Innate Immune Control of HIVperspectivesinmedicine.cshlp.org/content/2/7/a007070.full.pdf · the immune system, including NK-cell recogni-tion, suggesting a role for these cells in

Innate Immune Control of HIV

Mary Carrington1,2 and Galit Alter1

1Ragon Institute of MGH, MIT, and Harvard, Charlestown, Massachusetts 021292Cancer and Inflammation Program, Laboratory of Experimental Immunology, SAIC Frederick, NCIFrederick, Frederick, Maryland 21702

Correspondence: [email protected]

Mounting evidence suggests a role for innate immunity in the early control of HIV infection,before the induction of adaptive immune responses. Among the early innate immune effectorcells, dendritic cells (DCs) respond rapidly following infection aimed at arming the immunesystem, through the recognition of viral products via pattern recognition receptors. This earlyresponse results in the potent induction of a cascade of inflammatory cytokines, intimatelyinvolved in directly setting up an antiviral state, and indirectly activating other antiviral cellsof the innate immune system. However, epidemiologic data strongly support a role for naturalkiller (NK) cells as critical innate mediators of antiviral control, through the recognition ofvirally infected cells through anetworkof receptors called the killer immunoglobulin-like recep-tors (KIRs). In this review, the earlyevents in innate immunerecognition ofHIV, focused on defin-ing the biology underlying KIR-mediated NK-cell control of HIV viral replication, are discussed.

Early events following HIV infection deter-mine the course of disease progression in

such a way that more robust control of viral rep-lication in acute HIV infection, resulting inlower viral set-point levels, is associated withslower HIV disease progression (Pantaleo et al.1997). However, reduction in viral replicationduring acute HIV infection often occurs beforethe induction of adaptive immune responsessuch as CD8þ T-cell responses (Alter et al.2007b), strongly suggesting that the innateimmune system, our body’s first line of defenseagainst invading pathogens, may play an earlyessential role in antiviral control.

THE INNATE IMMUNE SYSTEM

The innate immune system has evolved overmillennia to nonspecifically control and clear

invading pathogens. Unlike the adaptive armof the immune system, which uses antigen-spe-cific receptors to recognize foreign antigens, theinnate immune system uses an array of patternrecognition receptors to detect patterns associ-ated with bacteria, viruses, and/or parasites.These patterns relate to carbohydrate, protein,or lipid structures that are unique to pathogens,not normally produced in human cells (Mur-phy et al. 2011). Three classes of pattern recogni-tion receptors have been identified to date,including the (RIG-I)-like receptors (RLRs),the toll-like receptors (TLRs), and the nucleotideoligomerization domain (NOD)-like receptors(NLRs). Activation of different combinations ofthese receptors, on distinct innate immune cellsubsets, results in the induction of distinctinflammatory cues that result in the creation of

Editors: Frederic D. Bushman, Gary J. Nabel, and Ronald Swanstrom

Additional Perspectives on HIV available at www.perspectivesinmedicine.org

Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a007070

Cite this article as Cold Spring Harb Perspect Med 2012;2:a007070

1

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org

on March 9, 2021 - Published by Cold Spring Harbor Laboratory Press http://perspectivesinmedicine.cshlp.org/Downloaded from

http://perspectivesinmedicine.cshlp.org/

a nonspecific antiviral environment throughthe release of cytokines (including interferons[IFNs]) that block viral growth, the activationand recruitment of other immune cells, and theinduction of adaptive immune responses.

HIV, like other single-stranded RNAviruses,triggers innate immune receptors, includingTLR7 and TLR8, resulting in the potent activa-tion of dendritic cells (DCs) and the release ofcopious amounts of type 1 IFNs and tumornecrosis factor a (TNF-a), both involved inshutting down viral replication in infected cellswhile also promoting the activation of theimmune response (Diebold et al. 2004; Heilet al. 2004; Beignon et al. 2005). Interestingly,recent data suggest that DCs from femalesproduce higher levels of IFN-a, comparedwith DCs from age-matched men, on HIVRNA triggering of TLR7/8 (Meier et al. 2009).Given that women show overall lower viral setpoints than men, it is plausible that enhancedviral control in females may in part relate tothis enhanced antiviral innate immuneresponse. The difference in the ability of DCsfrom women and men to respond to TLR7/8triggering likely reflects a hormonal sensitiza-tion of DCs, specifically promoting TLR-induced IFN-a, but not TNF-a, production inwomen. However, whether enhanced antiviralcontrol reflects the direct activity of IFN-aalone, or its added effects on activating otherinnate immune cells (including natural killer[NK] cells), or in the induction of a more potentadaptive immune response is yet to be defined.

In addition to TLR7/8 recognition of HIV,TLR2, TLR4, and TLR9 have been implicatedin recognition and modulation of HIV viral rep-lication. Both TLR2 and TLR4 triggering on DCshas been associated with increased and reducedtransmission of HIV, respectively, owing to dif-ferential induction of type 1 IFNs (Thibaultet al. 2009). Furthermore, recent evidence alsopoints to a direct role for gp120 binding toTLR9, resulting in pDC activation, type 1 IFNsecretion, and activation of NK cells that maypromote early antiviral control (Martinelli et al.2007). However, the overall role of individualor combined TLR sensing in early recognitionand control of HIV has not been fully elucidated.

The early HIV-mediated triggering of DCs,and other TLR expressing innate immune cells,is associated with the induction of a robustcytokine storm (Stacey et al. 2009). This earlyresponse is marked by the rapid induction ofIFN-a, interleukin-15 (IL-15), and inducibleprotein-10 (IP-10), followed by a slower in-crease in proinflammatory factors, associatedfinally with a sustained increase in immunoreg-ulatory cytokines. Interestingly, the acute cyto-kine cascade is strikingly more pronouncedfollowing HIV infection compared with hepati-tis B and C infections. Thus, although the dra-matic increase in immunomodulators may begeared toward the priming of a robust immuneresponse against the incoming pathogen, it isplausible that the intensity and magnitude ofthis cascade may also contribute in part to theobserved immunopathology associated withearly HIV disease.

