CTL clones of low MHC-virus peptide affinity, i.e., clones previously below the recognition threshold. Some of these low-affinity CTL clones are likely to be self-reactive [
4] or even able to recognize MHC without peptide specificity [
5]. Thus, the increased avidity brought about by high MHC expression enables low-affinity, self-reactive clones, not normally involved in anti-viral immune responses, to lyse both infected and uninfected target cells [
6]. Adhesion molecules such as ICAM-1, as non-specific accessory molecules upregulated by WNV infection, also increase the avidity of CTL-target cell interactions, further lowering the affinity threshold for T cell recognition and target cell lysis [
7]. In addition, interferon-
γ (IFN-
γ), released by CTL on recognition of their cognate ligand, strongly increases MHC and ICAM-1 expression on neighboring target cells, further contributing to the progressive increase in avidity of interaction between CTL and target cells [
8]. In this context, the stage of the cell cycle in which a cell is infected is also important; cells infected by WNV in
G
0 (resting) increase MHC-I expression by 6-10-fold, compared to a 2-3-fold increase observed in cells infected during the cell cycle (
G
1, S,
G
2+
M) [
3]. WNV-infected
G
0 cells are approximately 10-fold more susceptible to CTL lysis than infected cycling cells exposed to the same CTL [
3]. Thus, WNV-infected cycling cells are less easily recognized, while the avidity of interaction between CTL and infected
G
0 cells is significantly enhanced by the higher levels of MHC-I and ICAM-1. Notably, WNV replicates significantly better in the poorly recognized cycling cells than in
G
0 cells. In vivo, most cells are in
G
0, presumably presenting an easy CTL target once infected, but a small population of productively infected cycling cells maintaining a low immunological profile, could substantially increase the probability of virus transmission to the next host [
4]. As indicated above, the release of IFN-
γ upon target cell recognition by CTL would also increase MHC and ICAM-1 expression on uninfected cells in the vicinity of virus- infected cells, making high MHC-I-expressing (uninfected) cells a potential target for lysis by low affinity virus-specific and/or self-reactive (i.e., cross-reactive) CTL clones. The collateral destruction of uninfected cells by low-affinity clones of this kind would cause substantial additional damage to the brain, with corresponding increases in morbidity and mortality [
9]. We have developed a model of the collateral damage caused by a West Nile Virus infection, which is supported by simulation results [
10]. A discussion of the underlying simulation code can be found in [
11]. We have also used these simulation results to explain the unusual ragged survival data seen in West Nile Virus infections [
12]. The previous work, in focusing on very low level details, based on first principles, could be regarded as a
micro model. Here we develop a
macro model, based on a much higher level approach and ideas. Each model has its pros and cons but we believe each brings complementary insights into a very complicated problem. Our focus here is therefore on developing a
macro level theoretical model of how the survival of a host depends on the level of initial viral dose. We believe this approach provides an abstract focus which can also be directed towards more general models of immunopathology and we will briefly mention those connections at the end. These more general models of autoimmune response are the focus of additional work we are doing.