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Impaired natural killer cell responses are associated with loss of the highly activated NKG2A+CD57+CD56dim subset in HIV-1 subtype D infection in Uganda

Naluyima, Prossya,b; Eller, Michael A.c,d; Laeyendecker, Olivere,f; Quinn, Thomas C.e,f; Serwadda, Davidg,h; Sewankambo, Nelson K.h,i; Gray, Ronald H.j; Michael, Nelson L.c; Wabwire-Mangen, Freda,g; Robb, Merlin L.c,d; Sandberg, Johan K.b

doi: 10.1097/QAD.0000000000000286
Basic Science: Concise Communication

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 HIV-infected 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 (IFNγ) production in response to K562 cells, or interleukin (IL)-12 and IL-18.

Results: CD56dim NK cells from HIV-infected individuals produced less IFNγ in response to IL-12 and IL-18 than did CD56dim NK cells from uninfected controls. Infected individuals had lower levels of CD56dim NK cells coexpressing the differentiation markers NKG2A and CD57 than controls. In addition, their NKG2A+CD57+ CD56dim NK cells displayed elevated activation levels as assessed by HLA-DR expression. Cytokine-induced IFNγ production correlated directly with coexpression of CD57 and NKG2A on CD56dim NK cells.

Conclusion: HIV-1 subtype D infection is associated with impaired NK cell responsiveness to cytokines, decline of the NKG2A+CD57+ CD56dim 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.

aMakerere University Walter Reed Project, Kampala, Uganda

bCenter for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

cUS Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring

dHenry M. Jackson Foundation for the Advancement of Military Medicine

eLaboratory of Immunoregulation, Division of Intramural Research, NIAID, NIH, Bethesda

fSchool of Medicine, Johns Hopkins University, Baltimore, Maryland, USA

gSchool of Public Health, Makerere University College of Health Sciences, Kampala

hRakai Health Sciences Program, Uganda Virus Research Institute, Entebbe

iFaculty of Medicine, Makerere University College of Health Sciences, Kampala, Uganda

jBloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.

Correspondence to Dr Johan K. Sandberg, Center for Infectious Medicine, Department of Medicine, F59, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden. Tel: +46 8 58583298; fax: +46 8 7467637; e-mail:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Received October 31, 2013

Accepted March 20, 2014

© 2014 Lippincott Williams & Wilkins, Inc.