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.

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

Zobrazit více v PubMed

Christensen JE, Thomsen AR. Co-ordinating innate and adaptive immunity to viral infection: mobility is the key. APMIS. 2009;117:338–355. PubMed

Gregoire C, Chasson L, Luci C, et al. The trafficking of natural killer cells. Immunol. Rev. 2007;220:169–182. PubMed PMC

Blum KS, Pabst R. Lymphocyte numbers and subsets in the human blood. Do they mirror the situation in all organs? Immunol. Lett. 2007;108:45–51. PubMed

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. 1975;5:117–121. PubMed

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. 1975;5:112–117. PubMed

Janeway CA. Natural killer cells: a primitive immune system. Nature. 1989;341:108. PubMed

Kim S, Poursine-Laurent J, Truscott SM, et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005;436:709–713. PubMed

Anfossi N, Andre P, Guia S, et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25:331–342. PubMed

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. 2004;172:123–129. PubMed

Piccioli D, Sbrana S, Melandri E, et al. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J. Exp. Med. 2002;195:335–341. PubMed PMC

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. 1993;177:155–164. PubMed PMC

Lu L, Ikizawa K, Hu D, et al. Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity. 2007;26:593–604. PubMed PMC

O’Leary JG, Goodarzi M, Drayton DL, et al. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat. Immunol. 2006;7:507–516. PubMed

Sun JC, Lanier LL. Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? Eur. J. Immunol. 2009;39:2059–2064. PubMed PMC

Alter G, Malenfant JM, Delabre RM, et al. Increased natural killer cell activity in viremic HIV-1 infection. J. Immunol. 2004;173:5305–5311. PubMed

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. 2007;124:277–283. PubMed

Martin MP, Qi Y, Gao X, et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet. 2007;39:733–740. PubMed PMC

Ritz J, Schmidt RE, Michon J, et al. Characterization of functional surface structures on human natural killer cells. Adv. Immunol. 1988;42:181–211. PubMed

Lanier LL, Testi R, Bindl J, et al. Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J. Exp. Med. 1989;169:2233–2238. PubMed PMC

Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–640. PubMed

Vossen MT, Matmati M, Hertoghs KM, et al. CD27 defines phenotypically and functionally different human NK cell subsets. J. Immunol. 2008;180:3739–3745. PubMed

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. Blood. 2003;101:3052–3057. PubMed

Ferlazzo G, Munz C. NK cell compartments and their activation by dendritic cells. J. Immunol. 2004;172:1333–1339. PubMed

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. 2007;178:4947–4955. PubMed

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. 2004;172:1455–1462. PubMed

Bradley TP, Bonavida B. Mechanism of cell-mediated cytotoxicity at the single cell level. I V. 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. 1982;129:2260–2265. PubMed

Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr. Top. Microbiol. Immunol. 2010 (Epub ahead of print) PubMed

Yagel S. The developmental role of natural killer cells at the fetal-maternal interface. Am. J. Obstet. Gynecol. 2009;201:344–350. PubMed

Kwak-Kim J, Park JC, Ahn HK, et al. Immunological modes of pregnancy loss. Am. J. Reprod. Immunol. 2010 (Epub ahead of print) PubMed

Redman CW, Sargent IL. Immunology of pre-eclampsia. Am. J. Reprod. Immunol. 2010 (Epub ahead of print) PubMed

Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med. 2006;12:1065–1074. PubMed

Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009;457:722–725. PubMed PMC

Sanos SL, Bui VL, Mortha A, et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 2009;10:83–91. PubMed PMC

Luci C, Reynders A, Ivanov II, et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 2009;10:75–82. PubMed

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. 2009;183:6579–6587. PubMed

Andrews DM, Smyth MJ. A potential role for RAG-1 in NK cell development revealed by ana lysis of NK cells during ontogeny. Immunol. Cell. Biol. 2010;88:107–116. PubMed

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. 2009;182:6168–6178. PubMed

Kamizono S, Duncan GS, Seidel MG, et al. Nfl3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 2009;206:2977–2986. PubMed PMC

Huntington ND, Legrand N, Alves NL, et al. IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J. Exp. Med. 2009;206:25–34. PubMed PMC

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. 2010;207:273–280. PubMed PMC

Yun S, Lee SH, Kang YH, et al. YC-1 enhances natural killer cell differentiation from hematopoietic stem cells. Int. Immunopharmacol. 2010;10(4):481–486. PubMed

Caligiuri MA. Human natural killer cells. Blood. 2008;112:461–469. PubMed PMC

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. Gastroenterology. 2007;133:559–573. PubMed