INNATE IMMUNE CELLS

An array of cell subsets, all derived from thebone marrow, forms the arsenal of the innateimmune system that responds to the acute cyto-kine cascade, each expressing distinct sets of in-nate immune receptors, endowing them with aunique capacity to respond to incoming patho-gens. These cells include phagocytes (mono-cytes, macrophages, DCs) primed for antigenclearance, cytolytic cells (NK cells and neutro-phils) geared toward the direct destruction ofthe pathogen or pathogen-infected cells, and pro-fessional antigen-presenting cells (DCs) aimed atcapturing foreign antigens to present to theadaptive immune response for the inductionof immunological memory. These cells per-sistently patrol peripheral tissues, primed torespond to foreign antigens on receptor engage-ment without the need for antigen sensitization.Thus, the innate immune response is not onlyresponsible for early pathogen containment,but also plays a central role in shaping the qual-ity of the ensuing adaptive immune responsethrough the release of potent inflammatorycues and the qualitative modulation of DCs.

Among the innate immune cells involved inearly antiviral control of HIV, epidemiologic

M. Carrington and G. Alter

2 Cite this article as Cold Spring Harb Perspect Med 2012;2:a007070

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



evidence strongly points to a central role for NKcells in antiviral containment. Most convinc-ingly, the coexpression of particular NK-cellreceptors (the killer immunoglobulin recep-tors) in conjunction with their ligands (majorhistocompatibility complex [MHC] class I al-leles) is associated with slower HIV disease pro-gression and early viral control of viremia(Martin et al. 2002, 2007). These data stronglysupport a role for these cytolytic effector cellsearly in infection, whereas the adaptive immuneresponse is just developing. However, whetherNK cells mediate their antiviral control strictlythrough cytolytic removal of infected cells orthrough the editing of particular DC popula-tions resulting in more potent adaptive immuneresponses is unknown.

NK CELLS

Unlike CD8þ T cells, NK cells are a subset oflarge granular lymphocytes that do not expressan antigen-specific receptor, but rather expressa variety of inhibitory and activating receptorson their surface that are involved in sensingchanges in their ligands on the surface of thebody’s cells (Lanier 1998). As such, these cellsare classified as cells of the innate immune sys-tem, as they are able to sense viral infectionbefore antigen sensitization. Given that thesecells are loaded with cytolytic granules thatcan cause a great deal of immunopathology,the activation of these cells is under tight regu-lation by a network of inhibitory and activatingself-reactive receptor/ligand interactions. NKcells survey the body for MHC class I expres-sion, using a network of receptors called thekiller immunoglobulin-like receptors (KIRs),and are inhibited on interaction with MHCclass I. However, lack of engagement of inhibi-tory receptors alone is not sufficient to activatean NK cell to kill a target cell, but rather an NKcell must receive an additional activating signalthrough recognition of ligand to induce cyto-lytic elimination of the target cell (Fig. 1) (Karreet al. 1986; Ljunggren and Karre 1990; Morettaet al. 1993). Alternatively, target cells thatup-regulate activating NK receptor ligands tolevels that outcompete the dominant inhibitory

signals delivered through normal MHC recog-nition by KIRs can also result in NK cell activa-tion (Cerwenka and Lanier 2001a). Ultimately,NK-cell activation hinges on the delicate balancebetween inhibition and activation deliveredthrough a variety of NK-cell receptors, includ-ing KIRs, that fine-tune their lytic activity.This concept has refined the “missing self”model of NK recognition to include two basicsteps: (1) loss of self, which may occur followinginfection or tumor transformation, as a first sig-nal to alert NK cells that a cell is aberrant, and(2) an activating signal that is required to fullyunleash the cytolytic activity of NK cells. Fur-thermore, over the past decade, accumulatingevidence suggests that NK cells may not be asinnate as once believed, but that individualNK-cell clones may show some target cell specif-icity (Malnati et al. 1995; Peruzzi et al. 1996),allowing them to play a critical early role in earlyantiviral control following infection with HIV.

NK CELLS IN HIV

The first immunomodulators in the acutecytokine storm (IFN-a and IL-15) (Staceyet al. 2009) are centrally involved in rapidlyarming and activating NK cells following infec-tion (Biron 1999). Thus, as anticipated, NK cellsexpand rapidly following acute infection,specifically in the acute seronegative window,with a preferential expansion of the cytolyticCD56dim NK-cell subpopulation (Alter et al.2007b; Alter et al. 2009). However, to com-pensate for this early burst of innate cytolyticeffector cells, HIV has devised multiple strat-egies to evade NK-cell recognition, indicatingthat these cells are able to place pressure onthe virus.

HIV EVASION OF NK CELLS THROUGH Nef

Viruses have evolved multiple strategies to evadethe immune system, including NK-cell recogni-tion, suggesting a role for these cells in the earlyresponse to infection (Lodoen and Lanier2005). Many viruses have specifically evolvedstrategies to down-regulate MHC class I fromthe surface of infected cells in an effort to avoid


Cite this article as Cold Spring Harb Perspect Med 2012;2:a007070 3

ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



CD8þ T-cell recognition. However, this loss ofMHC class I renders infected cells vulnerableto NK-cell-mediated recognition through in-hibitory NK-cell receptors. Viruses such ascytomegalovirus (CMV) have evolved a com-pensatory repertoire of MHC class I homologsaimed at providing inhibitory signals to NKcells (Cerwenka and Lanier 2001b; Arase et al.2002). Whereas CMV is a large DNA virus thathas the opportunity to accommodate multiplegenes for the evasion of both innate and adap-tive immune responses, HIV is a small RNAvirus that encodes only nine genes. Yet a num-ber of studies have shown that HIV uses a singlenonstructural gene, Nef, to evade both theinnate and adaptive immune response.

