Highly active antiretroviral therapy corrects hematopoiesis in HIV-1 infected patients: interest for peripheral blood stem cell-based gene therapy

Objectives: To study, in asymptomatic HIV-1-infected (HIV+) patients, whether peripheral blood hematopoietic progenitor/stem cells (PBPC) mobilized by granulocyte colony stimulating factor (G-CSF), can be used as a source of cells for retroviral gene therapy. Design: PBPC from two groups of HIV+ patients (treated or untreated by highly active antiretroviral therapy) and from seronegative donors were mobilized with G-CSF. Methods: PBPC collected by leukapheresis were enriched for-CD34 cells, immunophenotypically and functionally characterized, cultured and infected with retroviral vectors. HIV proviral integration was studied on fresh and cultured cells. Results: G-CSF moderately and transiently increased the viral load in untreated patients only, and induced in both groups of HIV+ patients mobilization of percentages and numbers of CD34 cells comparable to those of seronegative volunteers. The most immature CD34 cell subset, the clonogenic progenitor and long-term culture initiating cells were significantly decreased in leukapheresis products and CD34-enriched fractions from untreated HIV+ patients but not in those from treated HIV+ patients. Cell cycle activation and growth factor responses of CD34 cells from both groups of HIV+ patients were not different from those of the control group. Culture and retroviral infection of CD34 cells from HIV+ patients did not enhance HIV replication, and yielded transduction levels similar to those obtained using CD34 cells from seronegative donors. Conclusions: G-CSF-mobilized PBPC can be safely used for HIV retroviral gene therapy in asymptomatic treated patients while highly active antiretroviral therapy would control the G-CSF-induced increase in viral load and correct the defective hematopoiesis observed in untreated patients, without inhibiting the retroviral transduction of PBPC. (C) 2003 Lippincott Williams Wilkins.