Lynch L, O’Donoghue D, Dean J, et al. Detection and characterization of hemopoietic stem cells in the adult human small intestine. J. Immunol. 2006;176:5199–5204. PubMed

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. 2009;10:66–74. PubMed

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. 2009;182:3638–3649. PubMed PMC

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. 1999;49:459–465. PubMed

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. 1999;190:1505–1516. PubMed PMC

Sivori S, Vitale M, Morelli L, et al. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J. Exp. Med. 1997;186:1129–1136. PubMed PMC

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. 1998;187:2065–2072. PubMed PMC

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 ana lysis of α2,8-sialyltransferase gene expression. J. Leukoc. Biol. 2006;80:787–796. PubMed

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. 2010;184:2761–2768. PubMed

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. 1999;18:4250–4260. PubMed PMC

Bryceson YT, Ljunggren HG, Long EO. Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood. 2009;114:2657–2666. PubMed PMC

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. 2005;202:1075–1085. PubMed PMC

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. 2009;206:1219–1225. PubMed PMC

Robson NC, Wei H, McAlpine T, et al. Activin-A attenuates several human natural killer cell functions. Blood. 2009;113:3218–3225. PubMed

Tarazona R, Delgado E, Guarnizo MC, et al. Human prostasomes express CD48 and interfere with NK cell function. Immunobiology. 2010 (Epub ahead of print) PubMed

Krzewski K, Chen X, Strominger JL. WIP is essential for lytic granule polarization and NK cell cytotoxicity. Proc. Natl Acad. Sci. USA. 2008;105:2568–2573. PubMed PMC

Schleinitz N, March ME, Long EO. Recruitment of activation receptors at inhibitory NK cell immune synapses. PLoS ONE. 2008;3:e3278. PubMed PMC

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. Blood. 2008;112:2869–2877. PubMed PMC

Li Q. NK cell assays in immunotoxicity testing. Methods Mol. Biol. 2010;598:207–219. PubMed

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. USA. 1986;83:5286–5290. PubMed PMC

Daniel MD, Letvin NL, King NW, et al. Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science. 1985;228:1201–1204. PubMed

VandeWoude S, Apetrei C. Going wild: lessons from naturally occurring T-lymphotropic lentiviruses. Clin. Microbiol. Rev. 2006;19:728–762. PubMed PMC

Hahn BH, Shaw GM, De Cock KM, et al. AIDS as a zoonosis: scientific and public health implications. Science. 2000;287:607–614. PubMed

Webster RL, Johnson RP. Delineation of multiple subpopulations of natural killer cells in rhesus macaques. Immunology. 2005;115:206–214. PubMed PMC

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. Blood I. 2010;15(22):4439–4446. PubMed PMC

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. 2008;254:10–19. PubMed

Biassoni R, Fogli M, Cantoni C, et al. Molecular and functional characterization of NKG2D, NKp80, and NKG2C triggering NKcell receptors in rhesus and cynomolgus macaques: monitoring of NK cell function during simian HIV infection. J. Immunol. 2005;174:5695–5705. PubMed

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. 2010;40:1440–1450. PubMed

Vivier E, Tomasello E, Baratin M, et al. Functions of natural killer cells. Nat. Immunol. 2008;9:503–510. PubMed

Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 2008;9:495–502. PubMed PMC

Bryceson YT, March ME, Ljunggren HG, et al. Activation, coactivation, and costimulation of resting human natural killer cells. Immunol. Rev. 2006;214:73–91. PubMed PMC

Brooks AG, Posch PE, Scorzelli CJ, et al. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J. Exp. Med. 1997;185:795–800. PubMed PMC

Braud VM, Allan DS, O’Callaghan CA, et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391:795–799. PubMed

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. Immunogenetics. 2001;53:279–287. PubMed

Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8–19. PubMed PMC

Rajagopalan S, Long EO. A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. J. Exp. Med. 1999;189:1093–1100. PubMed PMC

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. 2007;179:5977–5989. PubMed

Tripathi P, Naik S, Agrawal S. HLA-E and immunobiology of pregnancy. Tissue Antigens. 2006;67:207–213. PubMed

Rebmann V, Pfeiffer K, Passler M, et al. Detection of soluble HLA-G molecules in plasma and amniotic fluid. Tissue Antigens. 1999;53:14–22. PubMed

Vowels BR, Gershwin ME, Gardner MB, et al. Natural killer cell activity of rhesus macaques against retrovirus-pulsed CD4+ target cells. AIDS Res. Hum. Retroviruses. 1990;6:905–918. PubMed

