Graft-versus-HIV-reservoir reactivity: Long term HIV remission after allogeneic stem cell transplantation from a donor with active CCR5 Free

Background

HIV cure is exceptionally rare and is documented in only six cases. All HIV cure cases were individuals receiving allogeneic stem cell transplantations (alloSCT) from donors with rare homozygous CCR5 Δ32 receptor mutation, that lead to functional defects of the CCR5 co-receptor that allows the virus to enter human immune cells.

Recently, reports from a cohort study (Lancet HIV 2024), a nonhuman primate model (Immunity 2024), and the case of the “Geneva patient” (Nat. Med. 2024) demonstrated substantial reductions in persistent HIV reservoirs and viral suppression following alloSCT with wild-type CCR5 donors suggesting CCR5-independent mechanisms. Here, we provide clinical and scientific evidence for this conceptual shift towards a major role of graft-versus-HIV-reservoir reactivity for HIV cure. We report an exceptionally long, treatment-free HIV remission following alloSCT with functionally active CCR5.

Methods

Quantification HIV-RNA, HIV-reservoir analyses, Q4ddPCR, Triplex IPDA, CCR5 receptor expression and function, viral characteristics, RNA-derived single genome sequencing, pseudovirus production, viral outgrowth, anti-HIV immune responses, antiretroviral drug screening, NK-cell characterization and functional assays, mathematical modelling.

Results

A heterozygous CCR5 wild-type/Δ32 male received myeloablative (8GyTBI/FLU) alloSCT from an HLA-matched unrelated heterozygous CCR5 wild-type/Δ32 female donor as treatment for AML (FLT3-TKD) in first complete remission in October 2015. No major complications except acute GVHD grade I occurred and complete donor chimerism was achieved. Three years after alloSCT (September 2017), the patient discontinued antiretroviral therapy (Raltegravir and Abacavir/Lamivudine). To date, HIV remission has been sustained for well over six years without antiretroviral therapy and plasma HIV RNA remains undetectable.

Reservoir analysis revealed intact proviral HIV before transplantation, but no HIV DNA or replication-competent virus in peripheral blood and intestinal biopsies after alloSCT. In addition, limiting dilution viral outgrowth assays on CD4 T cells were negative.

IgG antibodies against gp140 and gp120 increased after HIV diagnosis and decreased gradually to low/undetectable following alloSCT. We detected no HIV-1-specific T cell responses but persistent CMV-, EBV- and HHV-6-specific responses in repeated measurements after alloSCT.

The frequency of CCR5-expressing T cells was comparable between wild-type CCR5 and heterozygous CCR5 wild-type/Δ32 controls, including the current patient. However, CCR5 expression density was significantly lower in T cells of heterozygous individuals. We confirmed HIV susceptibility in peripheral blood mononuclear cells from the current patient with CCR5-, CXCR4-or dual X4/R5-tropic HIV strains and primary isolates. Notably, levels of infection were significantly lower in heterozygous compared to wild-type CCR5 individuals. We confirmed CCR5-tropism of plasma autologous virus by V3-loop sequencing and prediction of HIV-1 coreceptor usage by Geno2pheno computational algorithms.

Finally, we determined the likelihood of observed HIV remission as well as the probability of viral reactivation by applying different mathematical models of rebound time that were trained on data from large analytical treatment interruption trials. We estimated an extremely low probability of maintaining viral suppression without rebound for 6 years.

Conclusions and significance

The clinical course with more than six years treatment free HIV remission strongly suggests cure from HIV. This is the first case of HIV cure via alloSCT from a donor with active CCR5 and provides compelling evidence that “graft-versus-reservoir” reactivity is the key driver of viral reservoir clearance.

For alloSCT recipients living with HIV and their caregivers, these data demonstrate the possibility of HIV cure even when no HIV resistant (CCR5 Δ32/ Δ32) alloSCT donor can be identified. Outside the alloSCT field, our data builds the underlying rationale for HIV cure strategies based on effective viral reservoir reductions.