Most notably, HIV-1 Nef protein triggersthe accelerated endocytosis or retention ofMHC class I molecules in the Golgi, resultingin reduced MHC class I expression on the sur-face of infected cells (Schwartz et al. 1996),thereby preventing recognition by HIV-specificCD8þ T cells. However, reduced MHC class Iexpression may alert NK cells of a possible in-fection. Interestingly, Nef may overcome bothCD8- and NK-cell-mediated recognition bydown-regulating the dominant T-cell receptorligands HLA-A and -B molecules, while sparingthe dominant inhibitory KIR2D ligands, HLA-C (Le Gall et al. 1998; Cohen et al. 1999).

However, HLA-A appear to be down-regulatedrobustly, as compared with HLA-B (Cohenet al. 1999). These data strongly suggest thatNef has evolved a means to spare some KIRligands, allowing it to strike a balance betweenT- and NK-cell evasion.

Loss of MHC class I expression is not suffi-cient to trigger NK-cell destruction of anHIV-infected cell, but requires a second activat-ing signal. Viral infection often results in theup-regulation of the stress-inducible ligandsfor the activating c-type lectin NK-cell receptorNKG2D (Raulet 2003). These NKG2D-stressligands, the MHC class I-related chain-A and-B (MIC-A/B) or UL-16 binding proteins-1,-2, and -3 (ULBP-1/2/3), are homologs ofMHC class I alleles that are typically expressedfollowing tumor transformation or infection(Raulet 2003). Recent studies reveal that theexpression of MIC and ULBP on human tumorcells is sufficient to overcome the inhibitoryeffects of MHC class I expression (Zhang et al.2005). To circumvent this activity, the HIVNef protein has evolved the capacity to preventthe expression of some NKG2D ligands, suchas MIC A, ULBP-1, and -2, at the surface ofinfected cells (Cerboni et al. 2007). It appearsthen that Nef regulation of host protein expres-sion targets two host defense mechanisms, oneinvolving KIRs and the other NKG2D.

Recognition by KIR3DS1 ofaltered MHC complex with thepresentation of a stress/HIV

peptide

Stress/HIVpeptide

NKCD4+ T cell

No infection

Infection+

Figure 1. A model of KIR3DS1þ natural killer (NK)-cell recognition of an HIV-infected target cell. Accumulat-ing evidence suggests that specific amino acid changes in the peptides presented by major histocompatibilitycomplex (MHC) class I can have a profound impact on KIR recognition of peptide/MHC complexes. Alongthese lines, it is plausible that a viral or stress peptide generated during infection presented by Bw4-80I may alterthe affinity of the activating KIR3DS1 receptor expressed on NK cells for its putative ligand, resulting in thepotent activation of NK cells and rapid elimination of virally infected cells.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



A ROLE FOR KIR IN MODULATING HIVDISEASE PROGRESSION

KIRs can be divided into four groups basedon two features: the number of extracellular do-mains (two domain [2D] or three domain [3D]and the length of the cytoplasmic tail (long [L]or short [S]). The length of the cytoplasmic do-mains dictates whether the receptor is activatingor inhibitory, as long-tail KIRs contain immu-noreceptor tyrosine-based inhibition motifs(ITIMs) that deliver strong inhibitory signals,whereas the short cytoplasmic tails associatewith molecules that contain immunoreceptortyrosine-based activation motifs (ITAMs) (La-nier et al. 1998). In addition to differences ingene content, most KIR genes show allelic poly-morphism as well (Shilling et al. 2002; Carring-ton and Norman 2003).

Both epidemiological data and genome-wide association studies (GWASs) have pointedto a central role for particular MHC class Ialleles in modulating the rate of disease progres-sion (Carrington and O’Brien 2003; Fellay et al.2007), the majority of which are encoded by theMHC class 1-B locus. Most of the protectiveHLA-B alleles express the Bw4 epitope, the pri-mary ligands for KIR3DL1. Given the remark-able homology between alleles of KIR3DL1and its activating counterpart KIR3DS1, epide-miological studies aimed at defining whetherthese three-domain KIR had any role in modu-lating disease progression were tested (Martinet al. 2002, 2007). Interestingly, both the ac-tivating and a subset of inhibitory variants ofthis KIR gene had a profound impact on mod-ulating HIV disease progression in the contextof their putative MHC ligands. Furthermore,duplications and deletions within the 3DL1/S1 segment have been observed (Martin et al.2003), resulting in KIR haplotypes that canhave zero or two copies of the KIR3DL1/S1gene, and increasing doses of KIR3DS1 in thepresence of KIR3DL1 and its putative ligandare associated with more robust control ofHIV viremia in early disease (K Pelak and DGGoldstein, pers. comm.). These results suggestthat NK cells may contribute to control throughKIRs through at least two different mechanisms,

one modulated by inhibitory receptors and asecond mediated by an activating receptor,and that the activating and inhibitory receptorsmay interact to promote enhanced control ofHIV viral replication.

KIR3DS1-MEDIATED CONTROL OF HIV

A number of studies have highlighted theimpact of particular KIR/MHC combinationson HIV-1 disease outcome (Martin et al. 2002,2007; Jennes et al. 2006). Martin et al. showedthat subjects that coexpressed the activatingKIR3DS1 allele in conjunction with its putativeMHC class I ligand, Bw4 alleles with an isoleu-cine at position 80 of the peptide-bindinggroove (Bw4-80I) (Barber et al. 1997), pro-gressed significantly more slowly toward AIDSthan individuals that do not have this com-pound genotype (Martin et al. 2002). Althoughthe physical interaction between KIR3DS1 andHLA-Bw4-80I molecules has yet to be shown,this genetic epistasis suggests that this KIR/MHC interaction confers some antiviral signalto NK cells to allow them to control HIV infec-tion more effectively.

