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Natural Killer Cells in Perinatally HIV-1-Infected Children Exhibit Less Degranulation Compared to HIV-1-Exposed Uninfected Children and Their Expression of KIR2DL3, NKG2C, and NKp46 Correlates with Disease Severity¹

Wassim M. Ballan^2,*,, Bien-Aimee N. Vu^*, Brian R. Long^*, Christopher P. Loo^*, Jakob Michaëlsson, Jason D. Barbour, Lewis L. Lanier^¶, Andrew A. Wiznia^||, Jacobo Abadi^||, Glenn J. Fennelly^||, Michael G. Rosenberg^|| and Douglas F. Nixon^*

^* Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94110; Division of Pediatric Infectious Diseases, University of California, San Francisco, CA 94143; Center for Infectious Medicine, Karolinska Institutet, Stockholm, Sweden; Positive Health Program, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94110; ^¶ Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, CA 94143; ^|| Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461

NK cells play an integral role in the innate immune response by targeting virally infected and transformed cells with direct killing and providing help to adaptive responses through cytokine secretion. Whereas recent studies have focused on NK cells in HIV-1-infected adults, the role of NK cells in perinatally HIV-1-infected children is less studied. Using multiparametric flow cytometric analysis, we assessed the number, phenotype, and function of NK cell subsets in the peripheral blood of perinatally HIV-1-infected children on highly active antiretroviral therapy and compared them to perinatally exposed but uninfected children. We observed an increased frequency of NK cells expressing inhibitory killer Ig-like receptors in infected children. This difference existed despite comparable levels of total NK cells and NK cell subpopulations between the two groups. Additionally, NK cell subsets from infected children expressed, with and without stimulation, significantly lower levels of the degranulation marker CD107, which correlates with NK cell cytotoxicity. Lastly, increased expression of KIR2DL3, NKG2C, and NKp46 on NK cells correlated with decreased CD4⁺ T-lymphocyte percentage, an indicator of disease severity in HIV-1- infected children. Taken together, these results show that HIV-1-infected children retain a large population of cytotoxically dysfunctional NK cells relative to perinatally exposed uninfected children. This reduced function appears concurrently with distinct NK cell surface receptor expression and is associated with a loss of CD4⁺ T cells. This finding suggests that NK cells may have an important role in HIV-1 disease pathogenesis in HIV-1-infected children.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Support for this work was provided by the National Institutes of Health (AI064520 and AI060379), the Swedish Research Council, the Swedish Foundation for Strategic Research, the University of California San Francisco Dean’s Fellowship, the Alpha Omega Alpha Medical Honors Society Research Fellowship, the American Pediatric Society, and the University of California San Francisco AIDS Research Institute (ARI). L.L.L. is an American Cancer Society Research Professor.

² Address correspondence and reprint requests to Dr. Wassim M. Ballan, Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, 1001 Potrero Avenue, B3-609, Box 1234, San Francisco, CA 94143-1234. E-mail address: wassimballan{at}gmail.com

³ Abbreviations used in this paper: KIR, killer cell Ig-like receptor; EU, exposed uninfected; FSC, forward scatter; HCMV, human CMV; NCR, natural cytotoxicity receptor.

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