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. 2001;31:3546–3556. PubMed

LaBonte ML, Hershberger KL, Korber B, et al. The KIR and CD94/NKG2 families of molecules in the rhesus monkey. Immunol. Rev. 2001;183:25–40. PubMed

Mavilio D, Benjamin J, Kim D, et al. Identification of NKG2A and NKp80 as specific natural killer cell markers in rhesus and pigtailed monkeys. Blood. 2005;106:1718–1725. PubMed PMC

Hershberger KL, Shyam R, Miura A, et al. Diversity of the killer cell Ig-like receptors of rhesus monkeys. J. Immunol. 2001;166:4380–4390. PubMed

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. 2005;35:922–935. PubMed

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. 2002;169:220–229. PubMed

Cadavid LF, Lun CM. Lineage-specific diversification of killer cell Ig-like receptors in the owl monkey, a New World primate. Immunogenetics. 2009;61:27–41. PubMed

Sambrook JG, Bashirova A, Palmer S, et al. Single haplotype ana lysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates. Genome Res. 2005;15:25–35. PubMed PMC

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. 2008;181:6301–6308. PubMed PMC

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. 2010;263(2):176–187. PubMed PMC

Blokhuis JH, van der Wiel MK, Doxiadis GG, et al. The mosaic of KIR haplotypes in rhesus macaques. Immunogenetics. 2010;62:295–306. PubMed PMC

Kruse PH, Rosner C, Walter L. Characterization of rhesus macaque KIR genotypes and haplotypes. Immunogenetics. 2010;62:281–293. PubMed

Orange JS. Human natural killer cell deficiencies. Curr. Opin. Allergy Clin. Immunol. 2006;6:399–409. PubMed

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. Immunity. 2003;19:561–569. PubMed

Alter G, Altfeld M. NK cells in HIV-1 infection: evidence for their role in the control of HIV-1 infection. J. Intern. Med. 2009;265:29–42. PubMed PMC

Weber K, Meyer D, Grosse V, et al. Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy. Immunobiology. 2000;202:172–178. PubMed

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. 2008;84:27–49. PubMed

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. 2008;84:1–26. PubMed

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. Blood. 2004;104:2087–2094. PubMed

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. Immunity. 1999;10:661–671. PubMed

Brenner BG, Dascal A, Margolese RG, et al. Natural killer cell function in patients with acquired immunodeficiency syndrome and related diseases. J. Leukoc. Biol. 1989;46:75–83. PubMed

Ahmad A, Menezes J. Antibody-dependent cellular cytotoxicity in HIV infections. FASEB J. 1996;10:258–266. PubMed

Ullum H, Gotzsche PC, Victor J, et al. Defective natural immunity: an early manifestation of human immunodeficiency virus infection. J. Exp. Med. 1995;182:789–799. PubMed PMC

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. 1994;24:1874–1878. PubMed

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. 2009;83:8705–8712. PubMed PMC

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. 2003;187:1038–1045. PubMed

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. Immunology. 2009;129(2):220–233. PubMed PMC

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. 2010;53:564–573. PubMed

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. 2010;84:1183–1188. PubMed PMC

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. USA. 2003;100:15011–15016. PubMed PMC

Alter G, Teigen N, Davis BT, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood. 2005;106:3366–3369. PubMed

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. 2003;33:2410–2418. PubMed

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. AIDS. 2008;22:1487–1491. PubMed

Martin MP, Gao X, Lee JH, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat. Genet. 2002;31:429–434. PubMed

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. 2006;36:2424–2433. PubMed

Choi EI, Reimann KA, Letvin NL. In vivo natural killer cell depletion during primary simian immunodeficiency virus infection in rhesus monkeys. J. Virol. 2008;82:6758–6761. PubMed PMC

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. Retroviruses. 2008;24:52–61. PubMed

Locker GJ, Kapiotis S, Veitl M, et al. Activation of endothelium by immunotherapy with interleukin-2 in patients with malignant disorders. Br. J. Haematol. 1999;105:912–919. PubMed

Ponce R. Adverse consequences of immunostimulation. J. Immunotoxicol. 2008;5:33–41. PubMed

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. Retroviruses. 2008;24:1435–1443. PubMed

Strbo N, de Armas L, Liu H, et al. IL-21 augments natural killer effector functions in chronically HIV-infected individuals. AIDS. 2008;22:1551–1560. PubMed PMC

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. 2010;184:4327–4337. PubMed PMC