Functional data support the interactionbetween KIR3DS1 and Bw4-80I, as KIR3DS1þ

NK cells degranulated more potently in re-sponse to HIV-infected Bw4-80Iþ CD4þ T cellsand suppressed viral replication in a Bw4-80I-dependent manner (Alter et al. 2007a).Additionally, these KIR3DS1þ NK cells ex-panded robustly following acute HIV infection(Alter et al. 2009), but only in subjects that coex-pressed Bw4-80I, further suggesting thatKIR3DS1 may receive proliferative signalsfrom its putative ligand early on following infec-tion, allowing NK cells expressing this receptorto expand robustly to help contain early viralreplication. Moreover, NK cells derived fromindividuals that encoded for KIR3DS1 re-sponded more potently to HLA-class I negativetarget cells than NK cells from KIR3DS1neg sub-jects (Long et al. 2008). Although KIR3DS1alone was sufficient to confer elevated NK-cellresponsiveness to class I devoid targets, NK-cellresponses were strongest among individualsthat coexpressed KIR3DS1 and Bw4-80I (Long



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



et al. 2008). Finally, elevated KIR3DS1 tran-scripts were identified in persistently negativebut highly exposed individuals, suggesting thatKIR3DS1 may also be involved in protectionfrom infection (Ravet et al. 2007). Taken to-gether, these epidemiological and functionaldata support a role for KIR3DS1þ NK cells inrestricting HIV infection in a “specific” mannerin individuals that coexpress its putative ligandBw4-80I.

Although a physical interaction has yet to beobserved between KIR3DS1 and Bw4-80I, epi-demiological and functional evidence stronglysupport that these two molecules are likely tointeract either directly or indirectly to activateNK cells during HIV infection. Several potentialscenarios may underlie this enigmatic interac-tion, including the possibility that a viral orstress peptide generated during infection pre-sented by Bw4-80I may alter the affinity of theactivating 3DS1 for its putative ligand (Fig. 2).Although data exist demonstrating that amino

acid variation within a peptide, particularly atpositions 7 and 8, can dramatically alter inhib-itory KIR recognition of MHC class I complexeson a target cell, little is known about the partic-ular changes in the MHC class I bound peptidethat may alter activating KIR binding and acti-vation. However, recent data now suggest thatKIR3DS1 may in fact recognize discrete aminoacids within the HIV proteome, as distinct foot-prints have now been identified that emergepreferentially in individuals that express thisactivating KIR (G Alter, unpubl.). Like theescape mutations that emerge in CD8þ T-cell-restricted epitopes, it is plausible that KIR-asso-ciated footprints may also reflect NK-restrictedantiviral pressure. Alternatively, data from themurine model of Ly49p-mediated protectionin murine cytomegalovirus (MCMV) infectionsuggest that instead of a peptide, the activatingLy49p NK-cell receptor interacts with its puta-tive ligand, H2-Dk, only in the presence of athird, undefined protein (Lee et al. 2001).

IFN-αFas-FasLPerforin/granzyme

1. Self-recognition(dominant inhibitory signal )

2. Lack of self-recognitionbut no killing

(lack of an activating signal )

3. Lack of self-recognitionand potent activation

(activating signal to release killing )

NK

NK+

?

NK

Targetcell

Targetcell

Targetcell

–

Figure 2. A model of two-step NK-cell activation. NK-cell killing of target cells is tightly regulated by a balance ofactivating and inhibitory signals delivered through the arsenal of NK-cell receptors expressed on the surface of agiven NK-cell clone. NK cells survey the body’s cells for normal MHC class-I expression, delivering a potentinhibitory signal to NK cells through inhibitory KIRs (1). Although the missing self-hypothesis states thatthe loss of MHC class I should trigger NK-cell killing of a target cell, this loss of inhibition is not sufficientto release the cytolytic activity of NK cells (2). Instead, an activating signal (including a stress ligand), to tipthe balance toward activation, releases the full cytolytic power of a given NK-cell clone.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Overall, these data suggest that the affinity of3DS1 for Bw4-80I may be altered during HIVinfection, either by a stress/viral peptide orcoactivating protein, resulting in potent NK-cell activation. The attraction of the latter possi-bility is that it implies nonspecificity of 3DS1for HIV, which is what is expected for theseinnate immune receptors.

3DL1-MEDIATED CONTROL OF HIV

In addition to 3DS1, epidemiological studieslater showed that additional inhibitory allo-types of 3DL1 are also associated with slowerHIV disease progression (Martin et al. 2007).Distinct 3DL1 allotypes are expressed at variablelevels on the surface of NK cells (Yawata et al.2006), resulting in differing NK-cell functionalpotencies. Among the 3DL1 allotypes, threesubclassifications have been defined: (1) high-expressing alleles that are associated withpotent NK-cell effector functions in the pres-ence of MHC-devoid target cells (3DL1�001,�002, �005, �008, �015, and �020), (2) low-expressing alleles that are associated with weakerNK-cell responsiveness to the same target cells(3DL1�005, �007, and �009), and (3) a nonex-pressing allotype with unknown functionalproperties (3DL1�004). Interestingly, 3DL1 al-leles expressed at high levels or not expressedat all were associated with slower HIV-1 diseaseprogression, when coexpressed with Bw4-80Ialleles (Martin et al. 2007).

