Impact of gene-modified T cells on HIV infection dynamics.
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.
von Laer
Dorothee
D
Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42, 60596 Frankfurt a. M., Germany. laer@em.uni-frankfurt.de
Hasselmann
Susanne
S
Hasselmann
Klaus
K
D019264:Adoptive Transfer / Q000379:methods*; D003198:Computer Simulation; D005805:Genes, MHC Class I; D015316:Genetic Therapy / Q000379:methods*; D015658:HIV Infections / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D008285:Major Histocompatibility Complex; D008954:Models, Biological; D013601:T-Lymphocytes / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication