Abstract Body

Background: Enhancing HIV-1 specific immunity without CD4 T cell activation may clear productively infected cells, a key aspect of eradication strategies. We assessed the safety and immunogenicity of AGS-004 dendritic cell (DC) therapy in patients initiating ART during acute HIV infection (AHI). Methodology: In an open-label, single arm sub-study of AGS-004-003, DC therapy was administered to patients who initiated ART within 45 days of AHI (HIV RNA <50 c/ml for > 6 months). AHI was defined as a negative/indeterminate EIA or negative HIV RNA test within 45 days of detectable plasma HIV RNA. AGS-004 consists of matured autologous DCs co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens (Gag, Vpr, Rev, and Nef) plus synthetically derived CD40 ligand RNA to achieve DC functionality. Patients received monthly doses of AGS-004 on ART followed by measurement of immune responses after 3-4 doses (week 12 or 16). HIV RNA was measured at 4 time points by a single-copy assay (SCA). The frequency of resting CD4+ T-cell infection (RCI) was measured by quantitative viral outgrowth assay at baseline and after 3 doses (week 10) while on ART. Patients meeting a priori criteria for increased immune response after 3 doses were eligible for voluntary analytic treatment interruption (ATI) with continued monthly DC dosing. Criteria for restarting ART included CD4 count <350 cell/mm3, >20% decline in absolute CD4 count or percentage, or confirmed HIV RNA ≥10,000 c/ml. Results: Since January 2012, 6 male patients were enrolled with median age 35 (range 26-56) and median baseline CD4 T cell counts 618 cells/mm3 (range 397- 937). All six (100%) demonstrated positive immune responses defined as ≥2-fold increase from baseline in the number of CD28+/CD45RACD8+ CTL that were also ≥3 standard deviations above the negative control. RCI was low in all 6 patients treated in AHI (0.043 to 0.767 infected resting CD4+ cells per million). Only one patient had a > 2-fold decrease in the frequency of RCI at week 10. HIV RNA by SCA was <1c/ml in 5 patients prior to ATI (6th pending). All 6 patients underwent ATI with a median duration off ART of 74 days (range 34 -152). One participant with the lowest RCI (0.046 IUPM) had the longest ATI (152 days), and another is still in ATI (120 days). The patient whose RCI declined > 2-fold (from 0.179 to 0.067 IUPM) underwent ATI for 90 days. All 5 patients who restarted ART suppressed viremia. The few treatment-related adverse events were all grade 1. Conclusions: AGS-004 DC therapy was safe, well-tolerated, and led to increased HIV-specific immune responses, but did not allow sustained ART interruption. However, this DC therapy might result in depletion of persistent HIV infection in ART-suppressed patients following administration of anti-latency therapy.