Background: Innate immunity, including natural killer (NK) cells, may play a significant role in maintaining natural resistance to infection in highly HIV-exposed seronegative (HESN) subjects. The differences between NK-cell subsets, regarding their activating/maturing marker expression and their memory markers, in HESN subjects are not fully defined.

Methods: We have conducted an analysis of the activating/memory markers and intracellular CD107a and interferon γ (IFN-γ) expression in NK-cell subsets from HESN and HIV-infected and healthy subjects.

Results: HESN individuals showed an increased expression of activating markers, such as NKG2D in CD56(bright) and CD56(dim) NK cells, and an increased frequency of CD56(bright)CD127⁺ and fully mature CD56(dim)CD57⁺ NK cells compared with HIV-infected patients and healthy control subjects. Of note, HESN individuals showed an increased frequency of memory CD56(dim)CD57⁺ NK cells, and this is known to be expanded on cytomegalovirus infection, as evidenced by their high rate of cytomegalovirus seropositivity. Simultaneous expression of the CD94, NKG2A, NKG2C, and NKG2D receptors on CD56(bright) NK cells was detected in HESN subjects, whereas in the HIV-1 group, the expression of these 4 receptors was enhanced in CD56(dim) NK cells. It was also found that CD56(bright) and CD56(dim) NK cells in HESN subjects showed increased CD107a and/or IFN-γ expression.

Conclusions: The NK cells from HESN individuals presented a unique activation profile, with increased expression of NKG2D, CD107a, and IFN-γ and "memory" CD57⁺CD56(dim) NK cells. The complex network of functional NK-cell activities in HESN individuals may be exploited for long-term protection through vaccination.