We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Innate immune natural killer cells and their role in HIV and SIV infection

    Pavel Bostik

    Faculty of Military Health Sciences, University of Defense & Department of Infectious Diseases, Charles University School of Medicine, Hradec-Kralove, Czech Republic

    ,
    Yoshiaki Takahashi

    Room 2309 WMB, Department of Pathology, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA

    ,
    Ann E Mayne

    Room 2309 WMB, Department of Pathology, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA

    &
    Published Online:https://doi.org/10.2217/hiv.10.28

    The findings that early events during HIV-1 and SIV infection of Asian rhesus macaques dictate the levels of viremia and rate of disease progression prior to the establishment of mature and effective adaptive immune responses strongly suggest an important role for innate immune mechanisms. In addition, the fact that the major target of HIV and SIV during this period of acute infection is the gastrointestinal tissue suggests that whatever role the innate immune system plays must either directly and/or indirectly focus on the GI tract. The object of this article is to provide a general overview of the innate immune system with a focus on natural killer (NK) cells and their role in the pathogenesis of lentivirus infection. The studies summarized include our current understanding of the phenotypic heterogeneity, the putative functions ascribed to the subsets, the maturation/differentiation of NK cells, the mechanisms by which their function is mediated and regulated, the studies of these NK-cell subsets, with a focus on killer cell immunoglobulin-like receptors (KIRs) in nonhuman primates and humans, and finally, how HIV and SIV infection affects these NK cells in vivo. Clearly much has yet to be learnt on how the innate immune system influences the interaction between lentiviruses and the host within the GI tract, knowledge of which is reasoned to be critical for the formulation of effective vaccines against HIV-1.

