The model incorporates both an immune response , which is believed to be a major factor limiting viral expansion by killing of infected cells, and the formation of long lived latently infected cells, which are believed to play an important role in limiting the longterm effects of antiviral therapy.

In this paper we develop a new mathematical model which incorporates the basic principles of previous host-centric models including a virus-dependent immune response [8] , viral latency and a progressive increase in cell activation [26, 27].

Values for five parameters (Q0, 80, NM, K and D) describing the characteristics of the immune response were chosen for each patient to minimise the error of the predicted quasi-stable level of T cell counts (N5) and viral load (V5), and the time of progression to AIDS (tA).

And we use the term K % to model the death of infected T cells by the cellular immune response .

K is initially 0 and changes to a higher value in Table 1 when the cellular immune response kicks in D (default value: 30) days after the initial infection.

The term captures the relationship between the strength of the immune response and the density of infected CD4+ T cells [8].

When either route is abolished, infection is blocked completely; T cell level returns to normal and virus is cleared after the cellular immune response kicks in.

In the context of the model, the transition from phase 1 (acute) to phase 2 (stable chronic) is driven by a balance between several processes, including viral spreading through two parallel modes, and the cellular immune response , i.e.

when activation rate is fixed), HIV infection would not progress to AIDS after the onset of the cellular immune response .

Clearance of anogenital and oropharyngeal HPV infections is attributed primarily to a successful adaptive immune response .

In particular, we find that in immunocompetent adolescents with cervical HPV infections, the immune response may contribute less than 20% to virus clearance—the rest is taken care of by the stochastic proliferation dynamics in the basal layer.

In HIV-negative individuals, the contribution of the immune response may be negligible.

Clearance of HPV infection is usually attributed to an effective immune response , and the observation of longer clearance times in immunocompromised individuals further corroborates this assumption [9].

On the other hand, the fact that development of antibodies preventing future reinfection after clearing of the virus (known as seroconversion) occurs only partially [10—14] suggests that mechanisms other than an effective immune response may contribute to viral clearance.

Immune response .

Even though HPV is equipped with molecular mechanisms that facilitate immune evasion after infection, it is generally assumed that clearance of the Virus is the result of a successful immune response [25, 33].

Initially, detection of the infection triggers an innate immune response which targets the Virions that are released at the surface, as well as infected cells in the superficial layers.

Stochasticity vs immune response

In particular, the coexistence of preexisting and mutated strains triggers a heightened immune response due to the larger total pathogen population; this feedback can smother mutated strains before they reach an ample size and establish.

This evolution can either result in the production of neW pathogens, or neW strains of existing pathogens that escape prevailing drug treatments or immune responses .

Specifically, once a mutated pathogen arises that spreads more quickly than the initial (resident) strain, it potentially triggers a heightened immune response that can eliminate the mutated strain before it spreads.

Parasite and pathogen evolution can radically affect the course of infections in hosts able to mount immune responses .

All these scenarios can be analysed in the larger framework of evolutionary rescue [18, 19] , where a change in the environment (in this case, the activation of an immune response ) will cause the population to go extinct unless it evolves (develops an increased replicative ability, then subsequently rise to a large enough size to avoid stochastic loss).

This effect can be exacerbated by the fact that the mutated strain also prompts an increased immune response , so the emerging infection has a stronger defence to initially compete with (assuming immune growth is proportional to the total size of the pathogen population).

(P1, (P2 Growth rate of initial, mutated infection x1, x2 Size of initial, mutated infection y Size of immune response

K Maximum size of immune response r Unscaled growth rate of immune response

Immune responses are regulated by diffusible mediators, the cytokines, which act at sub-nanomolar concentrations.

The discovery that immune responses are regulated by small diffusible proteins — the cytokines — has been surprising because cytokine diffusion to ‘bystander’ cells might compromise specificity.

Recent experimental observations suggest that also paracrine IL-2 signals towards other Th cells are important for regulation of immune responses , while true au-tocrine IL-2 signals are suppressed by the intracellular signal transduction pathway [5,37].

However, our simulations show that the need for paracrine cytokine signals provides several checkpoints for the induction of immune responses downstream of the T cell receptor.

Adaptive immune responses must be rapid and effective in the case of strong infection, but also carefully controlled to avoid autoimmune diseases.

The physiological cytokine milieu regulates critical processes like the type and strength of the immune response .

It is not known how they diffuse under such conditions and, in turn, regulate immune responses .

Table 4 shows that these interaction modules were associated with biological processes related to ligase activity, ubiquitination, protein modification, transcription and translation, immune response , signaling, cytoskeleton organization, development, and mRNA processing.

For example, the interaction modules allowed us to identify a biological process termed “pos-itive regulation of protein ubiquitination” instead of just “protein ubiquitination.” Importantly, the analysis provided evidence of a much larger effort to target intracellular host signaling processes, in particular those related to the immune response .

Each of the interaction modules constituting ubiquitination and ligase activity, transcriptional regulation, immune response , cy-toskeleton organization, and mRNA processing, consisted of proteins and interactions that were closely grouped together in the largest connected component (Fig.

Here, we performed a systematic analysis of these interactions to investigate the mechanisms by which B. mallei virulence factors interact with host proteins to establish infection, evade host immune responses , and spread within the host.

Analyses of these host-pathogen PPI datasets showed that virulence-associated pathogen proteins preferentially target host proteins involved in biological processes essential for cell vitality, e.g., signaling, cell cycle, or immune response [9—13].

To further analyze the observed differences in immune response between cases resulting in tumor death vs. survival, we defined a statistical metric for assessing the relative prevalence of M2 cells within the overall macrophage population.

We next evaluated whether the early immune response , as measured by the MPI, remains highly predictive of tumor survival over a range of model parameterizations.

Thus, a general feature of our simulations was that tumor survival or death is a nearly deterministic consequence of the early immune response long before growth of the tumor is impacted.

Conversely, the immune surveillance theory of cancer predicts that some neoplasms and metastases are controlled by the immune response [12] , and moreover, it is widely hypothesized that the initial response to cancer is inflammatory and immunostimulatory [13,14].

In this study, we used a computational approach to elucidate general principles by which heterogeneities in the spatial structure of the TME and in immune cell phenotype may drive the dynamic evolution of the collective immune response to a nascent metastatic tumor.