Background
ART suppresses HIV replication but fails to eliminate the virus, necessitating innovative strategies for curing HIV. CCR5-/- CD4+ T cells from CCR5Δ32 HSCT have eliminated HIV but are invasive and induce toxicity. Autologous CCR5 knockout (CCR5-/-) CD4 T cell therapy trials offer a safer alternative. We have shown that the persistence of CCR5-/- stem-like CD4 T (Tscm) cells post-infusion of CCR5 edited memory T cells was associated with reduced latent HIV and control of viremia upon Analytical Treatment Interruption (ATI). Here, we used a SIV-infection model to assess whether CCR5-/- CD4 Tscm can control viremia upon ATI.
Methods
20 non-human primates (NHPs) were infected with the stringent SIV SIV-mac239 for 4 weeks before being put on ART. 40 weeks post-ART, a single infusion of autologous CCR5-/- Tscm product (5M cells/kg) was infused after mild chemotherapy, along with B cell depletion using an anti-CD20 antibody (n = 10). Bi-allelic knockout of CCR5 in ~80% of the cells within the product was attained using CRISPR-Cas9 editing and Tscm phenotype was obtained using a cytokine mix. ATI was started 16 weeks after infusion and rebound was tracked for 12 weeks.
Results
Nine NHPs infused showed significant control of viremia at 4 weeks post-ATI and maintained control of viremia (<5000 copies/mL) at 12 weeks; anti-CD20 did not impact this virological outcome. The enrichment of CD28+CD95+TCF1+CD27+CCR7+ Tscm cells that were Ki67- in the infused product was associated with the control of viremia at the 4th week post-ATI (p-val=0.06). While high viremia at 4 weeks of ATI was correlated with plasma levels of IL-15 and IL-17 (p-val<0.05) before product infusion; this cytokine milieu likely promotes persistence of effector CD4 T cells that are permissive to infection. Importantly, an enrichment of CD4 Tscm phenotype was detected 6-days post-product infusion in the controllers, where sustained viral control was observed 12 weeks post-ATI.
Conclusions
We show that a single infusion of autologous CCR5 edited CD4 Tscm cells leads to sustained control of viremia for up to 12 weeks post-ATI. The efficacy of these cells is dampened if an effector cytokine milieu in the host, that promotes survival of virally permissive effector CD4 T cells, precedes the infusion of the product. These data show that the success of cell-based therapies depends on the stemness of infused product and an antiviral host environment that promotes innate and adaptive immune responses to control SIV dissemination.