    Bibliography

    • Christensen JE, Thomsen AR: Co-ordinating innate and adaptive immunity to viral infection: mobility is the key. APMIS117,338–355 (2009).
    • Gregoire C, Chasson L, Luci C et al.: The trafficking of natural killer cells. Immunol. Rev.220,169–182 (2007).
    • Blum KS, Pabst R: Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? Immunol. Lett.108,45–51 (2007).
    • Kiessling R, Klein E, Pross H et al.: “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur. J. Immunol.5,117–121 (1975).
    • Kiessling R, Klein E, Wigzell H: “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol.5,112–117 (1975).
    • Janeway CA: Natural killer cells: a primitive immune system. Nature341,108 (1989).
    • Kim S, Poursine-Laurent J, Truscott SM et al.: Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature436,709–713 (2005).
    • Anfossi N, Andre P, Guia S et al.: Human NK cell education by inhibitory receptors for MHC class I. Immunity25,331–342 (2006).
    • Hayakawa Y, Screpanti V, Yagita H et al.: NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J. Immunol.172,123–129 (2004).
    • 10  Piccioli D, Sbrana S, Melandri E et al.: Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J. Exp. Med.195,335–341 (2002).
    • 11  Takeda K, Dennert G: The development of autoimmunity in C57BL/6 lpr mice correlates with the disappearance of natural killer type 1-positive cells: evidence for their suppressive action on bone marrow stem cell proliferation, B cell immunoglobulin secretion, and autoimmune symptoms. J. Exp. Med.177,155–164 (1993).
    • 12  Lu L, Ikizawa K, Hu D et al.: Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity26,593–604 (2007).
    • 13  O’Leary JG, Goodarzi M, Drayton DL et al.: T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol.7,507–516 (2006).
    • 14  Sun JC, Lanier LL: Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? Eur. J. Immunol.39,2059–2064 (2009).
    • 15  Alter G, Malenfant JM, Delabre RM et al.: Increased natural killer cell activity in viremic HIV-1 infection. J. Immunol.173,5305–5311 (2004).
    • 16  O’Connor GM, Holmes A, Mulcahy F et al.: Natural killer cells from long-term non-progressor HIV patients are characterized by altered phenotype and function. Clin. Immunol.124,277–283 (2007).
    • 17  Martin MP, Qi Y, Gao X et al.: Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet.39,733–740 (2007).
    • 18  Ritz J, Schmidt RE, Michon J et al.: Characterization of functional surface structures on human natural killer cells. Adv. Immunol.42,181–211 (1988).
    • 19  Lanier LL, Testi R, Bindl J et al.: Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J. Exp. Med.169,2233–2238 (1989).
    • 20  Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer-cell subsets. Trends Immunol.22,633–640 (2001).
    • 21  Vossen MT, Matmati M, Hertoghs KM et al.: CD27 defines phenotypically and functionally different human NK cell subsets. J. Immunol.180,3739–3745 (2008).
    • 22  Fehniger TA, Cooper MA, Nuovo GJ et al.: CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood101,3052–3057 (2003).
    • 23  Ferlazzo G, Munz C: NK cell compartments and their activation by dendritic cells. J. Immunol.172,1333–1339 (2004).
    • 24  Romagnani C, Juelke K, Falco M et al.: CD56brightCD16- killer Ig-like receptor- NK cells display longer telomeres and acquire features of CD56dim NK cells upon activation. J. Immunol.178,4947–4955 (2007).
    • 25  Ferlazzo G, Thomas D, Lin SL et al.: The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J. Immunol.172,1455–1462 (2004).
    • 26  Bradley TP, Bonavida B: Mechanism of cell-mediated cytotoxicity at the single cell level. IV. Natural killing and antibody-dependent cellular cytotoxicity can be mediated by the same human effector cell as determined by the two-target conjugate assay. J. Immunol.129,2260–2265 (1982).
    • 27  Maghazachi AA: Role of chemokines in the biology of natural killer cells. Curr. Top. Microbiol. Immunol. (2010) (Epub ahead of print).
    • 28  Yagel S: The developmental role of natural killer cells at the fetal-maternal interface. Am. J. Obstet. Gynecol.201,344–350 (2009).
    • 29  Kwak-Kim J, Park JC, Ahn HK et al.: Immunological modes of pregnancy loss. Am. J. Reprod. Immunol. (2010) (Epub ahead of print).
    • 30  Redman CW, Sargent IL: Immunology of pre-eclampsia. Am. J. Reprod. Immunol. (2010) (Epub ahead of print).
    • 31  Hanna J, Goldman-Wohl D, Hamani Y et al.: Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med.12,1065–1074 (2006).
    • 32  Cella M, Fuchs A, Vermi W et al.: A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature457,722–725 (2009).
    • 33  Sanos SL, Bui VL, Mortha A et al.: RORgt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol.10,83–91 (2009).
    • 34  Luci C, Reynders A, Ivanov, II et al.: Influence of the transcription factor RORgt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol.10,75–82 (2009).
