Impaired natural killer cell responses are associated with loss of the highly activated NKG2A⁺CD57⁺CD56^dim subset in HIV-1 subtype D infection in Uganda

Objective: Of the predominant HIV-1 subtypes in Uganda, subtype D infection confers a worse prognosis. HIV-1 infection causes perturbations to natural killer (NK) cells, and yet these cells can exert immune pressure on the virus and influence clinical outcome. Here, we studied NK cell activation and function in Ugandans with chronic untreated HIV-1 subtype D infection in comparison to uninfected community matched controls. Methods: Cryopreserved peripheral blood mononuclear cells (PBMCs) from 42 HIVinfected individuals and 28 HIV-negative controls were analysed using eight-colour flow cytometry. NK cell surface expression of CD16, CD56, CD57, HLA-DR and NKG2A were used to investigate activation, maturation and differentiation status. NK cell function was evaluated by measuring interferon-gamma (IFNg) production in response to K562 cells, or interleukin (IL)-12 and IL-18. Results: CD56^dim NK cells from HIV-infected individuals produced less IFNg in response to IL-12 and IL-18 than did CD56^dim NK cells from uninfected controls. Infected individuals had lower levels of CD56^dim NK cells coexpressing the differentiation markers NKG2A and CD57 than controls. In addition, their NKG2A⁺CD57⁺ CD56^dim NK cells displayed elevated activation levels as assessed by HLA-DR expression. Cytokine-induced IFNg production correlated directly with coexpression of CD57 and NKG2A on CD56^dim NK cells. Conclusion: HIV-1 subtype D infection is associated with impaired NK cell responsiveness to cytokines, decline of the NKG2A⁺CD57⁺ CD56^dim NK cell subset, as well as elevated activation in this subset. These alterations within the NK cell compartment may contribute to immunopathogenesis of HIV-1 subtype D infection in Ugandans.