Although the role of the nonexpressed3DL1�004 allele remains an enigma, an explan-ation has been proposed for the high-expressed3DL1 alleles. In 2005, a breakthrough wasachieved in our understanding of the influenceof KIR on NK cell function. In addition to therole of inhibitory KIR in monitoring for normalexpression of MHC class I on the surface of cells(“missing self” hypothesis), a series of reportsindicated that both Ly49 in mice and KIR inhumans regulate NK-cell function by recogni-tion of self-MHC class I providing signals forfunctional competence of the NK cell duringdevelopment, a process called “licensing” (Fer-nandez et al. 2005; Kim et al. 2005; Anfossiet al. 2006; Kim et al. 2008). These studies

suggest that NK cells undergo a self-MHC classI-dependent maturation process that delivers apositive signal resulting in the ability of NK cellsto distinguish self from autologous target cellsthat have lost MHC class I (Kim et al. 2005;Anfossi et al. 2006). This model helped explainthe fraction of NK cells in the periphery thatare hyporesponsive, which are the subgroup ofNK cells that lack inhibitory KIR for self, andare not educated to respond against aberranttargets (Anfossi et al. 2006). Additionally,more detailed models termed “arming” or “tun-ing” helped to refine the licensing model, takinginto account the balance between activatingMHC-binding receptors that are sometimesexpressed in the absence or lower levels of inhib-itory self-binding receptors. In these models,the investigators proposed that the presence ofa dominant inhibitory signal during develop-ment helps to “arm” an NK cell, whereas lackof inhibition and/or excessive activation leadsto disarming (Fernandez et al. 2005) or tuning(Salcedo et al. 1998) of NK-cell responsiveness,resulting in the accumulation of a subset ofhyporesponsive cells.

Thus, KIR3DL1 protection may be relatedto NK-cell education, where higher expressionof KIR3DL1 on a developing NK cell in the pres-ence of its ligand may result in the generation ofa larger pool of functionally competent cyto-lytic cells, which on infection may respondmore aggressively (Fig. 3). This possibilityrelates to the “missing self” hypothesis in thatcells expressing higher levels of 3DL1 areexpected to require a greater number of KIR/MHC interactions to inhibit such a cell, sothey may be more sensitive to small losses ofMHC class I following infection, respondingvigorously to the target.

A POTENTIAL ROLE FOR TWO-DOMAINKIRs IN CONTROL OF HIV?

GWASs in large cohorts of HIV-infected indi-viduals identified a number of single nucleotidepolymorphisms (SNPs) associated with slowerHIV disease progression, all of which mappedto a single region of the human genomeon chromosome 6 located within the MHC.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Among these SNPs, the GWASs confirmedprevious epidemiological data demonstratinga protective role for the HLA-B allele B�57 (Car-rington and O’Brien 2003), but also identifieda number of additional SNPs, including onelocated 35 kb upstream of HLA-C (Thomaset al. 2009). The protective variant is associatedwith increased HLA-C expression on the surfaceof CD3þ T cells (Fellay et al. 2007; Thomas et al.2009). Interestingly, the protective effect of thisSNP could not be assigned to a specific HLA-Callele or phylogenetically related subgroup(Thomas et al. 2009), suggesting a potentialnon-CD8-dependent protective mechanism.As HLA-C alleles serve as ligands for KIR2Dreceptors (Vitale et al. 1995; Stewart et al.2005), several groups have now begun to specu-late that this protective effect in HIV infection isNK-cell-dependent through the interaction ofKIR2D with its ligand. Based on the NK-celleducation models, HLA-C alleles expressed athigher levels on the surface of a cell during devel-opment may generate more potent cytolytic NK

cells (Kim et al. 2008; Brodin et al. 2009), but thispossibility remains to be answered.

KIRs DRIVE VIRAL EVOLUTION

Most recently, efforts to define the mechanismby which NK cells may contribute to HIV viralcontrol have sought to determine whether NKcells may recognize and place pressure on thevirus directly in vivo. Historically, the identifi-cation of “footprints,” amino acid substitutionsin the viral proteome that accumulate specifi-cally in the presence of specific HLA-class Ialleles, have been regarded as a marker ofCD8þ T-cell pressure (Allen et al. 2000). Like-wise, recent data have shown that similar foot-prints arise in the HIV proteome in thepresence of distinct KIR genes (Alter et al.2011). These data suggest that like T cells, NKcells may also recognize specific regions of theHIV virus, placing pressure on the virus.

How can KIRs see specific regions of theHIV proteome? Several lines of evidence suggest

Potent effector functionsin response to reduced MHC

(Nef?)

Strong activation =potent effector functions

Infection

Development

Bone marrow stroma NK

NKCD4+ T cell

+

+

+

Figure 3. A model of KIR3DL1þ NK-cell recognition of an HIV-infected target cell. Given that inhibitory KIRshave been recently implicated in NK-cell education, in such a way that inhibitory KIRs expressed at higher levelsare associated with the generation of more functional NK-cell clones, it is possible that the expression ofKIR3DL1 at higher levels on a developing NK cell in the presence of its ligand may result in the generation ofa larger pool of functionally competent cytolytic cells. These more functionally competent cells may thenrespond more aggressively on HIV infection to cells that have lost MHC class I ligands, that are down-regulatedby the HIV Nef protein.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



that affinity changes between KIRs and histo-compatibility leukocyte antigen (HLA) class Imay be induced by the peptide bound in theMHC class I binding groove. Crystal structuresof KIR/MHC class I complexes show that KIRinteracts with the a1 and a2 helix of MHC classI and makes direct contact with the carboxy-terminal portion of the bound peptide (Boying-ton et al. 2000; Fan et al. 2001). The impact ofthe bound peptide on KIR/MHC interactionshas further been examined in a number of stud-ies demonstrating that particular amino acidchanges in the peptide, particularly at positions7 or 8, results in the abrogation of inhibitionthrough KIR, resulting in target cell lysis (Cor-rea and Raulet 1995; Malnati et al. 1995; Peruzziet al. 1996; Rajagopalan and Long 1997; Zappa-costa et al. 1997; Fadda et al. 2010). Thus, it ispossible that whereas self-peptides bound toMHC class I provide a strong inhibitory signalto the inhibitory KIR, particular viral peptidesproduced during infection may bind differen-tially to KIR, whereby decreased binding to aninhibitory KIR may trigger “missing self”NK-cell activation, or increased binding to anactivating KIR may activate NK-cell cytotoxic-ity. This direct KIR-mediated antiviral pressuremay drive the virus to incorporate “escapemutations” aimed at evading this form of innaterecognition (Alter et al. 2011). However, theoverall impact of this specific innate immuneresponse has yet to be defined.

