Background
Five persons have been reported to achieve long-term HIV remission through CCR5∆32/∆32 allogeneic stem cell transplantation (SCT). Dynamics of HIV elimination after SCT are uncertain, and there are no data regarding timing of analytic treatment interruption (ATI) post SCT. Here we report sustained HIV remission despite HIV reactivation following CCR5∆32/∆32 SCT.
Methods
The HEME-17 protocol evaluates persons with HIV pre- and post-allogeneic CCR5∆32/∆32 SCT, with analysis of coreceptor tropism (Trofile), frequent single copy determination of HIV RNA in plasma and HIV RNA and DNA in peripheral blood mononuclear cells (PBMCs). Chimerism is monitored by standard assays, and persistence of wild-type (wt) CCR5 DNA post-SCT is assessed by PCR. HIV env sequences in plasma are determined by single-genome sequencing, and env tropism predicted using Geno2pheno. Plasma antibodies to HIV gp120, p24, RT, and MA are quantified by luciferase immunoprecipitation assays. Antigen-reactive T cells in PBMC were quantified by staining for activation induced markers and intracellular cytokines.
Results
A 67-year-old man with HIV and acute myeloid leukemia (AML) received reduced-intensity SCT from a 10/10 CCR5∆32/∆32 matched unrelated donor; SCT was successful, (100% engraftment by 1 month). Plasma HIV-1 RNA declined to <0.3 c/mL and HIV RNA/DNA in PBMC declined to <0.3 copy/million cells (Fig.1). At 12 months, wt CCR5 DNA was undetectable in PBMC (Fig. 1). Anti-HIV antibodies declined to levels comparable to those of HIV-uninfected controls, and HIV-reactive CD8 and CD4 T cells were undetectable. HIV rebounded (780, 300 copies/ml at weeks 8 and 9 following ATI) and ART was reintroduced . Despite rebound, no cell-associated HIV-1 RNA or DNA was identified in PBMCs (< 0.14 copies/million), which remained 100% donor (Fig. 1). HIV env sequences in rebound HIV were predicted to be R5-tropic. HIV RNA/DNA and HIV-reactive CD8 and CD4 T cells were undetectable in PBMC at rebound or thereafter. A second ATI was initiated 24 months after ART re-initiation which resulted in 7-month and ongoing HIV remission.
Conclusions
We report the first known case of sustained HIV remission after documented HIV-1 reactivation on ATI following CCR5∆32/∆32 SCT. Rebound does not rule out eradication or the possibility of HIV cure post SCT. Understanding dynamics of host, virus, and treatment factors after CCR5∆32/∆32 allogeneic SCT is essential to advance CCR5-gene-based approaches in HIV cure research.