Background:
To date, four persons living with HIV infection (PLWH) have achieved HIV cure through CCR5∆32 homozygous allogeneic stem cell transplantation (SCT). Post-SCT events leading to remission in this setting are uncertain, and no detailed analyses of HIV reactivation have been reported. Here we conducted virologic and immunologic analyses of HIV reactivation after CCR5∆32/∆32 SCT.
Methods:
The HEME-17 protocol evaluates HIV-1 persistence in PLWH pre and post allogeneic SCT utilizing CCR5∆32/∆32 donors. Plasma and peripheral blood mononuclear cells (PBMCs) samples were analyzed by single-copy quantification of CCR5/CCR5∆32 (digital PCR, dPCR) and of HIV gag DNA and RNA (HMMC-gag), and by single-genome sequencing (SGS) of HIV env. Plasma antibodies to HIV Gag, Env, and Nef were quantified by a luciferase immunoprecipitation system.
Results:
A 67 yo male PLWH with 100% R5-tropic HIV undergoing ART with HIV RNA < 50 copies/ml for 14 years developed acute myeloid leukemia. The patient underwent a reduced intensity allogeneic SCT with a 10/10 CCR5∆32/∆32 matched unrelated donor. By day 30, 100% engraftment was achieved. HIV was not detected in plasma (< 0.3 copies HIV-1 RNA/ml) or in PBMC (< 0.3 copy HIV RNA or DNA/million) at 3, 9, 12, and 15 months post SCT; no WT CCR5 was detected in the PBMC at 1 year by dPCR (Fig 1). Antiretroviral treatment interruption (ATI) was initiated 15 months post-SCT. At ATI, weekly HIV-1 qPCR demonstrated undetectable HIV-1, (< 20 copies/ml), until 8 weeks, when the plasma VL was detected at 780 copies/ml. A repeat VL, one week later, demonstrated a drop in the viral load to 300 copies/ml, when ART was re-initiated. Five (7) plasma HIV env sequences obtained at this time were genetically diverse and all had predicted R5 tropism. At viral rebound, HIV cell-associated DNA/RNA (< 0.14 copies/million) and wt CCR5 (< 20 copies/million) were not detected. Three months after ART re-initiation, HIV was detected in plasma (0.39 copies/ml) but not in PBMC (< 0.14 c/million PBMC). Levels of anti-HIV antibodies remained lower than those detected in PLWH undergoing ART and were comparable to HIV-uninfected controls.
Conclusions:
We report the first known case of HIV reactivation during ATI following CCR5∆32/∆32 SCT for AML. Our findings indicate that residual R5-tropic HIV can persist and potentially spread in vivo even >1 year after clinically successful CCR5d32/d32 allo-SCT.
Figure 1.