    • 35  Satoh-Takayama N, Dumoutier L, Lesjean-Pottier S et al.: The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium. J. Immunol.183,6579–6587 (2009).
    • 36  Andrews DM, Smyth MJ: A potential role for RAG-1 in NK cell development revealed by analysis of NK cells during ontogeny. Immunol. Cell. Biol.88,107–116 (2010).
    • 37  Haraguchi K, Suzuki T, Koyama N et al.: Notch activation induces the generation of functional NK cells from human cord blood CD34-positive cells devoid of IL-15. J. Immunol.182,6168–6178 (2009).
    • 38  Kamizono S, Duncan GS, Seidel MG et al.: Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med.206,2977–2986 (2009).
    • 39  Huntington ND, Legrand N, Alves NL et al.: IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J. Exp. Med.206,25–34 (2009).
    • 40  Satoh-Takayama N, Lesjean-Pottier S, Vieira P et al.: IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med.207,273–280 (2010).
    • 41  Yun S, Lee SH, Kang YH et al.: YC-1 enhances natural killer cell differentiation from hematopoietic stem cells. Int. Immunopharmacol.10(4),481–486 (2010).
    • 42  Caligiuri MA: Human natural killer cells. Blood112,461–469 (2008).
    • 43  Chinen H, Matsuoka K, Sato T et al.: Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells. Gastroenterology133,559–573 (2007).
    • 44  Lynch L, O’Donoghue D, Dean J et al.: Detection and characterization of hemopoietic stem cells in the adult human small intestine. J. Immunol.176,5199–5204 (2006).
    • 45  Cupedo T, Crellin NK, Papazian N et al.: Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol.10,66–74 (2009).
    • 46  Bostik P, Kobkitjaroen J, Tang W et al.: Decreased NK cell frequency and function is associated with increased risk of KIR3DL allele polymorphism in simian immunodeficiency virus-infected rhesus macaques with high viral loads. J. Immunol.182,3638–3649 (2009).
    • 47  Ding Y, Sumitran S, Holgersson J: Direct binding of purified HLA class I antigens by soluble NKG2/CD94 C-type lectins from natural killer cells. Scand. J. Immunol.49,459–465 (1999).
    • 48  Pende D, Parolini S, Pessino A et al.: Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med.190,1505–1516 (1999).
    • 49  Sivori S, Vitale M, Morelli L et al.: p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J. Exp. Med.186,1129–1136 (1997).
    • 50  Vitale M, Bottino C, Sivori S et al.: NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J. Exp. Med.187,2065–2072 (1998).
    • 51  Avril T, North SJ, Haslam SM et al.: Probing the cis interactions of the inhibitory receptor Siglec-7 with α2,8-disialylated ligands on natural killer cells and other leukocytes using glycan-specific antibodies and by analysis of α2,8-sialyltransferase gene expression. J. Leukoc. Biol.80,787–796 (2006).
    • 52  Betser-Cohen G, Mizrahi S, Elboim M et al.: The association of MHC class I proteins with the 2B4 receptor inhibits self-killing of human NK cells. J. Immunol.184,2761–2768 (2010).
    • 53  Vales-Gomez M, Reyburn HT, Erskine RA et al.: Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. EMBO J.18,4250–4260 (1999).
    • 54  Bryceson YT, Ljunggren HG, Long EO: Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood114,2657–2666 (2009).
    • 55  Ghiringhelli F, Menard C, Terme M et al.: CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J. Exp. Med.202,1075–1085 (2005).
    • 56  Kawakami Y, Tomimori Y, Yumoto K et al.: Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J. Exp. Med.206,1219–1225 (2009).
    • 57  Robson NC, Wei H, McAlpine T et al.: Activin-A attenuates several human natural killer cell functions. Blood113,3218–3225 (2009).
    • 58  Tarazona R, Delgado E, Guarnizo MC et al.: Human prostasomes express CD48 and interfere with NK cell function. Immunobiology (2010) (Epub ahead of print).
    • 59  Krzewski K, Chen X, Strominger JL: WIP is essential for lytic granule polarization and NK cell cytotoxicity. Proc. Natl Acad. Sci. USA105,2568–2573 (2008).
    • 60  Schleinitz N, March ME, Long EO: Recruitment of activation receptors at inhibitory NK cell immune synapses. PLoS ONE3,e3278 (2008).
    • 61  Whittaker GC, Burshtyn DN, Orr SJ et al.: Analysis of the linker for activation of T cells and the linker for activation of B cells in natural killer cells reveals a novel signaling cassette, dual usage in ITAM signaling, and influence on development of the Ly49 repertoire. Blood112,2869–2877 (2008).
    • 62  Li Q: NK cell assays in immunotoxicity testing. Methods Mol. Biol.598,207–219 (2010).
    • 63  Fultz PN, McClure HM, Anderson DC et al.: Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc. Natl Acad. Sci. USA83,5286–5290 (1986).
    • 64  Daniel MD, Letvin NL, King NW et al.: Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science228,1201–1204 (1985).
    • 65  VandeWoude S, Apetrei C: Going wild: lessons from naturally occurring T-lymphotropic lentiviruses. Clin. Microbiol. Rev.19,728–762 (2006).
    • 66  Hahn BH, Shaw GM, De Cock KM et al.: AIDS as a zoonosis: scientific and public health implications. Science287,607–614 (2000).
