Item

Abstract

Previous clinical trials in HIV-infected patients involving infusion of T cells protected by an antiviral gene have failed to show any
therapeutic benefit. The value of such a treatment approach is thus still highly controversial. In this study, the anticipated effects of
gene-modified cells on virus and T-cell kinetics are analysed by mathematical modeling. Because technically only a small fraction of
all T cells in a patient can be manipulated ex vivo, therapeutic success will depend on the accumulation of gene-modified cells after
infusion into the patient by in vivo selection. Our simulations predict that a significant therapeutic benefit is conferred only by
antiviral genes that inhibit HIV replication before virus integration (class I genes). Genes that inhibit viral protein expression (class
II, used in previous clinical trials), require a much higher inhibitory activity than class I genes to promote the regeneration of T cells
and reduce the viral load. Inhibition of virus assembly and release alone (class III) confers no selective advantage to the T cell and is
therefore ineffective unless combined with class I (or, possibly, class II) genes. Also crucial in determining the clinical outcome are
the regenerative capacity of the gene-modified cells and the level of HIV replication in the patient. These results can be important for
guiding future strategies in the field of gene therapy for HIV infection.