Understanding the early immune response to HIV-1 infection represents a unique opportunity for the identification of novel targets for prophylactic/therapeutic approaches. Natural Killer (NK) cells are an important component of innate immunity that can modulate the pathogenesis of acute HIV-1 infection (AHI). However, the role of NK cells in mediating early host defence against infection with different HIV-1 subtypes, and clinical outcomes, remains poorly understood. Here, we studied the early imprinting effects of different HIV-1 subtypes and pro-inflammatory environment on the NK cell compartment in a unique cohort with AHI.
Participants with AHI were sampled longitudinally in different sub-Saharan African sites under ‘IAVI protocol C’ (n=25 subtype A, n=17 subtype C, n=7 subtype D). The median estimated days post infection for subtype A and non-subtype A was 32 and 35 days respectively (visit 1), and 95 and 92 days (visit 2). Multiparameter flow cytometry was used for the phenotypic characterisation. NK cell ADCC responses were determined against antibody coated Raji cells. The metabolic profile was assessed by a Seahorse technology. Soluble markers were measured using multiplexed assays.The Mann–Whitney U, Wilcoxon-test, and Spearman tests were used in the analysis.
NK cell subsets with adaptive/memory features expand during AHI with subtype A compared to non-A (visit 1 p=0.008, visit 2 p=0.005). This adaptive NK cell signature was delineated by lower expression of the transcription factor PLZF and was further enriched by higher expression of the activating receptor NKG2C and lower expression of the signalling molecule Fc?R?. Individuals with high frequency of adaptive NK cells exhibited higher levels of IL-12p70 (p=0.03). Increased frequencies of adaptive NK cells were associated with lower HIV viral load (p=0.017) and higher CD4 T cell counts (>500). These phenotypic attributes were accompanied by enhanced NK cell ADCC capacity and higher IFN-? (p=002) and TNF-? (p=0.0165) production in subtype A versus non-A. Notably, NK cell IFN-? production correlated inversely with HIV-1 viral load (r=-0.343, p=0.03). The enhanced functionality of NK cells was reflected in their superior capacity for oxidative phosphorylation (p=0.035).
These data suggest that specific NK cell subsets could confer better HIV-1 control, highlighting their potential role as a prognostic marker and as a new target for the development of novel immunotherapeutic and ‘cure’ strategies.