    • 67  Webster RL, Johnson RP: Delineation of multiple subpopulations of natural killer cells in rhesus macaques. Immunology115,206–214 (2005).
    • 68  Reeves RK, Gillis J, Wong FE et al.: CD16- natural killer cells: enrichment in mucosal and secondary lymphoid tissues and altered function during chronic SIV infection. Blood115(22),4439–4446 (2010).
    • 69  Pereira LE, Johnson RP, Ansari AA: Sooty mangabeys and rhesus macaques exhibit significant divergent natural killer cell responses during both acute and chronic phases of SIV infection. Cell. Immunol.254,10–19 (2008).
    • 70  Biassoni R, Fogli M, Cantoni C et al.: Molecular and functional characterization of NKG2D, NKp80, and NKG2C triggering NK cell receptors in rhesus and cynomolgus macaques: monitoring of NK cell function during simian HIV infection. J. Immunol.174,5695–5705 (2005).
    • 71  Rutjens E, Mazza S, Biassoni R et al.: CD8+ NK cells are predominant in chimpanzees, characterized by high NCR expression and cytokine production, and preserved in chronic HIV-1 infection. Eur. J. Immunol.40,1440–1450 (2010).
    • 72  Vivier E, Tomasello E, Baratin M et al.: Functions of natural killer cells. Nat. Immunol.9,503–510 (2008).
    • 73  Lanier LL: Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol.9,495–502 (2008).
    • 74  Bryceson YT, March ME, Ljunggren HG et al.: Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev.214,73–91 (2006).
    • 75  Brooks AG, Posch PE, Scorzelli CJ et al.: NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J. Exp. Med.185,795–800 (1997).
    • 76  Braud VM, Allan DS, O’Callaghan CA et al.: HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature391,795–799 (1998).
    • 77  Steinle A, Li P, Morris DL et al.: Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics53,279–287 (2001).
    • 78  Middleton D, Gonzelez F: The extensive polymorphism of KIR genes. Immunology129,8–19 (2010).
    • 79  Rajagopalan S, Long EO: A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J. Exp. Med.189,1093–1100 (1999).
    • 80  Yu J, Heller G, Chewning J et al.: Hierarchy of the human natural killer cell response is determined by class and quantity of inhibitory receptors for self-HLA-B and HLA-C ligands. J. Immunol.179,5977–5989 (2007).
    • 81  Tripathi P, Naik S, Agrawal S: HLA-E and immunobiology of pregnancy. Tissue Antigens67,207–213 (2006).
    • 82  Rebmann V, Pfeiffer K, Passler M et al.: Detection of soluble HLA-G molecules in plasma and amniotic fluid. Tissue Antigens53,14–22 (1999).
    • 83  Vowels BR, Gershwin ME, Gardner MB et al.: Natural killer cell activity of rhesus macaques against retrovirus-pulsed CD4+ target cells. AIDS Res. Hum. Retroviruses6,905–918 (1990).
    • 84  De Maria A, Biassoni R, Fogli M et al.: Identification, molecular cloning and functional characterization of NKp46 and NKp30 natural cytotoxicity receptors in Macaca fascicularis NK cells. Eur. J. Immunol.31,3546–3556 (2001).
    • 85  LaBonte ML, Hershberger KL, Korber B et al.: The KIR and CD94/NKG2 families of molecules in the rhesus monkey. Immunol. Rev.183,25–40 (2001).
    • 86  Mavilio D, Benjamin J, Kim D et al.: Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys. Blood106,1718–1725 (2005).
    • 87  Hershberger KL, Shyam R, Miura A et al.: Diversity of the killer cell Ig-like receptors of rhesus monkeys. J. Immunol.166,4380–4390 (2001).
    • 88  Hershberger KL, Kurian J, Korber BT et al.: Killer cell immunoglobulin-like receptors (KIR) of the African-origin sabaeus monkey: evidence for recombination events in the evolution of KIR. Eur. J. Immunol.35,922–935 (2005).
    • 89  Guethlein LA, Flodin LR, Adams EJ et al.: NK cell receptors of the orangutan (Pongo pygmaeus): a pivotal species for tracking the coevolution of killer cell Ig-like receptors with MHC-C. J. Immunol.169,220–229 (2002).
    • 90  Cadavid LF, Lun CM: Lineage-specific diversification of killer cell Ig-like receptors in the owl monkey, a New World primate. Immunogenetics61,27–41 (2009).
    • 91  Sambrook JG, Bashirova A, Palmer S et al.: Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates. Genome Res.15,25–35 (2005).
    • 92  Bimber BN, Moreland AJ, Wiseman RW et al.: Complete characterization of killer Ig-like receptor (KIR) haplotypes in Mauritian cynomolgus macaques: novel insights into nonhuman primate KIR gene content and organization. J. Immunol.181,6301–6308 (2008).
    • 93  Chaichompoo P, Bostik P, Stephenson S et al.: Multiple KIR gene polymorphisms are associated with plasma viral loads in SIV infected rhesus macaques. Cell. Immuol.263(2),176–187 (2010) .
    • 94  Blokhuis JH, van der Wiel MK, Doxiadis GG et al.: The mosaic of KIR haplotypes in rhesus macaques. Immunogenetics62,295–306 (2010).
    • 95  Kruse PH, Rosner C, Walter L: Characterization of rhesus macaque KIR genotypes and haplotypes. Immunogenetics62,281–293 (2010).
    • 96  Orange JS: Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol.6,399–409 (2006).
