Mathematical modelling of the impact of haematopoietic stem cell-delivered gene therapy for HIV.
BACKGROUND
Gene therapy represents a new treatment paradigm for HIV that is potentially delivered by a safe, once-only therapeutic intervention.


METHODS
Using mathematical modelling, we assessed the possible impact of autologous haematopoietic stem cell (HSC) delivered, anti-HIV gene therapy. The therapy comprises a ribozyme construct (OZ1) directed to a conserved region of HIV-1 delivered by transduced HSC (OZ1+HSC). OZ1+HSC contributes to the CD4+ T lymphocyte and monocyte/macrophage cell pools that preferentially expand under the selective pressure of HIV infection. The model was used to predict the efficacy of OZ1 in a highly active antiretroviral therapy (HAART) naïve individual and a HAART-experienced individual undergoing two structured treatment operations. In the standard scenario, OZ1+HSC was taken as 20% of total body HSC.


RESULTS
For a HAART-naïve individual, modelling predicts a reduction of HIV RNA at 1 and 2 years post-OZ1 therapy of 0.5 log(10) and 1 log(10), respectively. Eight years after OZ1 therapy, the CD4+ T-lymphocyte count was 271 cells/mm(3) compared to 96 cells/mm(3) for an untreated individual. In a HAART-experienced individual HIV RNA was reduced by 0.34 log(10) and 0.86 log(10) at 1 and 2 years. The OZ1 effect was maximal when both CD4+ T lymphocytes and monocytes/macrophages were protected from successful, productive infection by OZ1.


CONCLUSIONS
The modelling indicates a single infusion of HSC cell-delivered gene therapy can impact on HIV viral load and CD4 T-lymphocyte count. Given that gene therapy avoids the complications associated with HAART, there is significant potential for this approach in the treatment of HIV.
Murray
John M
JM
School of Mathematics and Statistics, University of New South Wales, Sydney, Australia. j.murray@unsw.edu.au
Fanning
Greg C
GC
Macpherson
Janet L
JL
Evans
Louise A
LA
Pond
Susan M
SM
Symonds
Geoff P
GP
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004337:Drug Carriers; D015316:Genetic Therapy; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006412:Hematopoietic Stem Cells; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008962:Models, Theoretical; D016337:RNA, Catalytic / Q000235:genetics* / Q000627:therapeutic use; D012367:RNA, Viral / Q000235:genetics; D016896:Treatment Outcome; D019562:Viral Load
D019380:Anti-HIV Agents; D004337:Drug Carriers; D016337:RNA, Catalytic; D012367:RNA, Viral