Background
Interruption of antiretroviral therapy (ART) typically leads to viral rebound within weeks in people with HIV-1. Post-intervention controllers (PICs) control viremia without ART after a therapeutic intervention. We characterised three PICs with suppressed viral load for >6.5 years (ID107), >7.5 years (ID9254) and 2.5 years (ID142) following HIV-1 broadly neutralising antibody administration.
Methods
The intact/inducible proviral reservoir was quantified using quantitative viral outgrowth assays (qVOA). Autologous neutralising antibody responses were assessed using pseudoviruses representing autologous qVOA env variants or qVOA isolates. HIV-1-specific CD8 T-cell responses were analysed by intracellular cytokine staining and further characterised using activation-induced marker (AIM)-sorted T-cells stimulated with HIV-1 peptide pools, followed by single-cell transcriptome and paired abTCR sequencing. The suppression capacity of HIV-1-specific CD8 T-cells was assessed in vivo using a participant-derived xenograft mouse model. For ID142, escape mutations at viral rebound after 2.5 years of ART-free control were characterised using near-full-length sequencing of plasma-derived HIV-1 genomes.
Results
All PICs had quantifiable inducible proviral reservoirs during ART-free control. Potent aNAb responses against inducible qVOA variants were detected in all PICs, with no evidence of cross-neutralisation capacity against unrelated variants. T-cell responses before ART interruption were characterised by high frequencies of CD8 T-cells that appeared pre-programmed to respond rapidly to HIV-1 antigen stimulation. These HIV-1-specific CD8 T-cell populations were dominated by clones that were present prior to ART interruption, and persisted during ART-free control. Mice engrafted with memory CD4 and CD8 T-cells from ID107 demonstrated direct suppression of autologous virus rebound in vivo. For ID142, viral rebound was caused by a viral variant that was genetically distinct to the persisting proviral reservoir, carrying mutations suggesting escape from aNAb and T-cell responses. Autologous IgG sourced from before and after viral rebound was unable to neutralise pseudoviruses representing rebound HIV-1 env, suggesting complete escape of the rebounding viral population from the potent aNAb response.
Conclusions
Our results show that potent immune responses, including aNAbs and rapidly responding HIV-1-specific CD8 T-cells, are crucial mediators of long-term ART-free control of HIV-1.