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The Natural Killer Cell Interferon-Gamma Response to Bacteria Is Diminished in Untreated HIV-1 Infection and Defects Persist Despite Viral Suppression

Dillon, Stephanie M. PhD*; Lee, Eric J. MS*; Bramante, Julia M. BS*; Barker, Edward PhD; Wilson, Cara C. MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2014 - Volume 65 - Issue 3 - p 259–267
doi: 10.1097/01.qai.0000435603.50598.2b
Basic and Translational Science

Objective: Natural killer (NK) cells are important in innate immune responses to bacterial and viral pathogens. HIV-1 infection is associated with opportunistic bacterial infections and with microbial translocation, but the nature of the NK cell response to bacteria during HIV-1 infection has not been studied extensively. The objective of this study was to compare NK cell responses to bacteria in HIV-1-infected versus that in uninfected individuals.

Methods: Multicolor flow cytometry was used to evaluate the ability of blood NK cell subsets (CD56+CD16, CD56+CD16+, and CD56CD16+) from treated, virally suppressed, and untreated viremic subjects with chronic HIV-1 infection and uninfected controls, to secrete interferon gamma (IFN-γ) in response to the in vitro stimulation of peripheral blood mononuclear cells with heat-killed commensal Escherichia coli or pathogenic Salmonella typhimurium.

Results: All 3 NK cell subsets produced IFN-γ in response to bacteria, but CD56CD16+ NK cells were least responsive. Untreated HIV-1–infected donors had increased frequencies of CD56CD16+ NK cells and lower overall frequencies of IFN-γ–producing NK cells responding to E. coli and S. typhimurium than did NK cells from uninfected donors. These NK cell defects were not fully restored in antiretroviral therapy–treated donors. Monocytes were necessary for NK cells to respond to bacteria, but the HIV-associated defect was intrinsic to NK cells because the addition of normal monocytes did not restore IFN-γ production in response to bacteria.

Conclusions: Functional defects and numeric alterations of NK cell subsets lead to decreased frequencies of bacteria-reactive, IFN-γ–producing NK cells in HIV-1–infected subjects, even those on antiretroviral therapy.

*Department of Medicine, Division of Infectious Diseases, University of Colorado Denver, Aurora, CO; and

Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL.

Correspondence to: Cara C. Wilson, MD, University of Colorado Anschutz Medical Campus, Medicine-Infectious Diseases, Mail Stop #B168, P15-11011, 12700 E. 19th Avenue, Aurora, CO 80045 (e-mail: cara.wilson@ucdenver.edu).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Presented in part at HIV Vaccines Symposia, March 21–26, 2012, Keystone Resort, Keystone, CO.

The authors have no conflicts of interest to disclose.

Supported by Grants from the National Institute of Health (R01 DK088663 and K24 AI074343).

Received September 05, 2013

Accepted September 05, 2013

© 2014 by Lippincott Williams & Wilkins