CONCLUSIONS

Over the past two decades, significant advanceshave been achieved in our basic understandingof the role of innate immunity in the controlof viral infections. Moreover, we have come toappreciate that this arm of the immuneresponse may directly contribute to antiviralcontrol but may also play a significant role inmodulating the quality of the ensuing adaptiveimmune response. In the context of HIV infec-tion, mounting epidemiologic data stronglyimplicate a role for NK cells in antiviral control,underscored by the fact that these innateimmune cells expand robustly in response toTLR-induced DC-secreted cytokines and have

now been shown to specifically place pressureon HIV in vivo. The failure of recent HIV-1 vac-cine trials to induce protective immunity inhumans has highlighted our lack of under-standing of the correlates of immune protectionin HIV-1 infection. Therefore, new therapeuticstrategies aimed at harnessing the power of theinnate immune response, and particular NKcells, may provide a new approach aimed atenhancing the quality of immune control in-duced via vaccination.

ACKNOWLEDGMENTS

This project was funded, in whole or inpart, by the National Cancer Institute, NationalInstitutes of Health (NIH), contract no.HHSN261200800001E. The content of thispublication does not necessarily reflect theviews or policies of the Department of Healthand Human Services, nor does mention of tradenames, commercial products, or organizationsimply endorsement by the U.S. government.This research was also supported, in part, bythe Intramural Research Program of the NIH,National Cancer Institute, Center for CancerResearch.

REFERENCES

Allen TM, O’Connor DH, Jing P, Dzuris JL, Mothe BR,Vogel TU, Dunphy E, Liebl ME, Emerson C, Wilson N,et al. 2000. Tat-specific cytotoxic T lymphocytes selectfor SIVescape variants during resolution of primary vir-aemia. Nature 407: 386–390.

Alter G, Martin MP, Teigen N, Carr WH, Suscovich TJ,Schneidewind A, Streeck H, Waring M, Meier A, BranderC, et al. 2007a. Differential natural killer cell-mediatedinhibition of HIV-1 replication based on distinct KIR/HLA subtypes. J Exp Med 204: 3027–3036.

Alter G, Teigen N, Ahern R, Streeck H, Meier A, RosenbergES, Altfeld M. 2007b. Evolution of innate and adaptiveeffector cell functions during acute HIV-1 infection.J Infect Dis 195: 1452–1460.

Alter G, Rihn S, Walter K, Nolting A, Martin M, RosenbergES, Miller JS, Carrington M, Altfeld M. 2009. HLA class Isubtype-dependent expansion of KIR3DS1þ andKIR3DL1þ NK cells during acute human immunodefi-ciency virus type 1 infection. J Virol 83: 6798–6805.

Alter G, Heckerman D, Schneidewind A, Fadda L, KadieCM, Carlson JM, Oniangue-Ndza C, Martin M, Li B,Khakoo SI, et al. 2011. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476: 96–100.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA,Breso V, Frassati C, Reviron D, Middleton D, et al. 2006.Human NK cell education by inhibitory receptors forMHC class I. Immunity 25: 331–342.

Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL.2002. Direct recognition of cytomegalovirus by activatingand inhibitory NK cell receptors. Science 296: 1323–1326.

Barber LD, Percival L, Arnett KL, Gumperz JE, Chen L, Par-ham P. 1997. Polymorphism in thea 1 helix of the HLA-Bheavy chain can have an overriding influence on peptide-binding specificity. J Immunol 158: 1660–1669.

Bashirova AA, Martin MP, McVicar DW, Carrington M.2006. The killer immunoglobulin-like receptor gene clus-ter: Tuning the genome for defense. Annu Rev GenomicsHum Genet 7: 277–300.

Beignon AS, McKenna K, Skoberne M, Manches O, DasilvaI, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD,Bhardwaj N. 2005. Endocytosis of HIV-1 activates plas-macytoid dendritic cells via Toll-like receptor-viralRNA interactions. J Clin Invest 115: 3265–3275.

Biron CA. 1999. Initial and innate responses to viral infec-tions—Pattern setting in immunity or disease. CurrOpin Microbiol 2: 374–381.

Boyington JC, Motyka SA, Schuck P, Brooks AG, Sun PD.2000. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand.Nature 405: 537–543.

Brennan J, Mager D, Jefferies W, Takei F. 1994. Expression ofdifferent members of the Ly-49 gene family defines dis-tinct natural killer cell subsets and cell adhesion proper-ties. J Exp Med 180: 2287–2295.

Brodin P, Lakshmikanth T, Johansson S, Karre K, Hoglund P.2009. The strength of inhibitory input during educationquantitatively tunes the functional responsiveness ofindividual natural killer cells. Blood 113: 2434–2441.

Carrington M, Norman P. 2003. The KIR gene cluster. NCBI,Bethesda, MD.

Carrington M, O’Brien SJ. 2003. The influence of HLA gen-otype on AIDS. Annu Rev Med 54: 535–551.

Cella M, Longo A, Ferrara GB, Strominger JL, Colonna M.1994. NK3-specific natural killer cells are selectivelyinhibited by Bw4-positive HLA alleles with isoleucine80. J Exp Med 180: 1235–1242.

Cerboni C, Neri F, Casartelli N, Zingoni A, Cosman D, RossiP, Santoni A, Doria M. 2007. Human immunodeficiencyvirus 1 Nef protein downmodulates the ligands of theactivating receptor NKG2D and inhibits natural killercell-mediated cytotoxicity. J Gen Virol 88: 242–250.

Cerwenka A, Lanier LL. 2001a. Ligands for natural killer cellreceptors: Redundancy or specificity. Immunol Rev 181:158–169.

Cerwenka A, Lanier LL. 2001b. Natural killer cells, virusesand cancer. Nat Rev Immunol 1: 41–49.

Ciccone E, Pende D, Viale O, Di Donato C, Tripodi G,Orengo AM, Guardiola J, Moretta A, Moretta L. 1992.Evidence of a natural killer (NK) cell repertoire for(allo) antigen recognition: Definition of five distinctNK-determined allospecificities in humans. J Exp Med175: 709–718.

