Background:
Understanding immune responses linked with viral control during early HIV-1 infection is critical to develop new prophylactic and therapeutic strategies. HIV-1 subtypes impact disease outcomes, but their association with diverse immune responses during acute HIV-1 infection (AHI) is unclear. Natural killer (NK) cells contribute to HIV-1 control and may influence the pathogenesis of AHI. Using longitudinal samples collected during and after peak HIV-1 viral load (VL) in a prospective unique cohort of ART-naïve individuals, we studied evolving NK cell responses in patients with different HIV-1 subtypes in relation to disease progression
Methods:
Participants with subtype A (n=28) and non-A subtype (n=17 subtype C and n=7 subtype D) were recruited from Kenya, Rwanda, Zambia, and Uganda between 2006-2011 under ‘IAVI Protocol C’. Samples were collected at two weeks (median=18 days), 1-month (median= 32 days), and 3-month (median=91 days) post-HIV-1 infection. Multiparameter flow cytometry was used for phenotypic characterisation. ADCC responses were determined against Raji cells. Soluble markers were evaluated using multiplexed assays
Results:
AHI induced expansion of NK cell subset with adaptive/memory features, as early as two weeks post-infection, increasing in magnitude after resolution of peak VL. This adaptive NK cell signature was delineated by lower expression of the signaling molecule FcεRγ and higher expression of the activating receptors NKG2C and CD2. The kinetics of NK cell responses differed based on the infecting HIV-1 subtype, with patients with subtype A exhibiting a higher magnitude of adaptive NK cells than those with non-A subtype infection (p=0.036). A stronger innate immune response induced by subtype A, including IL-15 (p=0.021) and IL-12 (p=0.009), correlated with the enrichment of adaptive NK cells. This early increase in adaptive NK cells was associated with enhanced ADCC (p=0.002) and correlated with higher levels of CD8+ T-cell activation during AHI (r=0.621, p=0.015).Notably higher frequencies of adaptive NK cells during the first month of infection were associated with future viral control in patients who maintained a persistently undetectable or low viral load (<10,000 copies/ml) up to six years post-infection
Conclusions:
These data provide insights into the beneficial role of adaptive NK cells during AHI, revealing previously unappreciated diversity of NK cell responses to different HIV-1 subtypes, thereby informing strategies toward NK-cell-directed therapies.