    • 97  Mocikat R, Braumuller H, Gumy A et al.: Natural killer cells activated by MHC class Ilow targets prime dendritic cells to induce protective CD8 T cell responses. Immunity19,561–569 (2003).
    • 98  Alter G, Altfeld M: NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J. Intern. Med.265,29–42 (2009).
    • 99  Weber K, Meyer D, Grosse V et al.: Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy. Immunobiology202,172–178 (2000).
    • 100  Iannello A, Debbeche O, Samarani S et al.: Antiviral NK cell responses in HIV infection: II. viral strategies for evasion and lessons for immunotherapy and vaccination. J. Leukoc. Biol.84,27–49 (2008).
    • 101  Iannello A, Debbeche O, Samarani S et al.: Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS. J. Leukoc. Biol.84,1–26 (2008).
    • 102  Bonaparte MI, Barker E: Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules. Blood104,2087–2094 (2004).
    • 103  Cohen GB, Gandhi RT, Davis DM et al.: The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity10,661–671 (1999).
    • 104  Brenner BG, Dascal A, Margolese RG et al.: Natural killer cell function in patients with acquired immunodeficiency syndrome and related diseases. J. Leukoc. Biol.46,75–83 (1989).
    • 105  Ahmad A, Menezes J: Antibody-dependent cellular cytotoxicity in HIV infections. FASEB J.10,258–266 (1996).
    • 106  Ullum H, Gotzsche PC, Victor J et al.: Defective natural immunity: an early manifestation of human immunodeficiency virus infection. J. Exp. Med.182,789–799 (1995).
    • 107  Sirianni MC, Mezzaroma I, Aiuti F et al.: Analysis of the cytolytic activity mediated by natural killer cells from acquired immunodeficiency syndrome patients in response to phytohemagglutinin or anti-CD16 monoclonal antibody. Eur. J. Immunol.24,1874–1878 (1994).
    • 108  Liu Q, Sun Y, Rihn S et al.: Matrix metalloprotease inhibitors restore impaired NK cell-mediated antibody-dependent cellular cytotoxicity in human immunodeficiency virus type 1 infection. J. Virol.83,8705–8712 (2009).
    • 109  Kottilil S, Chun TW, Moir S et al.: Innate immunity in human immunodeficiency virus infection: effect of viremia on natural killer cell function. J. Infect. Dis.187,1038–1045 (2003).
    • 110  Mantegani P, Tambussi G, Galli L et al.: Perturbation of the natural killer cell compartment during primary human immunodeficiency virus 1 infection primarily involving the CD56bright subset. Immunology129(2),220–233 (2009).
    • 111  Vieillard V, Fausther-Bovendo H, Samri A et al.: Specific phenotypic and functional features of natural killer cells from HIV-infected long-term nonprogressors and HIV controllers. J. Acquir. Immune Defic. Syndr.53,564–573 (2010).
    • 112  Hong HS, Eberhard JM, Keudel P et al.: HIV infection is associated with a preferential decline in less-differentiated CD56dim CD16+ NK cells. J. Virol.84,1183–1188 (2010).
    • 113  Mavilio D, Benjamin J, Daucher M et al.: Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc. Natl Acad. Sci. USA100,15011–15016 (2003).
    • 114  Alter G, Teigen N, Davis BT et al.: Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood106,3366–3369 (2005).
    • 115  De Maria A, Fogli M, Costa P et al.: The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur. J. Immunol.33,2410–2418 (2003).
    • 116  Boulet S, Kleyman M, Kim JY et al.: A combined genotype of KIR3DL1 high expressing alleles and HLA-B*57 is associated with a reduced risk of HIV infection. AIDS22,1487–1491 (2008).
    • 117  Martin MP, Gao X, Lee JH et al.: Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet.31,429–434 (2002).
    • 118  LaBonte ML, McKay PF, Letvin NL: Evidence of NK cell dysfunction in SIV-infected rhesus monkeys: impairment of cytokine secretion and NKG2C/C2 expression. Eur. J. Immunol.36,2424–2433 (2006).
    • 119  Choi EI, Reimann KA, Letvin NL: In vivo natural killer cell depletion during primary simian immunodeficiency virus infection in rhesus monkeys. J. Virol.82,6758–6761 (2008).
    • 120  Velilla PA, Shata MT, Lages CS et al.: Effect of low-dose IL-2 immunotherapy on frequency and phenotype of regulatory T cells and NK cells in HIV/HCV-coinfected patients. AIDS Res. Hum. Retroviruses24,52–61 (2008).
    • 121  Locker GJ, Kapiotis S, Veitl M et al.: Activation of endothelium by immunotherapy with interleukin-2 in patients with malignant disorders. Br. J. Haematol.105,912–919 (1999).
    • 122  Ponce R: Adverse consequences of immunostimulation. J. Immunotoxicol.5,33–41 (2008).
    • 123  Ramana Rao PV, Rajasekaran S, Raja A: Augumentation of natural killer activity with exogenous interleukins in patients with HIV and pulmonary tuberculosis coinfection. AIDS Res. Hum. Retroviruses24,1435–1443 (2008).
    • 124  Strbo N, de Armas L, Liu H et al.: IL-21 augments natural killer effector functions in chronically HIV-infected individuals. AIDS22,1551–1560 (2008).
    • 125  Hall LJ, Clare S, Dougan G: NK cells influence both innate and adaptive immune responses after mucosal immunization with antigen and mucosal adjuvant. J. Immunol.184,4327–4337 (2010).