Functional cure of a chronic virus infection by shifting the virus - host equilibrium state

Abstract

The clinical handling of chronic virus infections remains a challenge. Here we describe recent progress in the understanding of virus - host interaction dynamics. Based on the systems biology concept of multi-stability and the prediction of multiplicative cooperativity between virus-specific cytotoxic T cells and neutralising antibodies, we argue for the requirements to engage multiple immune system components for functional cure strategies. Our arguments are derived from LCMV model system studies and are translated to HIV-1 infection.

Keywords: Chronic virus infections; HIV (human immunodeficiency virus); LCMV (lymphocytic choriomeningitis virus); cure strategies; multi-stability; shifting equilibrium states.

Figure 1

High and low virus load (VL) equilibrium states in persistent chronic virus infections. (A) Schematic presentation of a high and low virus load state, and the associated pathology. (B) Mathematical model predictions of multiple virus equilibrium states (I to IV) in LCMV infections of mice as a function of the net virus growth rate β. Data are from (28). The four virus equilibrium states differ in their values of the virus load from the highest (state I) to the lowest (state IV). Stability of an equilibrium state or steady state means that the system returns back after some perturbation. Only stable equilibrium states are biologically observable. State I is always stable while state III is stable for a certain range of β (solid lines). States II and IV are unstable (broken lines) and cannot be observed biologically. A possible reduction of β by neutralising antibodies is indicated below. It represents the natural occurrence of a late, specific neutralizing antibody response during chronic LCMV infection that reduces the net virus growth rate represented by β. (C) Evolution of virus neutralising capacity of mouse sera during an experimental LCMV infection of mice. Experimental data are from (29) and converted into this presentation. Medians of viral loads at days 30 and 70 and their interquartile ranges are indicated in red. Solid line, sera from chronic infection; broken line, sera from acute infection.

Figure 2

Dynamic views of virus-host interactions. Lines with an arrow or T end represent expansion or reduction/suppression of the corresponding virus or cell populations, respectively. The specific processes by which this occurs are specified above the lines. (A) Conceptual dynamic view of a high and a low virus load state within an infected host. The underlying processes are indicated. A high VL state drives CTL exhaustion (grey cells) and reduces the population of effector CTL (green cells). B cells (blue cells) produce antibodies that eliminate infectious viruses. Both, effector CTL and antibodies from B cells, depending on their strength, contribute to the control of the virus load. (B) Cooperative engagement of individual immune components for functional cure strategies in HIV-1 infection. The combination of immune checkpoint inhibitors with CTL-based immunotherapy and neutralising antibody responses is indicated. aPDL1, anti-PDL1 antibodies; CTL, cytotoxic T cells; CTLex, exhausted CTL; CD4i, infected CD4 T cells; VL, virus load. The figure was created with BioRender.com.