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.
Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42, 60596 Frankfurt a. M., Germany. laer@em.uni-frankfurt.de
Dorothee
D
von Laer
Susanne
S
Hasselmann
Klaus
K
Hasselmann
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