Cohen GB, Gandhi RT, Davis DM, Mandelboim O, ChenBK, Strominger JL, Baltimore D. 1999. The selectivedownregulation of class I major histocompatibility com-plex proteins by HIV-1 protects HIV-infected cells fromNK cells. Immunity 10: 661–671.

Correa I, Raulet DH. 1995. Binding of diverse peptides toMHC class I molecules inhibits target cell lysis by acti-vated natural killer cells. Immunity 2: 61–71.

Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C.2004. Innate antiviral responses by means of TLR7-medi-ated recognition of single-stranded RNA. Science 303:1529–1531.

Dorfman JR, Raulet DH. 1996. Major histocompatibilitycomplex genes determine natural killer cell tolerance.Eur J Immunol 26: 151–155.

Dorfman JR, Raulet DH. 1998. Acquisition of Ly49 receptorexpression by developing natural killer cells. J Exp Med187: 609–618.

Fadda L, Borhis G, Ahmed P, Cheent K, Pageon SV, Cazaly A,Stathopoulos S, Middleton D, Mulder A, Claas FH, et al.2010. Peptide antagonism as a mechanism for NK cellactivation. Proc Natl Acad Sci 107: 10160–10165.

Fan QR, Long EO, Wiley DC. 2001. Crystal structure of thehuman natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Nat Immunol 2: 452–460.

Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, WealeM, Zhang K, Gumbs C, Castagna A, Cossarizza A, et al.2007. A whole-genome association study of major deter-minants for host control of HIV-1. Science 317: 944–947.

Fernandez NC, Treiner E, Vance RE, Jamieson AM, LemieuxS, Raulet DH. 2005. A subset of natural killer cellsachieves self-tolerance without expressing inhibitoryreceptors specific for self-MHC molecules. Blood 105:4416–4423.

Gardiner CM, Guethlein LA, Shilling HG, Pando M, CarrWH, Rajalingam R, Vilches C, Parham P. 2001. DifferentNK cell surface phenotypes defined by the DX9 antibodyare due to KIR3DL1 gene polymorphism. J Immunol 166:2992–3001.

Hanke T, Raulet DH. 2001. Cumulative inhibition of NKcells and T cells resulting from engagement of multipleinhibitory Ly49 receptors. J Immunol 166: 3002–3007.

Hanke T, Takizawa H, McMahon CW, Busch DH, PamerEG, Miller JD, Altman JD, Liu Y, Cado D, LemonnierFA, et al. 1999. Direct assessment of MHC class I bindingby seven Ly49 inhibitory NK cell receptors. Immunity 11:67–77.

Hanke T, Takizawa H, Raulet DH. 2001. MHC-dependentshaping of the inhibitory Ly49 receptor repertoire onNK cells: Evidence for a regulated sequential model.Eur J Immunol 31: 3370–3379.

Heil F, Hemmi H, Hochrein H, Ampenberger F, KirschningC, Akira S, Lipford G, Wagner H, Bauer S. 2004.Species-specific recognition of single-stranded RNA viatoll-like receptor 7 and 8. Science 303: 1526–1529.

Held W, Dorfman JR, Wu MF, Raulet DH. 1996. Major his-tocompatibility complex class I-dependent skewing ofthe natural killer cell Ly49 receptor repertoire. Eur JImmunol 26: 2286–2292.

Hsu KC, Liu XR, Selvakumar A, Mickelson E, O’Reilly RJ,Dupont B. 2002. Killer Ig-like receptor haplotype analysis



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



by gene content: Evidence for genomic diversity with aminimum of six basic framework haplotypes, each withmultiple subsets. J Immunol 169: 5118–5129.

Jennes W, Verheyden S, Demanet C, Adje-Toure CA, Vuyl-steke B, Nkengasong JN, Kestens L. 2006. Cutting edge:Resistance to HIV-1 infection among African femalesex workers is associated with inhibitory KIR in the ab-sence of their HLA ligands. J Immunol 177: 6588–6592.

Karre K. 2002. NK cells, MHC class I molecules and themissing self. Scand J Immunol 55: 221–228.

Karre K, Ljunggren HG, Piontek G, Kiessling R. 1986. Selec-tive rejection of H-2-deficient lymphoma variants sug-gests alternative immune defence strategy. Nature 319:675–678.

Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, SongYJ, Yang L, French AR, Sunwoo JB, Lemieux S, HansenTH, et al. 2005. Licensing of natural killer cells by hostmajor histocompatibility complex class I molecules.Nature 436: 709–713.

Kim S, Sunwoo JB, Yang L, Choi T, Song YJ, French AR, Vla-hiotis A, Piccirillo JF, Cella M, Colonna M, et al. 2008.HLA alleles determine differences in human natural killercell responsiveness and potency. Proc Natl Acad Sci 105:3053–3058.

Lanier LL. 1998. NK cell receptors. Annu Rev Immunol 16:359–393.

Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH. 1998.Immunoreceptor DAP12 bearing a tyrosine-based acti-vation motif is involved in activating NK cells. Nature391: 703–707.

Lee SH, Girard S, Macina D, Busa M, Zafer A, Belouchi A,Gros P, Vidal SM. 2001. Susceptibility to mouse cytomeg-alovirus is associated with deletion of an activating natu-ral killer cell receptor of the C-type lectin superfamily.Nat Genet 28: 42–45.

Le Gall S, Erdtmann L, Benichou S, Berlioz-Torrent C, Liu L,Benarous R, Heard JM, Schwartz O. 1998. Nef interactswith the mu subunit of clathrin adaptor complexes andreveals a cryptic sorting signal in MHC I molecules.Immunity 8: 483–495.

Ljunggren HG, Karre K. 1990. In search of the “missingself”: MHC molecules and NK cell recognition. ImmunolToday 11: 237–244.

