Abstract Body

HIV gene therapy could reduce viral load, preserve immunity and mitigate ART toxicities. Safety and feasibility of an anti-HIV-1 dual-gene construct LVsh5/C46 (Cal-1) in modified, autologous CD4+ T-cells (Ttn) and HSC (HSCtn) was assessed.


PLWH with CD4+ count > 500/mm3 and voluntary ART suspension (drug toxicities, treatment fatigue or other reasons) underwent aphereses for CD4+ T-cells and CD34+ HSC following mobilization, then gene-modified cell infusion. Busulfan pre-conditioning was: none (Cohort 1), 4 mg/kg on Day -2 (Cohort 2) and 3mg/kg (Day -2) to a total AUC exposure of 8,000 μmolar/min at Day -4 (Cohort 3). Subjects were followed for 48 weeks with ART reinitiation if CD4+ count or viral RNA reached safety thresholds, or participant decision. BM aspirates and GALT biopsies were taken at 24 and 48 weeks.


12 participants (4 per cohort) were treated. At 48 weeks, 4 remained off and 8 resumed ART. Only 1 unrelated SAE was reported. Procedure-related AEs included neutropenia, thrombocytopenia, fatigue, nausea, and back pain. One pt in Cohort 1 had Cal-1 marking in PB >1% at Wk 4 which was not sustained. All Cohort 2 pts had >1% marking at early time points which was not sustained. Cohort 3 had highest levels of Cal-1 marking at peak and longest persistence. While no association was seen between Cal-1 marking and Ttn dose, there was a correlation between HSCtn dose in Cohort 3. For all Cohorts, marking at wk 24 and 48 was not substantive in GALT and very low in BM. Higher busulfan AUC correlated with higher peak Cal-1 marking in PB. There was no effect on plasma HIV RNA. Absolute CD4+ counts were reduced following apheresis.

Delivery of HSCtn and Ttn was feasible and well-tolerated. Low to moderatedose busulfan was safely administered in an all-outpatient settingThe impact of HSCtn and Ttn on control of HIV replication could not be fully assessed because of low level of marking in PB. Busulfan exposure correlated with higher levels of marking. Potential reasons for the lack of long-term survival of Cal-1 transduced cells include persistent HIV viremia and inflammation.  Future research should focus on administering gene-modified stem cells in fully-suppressed individuals