Background
Mechanisms underlying sustained ART-free HIV cure/remission remain elusive. Very-early ART-treated children LWH after vertical transmission may have a high potential for cure/remission due to the tolerogenicity of early life immunity. We here evaluate a group of children LWH maintaining ART-free undetectable levels of HIV viral RNA and DNA termed “ putative cure” children. Previous publications in our group reveal that these children possess transmitted viruses with low replicative capacity, typically associated with increased type-I IFN resistance.
Methods
In KwaZulu-Natal, South Africa, we have followed from birth a cohort of 316 children LWH after in-utero vertical transmission. These children were categorized into 5 groups: ‘putative cure’ children, who maintained aviremia despite unscheduled ART discontinuation, determined by history and measurement of plasma ART levels by LC-MS/MS; 3 groups of HIV-infected children with 0, 1-2, or > 2 blips/spikes of plasma viraemia detected over the course of follow up of >36m (Groups 1-3, respectively); and healthy, HIV-negative controls. Employing flow cytometry for surface-level immunophenotyping and transcriptomic analysis via scRNA-seq (Seq-well), we characterized defining features of the “putative cure” individuals compared to the other groups.
Results
We show that ‘putative cure’ children closely resemble pediatric slow progressors (PSPs), with decreased CCR5 and CD73 expression on CD4+ T-cell memory subsets, associated with poor viral entry and smaller viral reservoirs. On CD8+ T-cell memory subsets, this similarity with PSPs is recapitulated via early, albeit transient PD-1 expression. Using scRNA-seq, geneset enrichment analysis and weighted gene correlation network analysis, we demonstrate unique TNFα and NFkB-dependent immune activation in conjunction with an absence of type-I IFN immune activation when compared to other children LWH.
Conclusions
These findings indicate that pediatric “putative cure” is linked to a distinct immune combination, leveraging the advantages of TNFα-driven immune activation whilst circumventing type-I IFN specific resistance, plus patient-specific protective features limiting the potential for HIV entry via CCR5 and establishment of latent virus at early time points via CD73. Targeting these potentially optimal immune signatures or augmentation of these distinct inflammatory pathways may ultimately inform future therapeutic developments in achieving HIV cure/remission.
Table or Figure