Ljunggren HG, Van Kaer L, Ploegh HL, Tonegawa S. 1994.Altered natural killer cell repertoire in Tap-1 mutantmice. Proc Natl Acad Sci 91: 6520–6524.

Lodoen MB, Lanier LL. 2005. Viral modulation of NK cellimmunity. Nat Rev Microbiol 3: 59–69.

Long BR, Ndhlovu LC, Oksenberg JR, Lanier LL, Hecht FM,Nixon DF, Barbour JD. 2008. Conferral of enhancednatural killer cell function by KIR3DS1 in early hu-man immunodeficiency virus type 1 infection. J Virol82: 4785–4792.

Maenaka K, Juji T, Nakayama T, Wyer JR, Gao GF, MaenakaT, Zaccai NR, Kikuchi A, Yabe T, Tokunaga K, et al. 1999.Killer cell immunoglobulin receptors and T cell receptorsbind peptide-major histocompatibility complex class Iwith distinct thermodynamic and kinetic properties. JBiol Chem 274: 28329–28334.

Malnati MS, Peruzzi M, Parker KC, Biddison WE, CicconeE, Moretta A, Long EO. 1995. Peptide specificity in the

recognition of MHC class I by natural killer cell clones.Science 267: 1016–1018.

Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ,Buchbinder S, Hoots K, Vlahov D, Trowsdale J, et al.2002. Epistatic interaction between KIR3DS1 andHLA-B delays the progression to AIDS. Nat Genet 31:429–434.

Martin MP, Bashirova A, Traherne J, Trowsdale J, CarringtonM. 2003. Cutting edge: Expansion of the KIR locus byunequal crossing over. J Immunol 171: 2192–2195.

Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F,Colombo S, Brown EE, Shupert WL, Phair J, et al.2007. Innate partnership of HLA-B and KIR3DL1 sub-types against HIV-1. Nat Genet 39: 733–740.

Martinelli E, Cicala C, Van Ryk D, Goode DJ, Macleod K,Arthos J, Fauci AS. 2007. HIV-1 gp120 inhibitsTLR9-mediated activation and IFN-a secretion in plas-macytoid dendritic cells. Proc Natl Acad Sci 104:3396–3401.

Maxwell LD, Wallace A, Middleton D, Curran MD. 2002.A common KIR2DS4 deletion variant in the humanthat predicts a soluble KIR molecule analogous to theKIR1D molecule observed in the rhesus monkey. TissueAntigens 60: 254–258.

Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, KulkarniS, Wen TF, Lindsay RJ, Orellana L, Mildvan D, et al. 2009.Sex differences in the Toll-like receptor-mediatedresponse of plasmacytoid dendritic cells to HIV-1. NatMed 15: 955–959.

Moesta AK, Abi-Rached L, Norman PJ, Parham P. 2009.Chimpanzees use more varied receptors and ligandsthan humans for inhibitory killer cell Ig-like receptorrecognition of the MHC-C1 and MHC-C2 epitopes.J Immunol 182: 3628–3637.

Moesta AK, Graef T, Abi-Rached L, Older Aguilar AM,Guethlein LA, Parham P. 2010. Humans differ from otherhominids in lacking an activating NK cell receptor thatrecognizes the C1 epitope of MHC class I. J Immunol185: 4233–4237.

Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L,Augugliaro R, Barbaresi M, Ciccone E, Moretta L. 1993.P58 molecules as putative receptors for major histocom-patibility complex (MHC) class I molecules in humannatural killer (NK) cells. Anti-p58 antibodies reconstitutelysis of MHC class I-protected cells in NK clones display-ing different specificities. J Exp Med 178: 597–604.

Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L.2002. What is a natural killer cell? Nat Immunol 3: 6–8.

Murphy K, Travers P, Walport M. 2011. Janeway’s immunobi-ology, 8th ed. Garland Science, New York.

Norman PJ, Stephens HA, Verity DH, ChandanayingyongD, Vaughan RW. 2001. Distribution of natural killer cellimmunoglobulin-like receptor sequences in three ethnicgroups. Immunogenetics 52: 195–205.

Pantaleo G, Demarest JF, Schacker T, Vaccarezza M, CohenOJ, Daucher M, Graziosi C, Schnittman SS, Quinn TC,Shaw GM, et al. 1997. The qualitative nature of the pri-mary immune response to HIV infection is a prognosti-cator of disease progression independent of the initiallevel of plasma viremia. Proc Natl Acad Sci 94: 254–258.

Peruzzi M, Parker KC, Long EO, Malnati MS. 1996. Peptidesequence requirements for the recognition of HLA-



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



B�2705 by specific natural killer cells. J Immunol 157:3350–3356.

Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, WalkerBD, Ripke S, Brumme CJ, Pulit SL, Carrington M, et al.2010. The major genetic determinants of HIV-1 controlaffect HLA class I peptide presentation. Science 330:1551–1557.

Rajagopalan S, Long EO. 1997. The direct binding of a p58killer cell inhibitory receptor to human histocompatibil-ity leukocyte antigen (HLA)-Cw4 exhibits peptide selec-tivity. J Exp Med 185: 1523–1528.

Raulet DH. 2003. Roles of the NKG2D immunoreceptor andits ligands. Nat Rev Immunol 3: 781–790.

Raulet DH, Held W, Correa I, Dorfman JR, Wu MF, Corral L.1997. Specificity, tolerance and developmental regulationof natural killer cells defined by expression of class I-specific Ly49 receptors. Immunol Rev 155: 41–52.

Ravet S, Scott-Algara D, Bonnet E, Tran HK, Tran T, NguyenN, Truong LX, Theodorou I, Barre-Sinoussi F, Pancino G,et al. 2007. Distinctive NK-cell receptor repertoiressustain high-level constitutive NK-cell activation inHIV-exposed uninfected individuals. Blood 109: 4296–4305.

Salcedo M, Andersson M, Lemieux S, Van Kaer L, ChambersBJ, