A mathematical model of HIV dynamics treated with a population of gene-edited haematopoietic progenitor cells exhibiting threshold phenomenon

Abstract

The use of gene-editing technology has the potential to excise the CCR5 gene from haematopoietic progenitor cells, rendering their differentiated CD4-positive (CD4+) T cell descendants HIV resistant. In this manuscript, we describe the development of a mathematical model to mimic the therapeutic potential of gene editing of haematopoietic progenitor cells to produce a class of HIV-resistant CD4+ T cells. We define the requirements for the permanent suppression of viral infection using gene editing as a novel therapeutic approach. We develop non-linear ordinary differential equation models to replicate HIV production in an infected host, incorporating the most appropriate aspects found in the many existing clinical models of HIV infection, and extend this model to include compartments representing HIV-resistant immune cells. Through an analysis of model equilibria and stability and computation of $R_0$ for both treated and untreated infections, we show that the proposed therapy has the potential to suppress HIV infection indefinitely and return CD4+ T cell counts to normal levels. A computational study for this treatment shows the potential for a successful ‘functional cure’ of HIV. A sensitivity analysis illustrates the consistency of numerical results with theoretical results and highlights the parameters requiring better biological justification. Simulations of varying level production of HIV-resistant CD4+ T cells and varying immune enhancements as the result of these indicate a clear threshold response of the model and a range of treatment parameters resulting in a return to normal CD4+ T cell counts.

Biallelic, Selectable, Knock-in Targeting of CCR5 via CRISPR-Cas9 Mediated Homology Directed Repair Inhibits HIV-1 Replication

“…Thus, after genetic modification, one obtains a diverse population of cells containing completely disrupted, partially disrupted, or undisrupted cells. Mathematical modeling estimates, for inhibition of viral replication in an individual, the fraction of cells (CD4 + T cells) refractory to infection needs to be above 75-87.5% ( 56 – 58 ). Another study suggests that only 10–20% CCR5 knock- out in CD34 + HSC would maintain CD4 + T cell counts >200 cells/μl after 10 years when the modified cells have a selective advantage ( 70 ).…”

“…Therefore, the efficiency of CRISPR mutations is important for a curative therapy. For inhibition of viral replication in an individual’s body, mathematical modeling estimates the fraction of susceptive cells needed to be made refractory to infection lies above 75 - 87.5% ( 56 – 58 ). Consequently, gene edited stem cells used for transplantation should have the highest possible or ideally complete mutational status.…”