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.
School of Mathematics and Statistics, University of New South Wales, Sydney, Australia. j.murray@unsw.edu.au
John M
JM
Murray
Greg C
GC
Fanning
Janet L
JL
Macpherson
Louise A
LA
Evans
Susan M
SM
Pond
Geoff P
GP
Symonds
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