Background
Understanding the immune response to HIV-1 in individuals maintaining long-term viral suppression after analytical treatment interruption (ATI) is crucial in the search for a functional cure. A subset of individuals, post-treatment controllers (PTCs), experience sustained virologic control following ATI, whilst non-controllers (NCs) require re-initiation of antiretroviral therapy (ART) to suppress rebounding viremia. We investigated the immune response in two PTCs (ID107 and 142) and two NCs (ID104 and 112) to uncover immunological mechanisms of PTC.
Methods
We characterized the distribution of CD8+ T subsets and HIV-1-specific memory T cells using a spectral flow cytometry-based intracellular cytokine staining assay on PBMCs from HIV-1 study participants collected pre-ATI and at either viral rebound (NCs) or at several time points during long-term ATI (PTCs). PBMCs were stimulated with HIV-1 peptide mix (Pol, Gag, Nef, or Env), negative control (DMSO), and secretion inhibitors. The spectral flow panel consisted of markers of differentiation (CD45RA, CCR7, CD27, CD95), cytokines/degranulation (IFNγ, TNF, IL2, IL4/13, CD107a), proliferation, transcription, effector proteins, and immune checkpoints.
Results
In PTCs, the CD8+ transitional memory population was expanded compared to NCs (25-50 % and 10-20 %, respectively). Conversely, the naïve, effector memory, and terminally differentiated populations were contracted in PTCs. Both PTCs had high frequencies of HIV-1-specific polyfunctional CD8+ and CD4+ memory T cells. ID107 exhibited a Gag-specific CD8+ T cell response, which declined during 6-year ATI. ID142 exhibited a Pol- and Nef-specific response which remained stable during 2.5-year ATI. Both PTCs exhibited a broader CD4+ T cell response, mainly towards Gag, Pol and Nef, increasing from pre-ATI to follow-up during ATI. The CD8+ T cell responses were dominated by IFN+TNF+ responses, while the CD4+ T cell responses were predominantly IFN+TNF+IL2+ and IL4/13+ in ID142. NCs had fewer primarily monofunctional, HIV-1-specific CD8+ and CD4+ memory T cells (Figure 1). The response profile of the PTCs correlated with results from IFNγ ELISpot assay.
Conclusions
PTC was associated with higher proportions of CD8+ transitional memory populations and lower naïve, effector memory and terminally differentiated populations. Further, PTCs showed a CD4+ and CD8+ memory phenotype with better capacity for viral control by their higher frequency of HIV-1-specific polyfunctional CD8+ and CD4+ T cells.