Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression.

The course of HIV-1 infection is typified by three phases; acute infection characterized by a rapid viraemia peak (3—6 weeks post-infection) followed by a rapid fall in virus levels, a stable chronic phase of variable length characterized by low level viraemia and slowly declining CD4+ T cell numbers, and a final stage (Acquired Immune Deficiency Syndrome, AIDS) characterized by multiple opportunistic infections and a rapid fall in CD4+ T cell count.

However the interplay of cell-to-cell spread and increased CD4+ T cell activation, that are likely to have profound influences on the progression of the disease have been hitherto little studied.

In this paper, unless otherwise stated, “T cells” refers to CD4+ T cells .

The production rate of new quiescent T cells from sources, such as thymus, within the human body is represented by b. Quiescent T cells are activated and become susceptible at a variable activation rate a(NM/N), where a is the activation coefficient and NM is the density of T cells at which proliferation stops.

We illustrate our methods potential to find intervention targets for cancer treatment and cell differentiation by applying it to a leukemia signaling network and to the network controlling the differentiation of helper T cells .

Intervention targets for each control strategy in the helper T cell network.

More specifically, we use our network control framework to predict network control interventions on previously developed logical dynamic models for a leukemia signaling network and for the network controlling the differentiation of helper T cells .

T cell large granular lymphocyte leukemia network.

Hence paracrine signaling will generally extend beyond the synapse but can be limited to cellular microenvi-ronments through uptake by target cells or strong competitors, such as regulatory T cells .

[9] have found that interleukin(IL)-4 is seen by most T cells in the lymph node upon parasite infection, including nonspecific ‘by-stander’ cells.

In this case, many T cells throughout the lymph node could be IL-4 producers.

However, it has been demonstrated that cyto-kine concentrations are not always well mixed, and locally higher cytokine concentrations can occur also in eX vivo T cell cultures [12].

However, T cells release IL-2 and other cytokines in a polarized fashion into the immunological synapse [10,21—23].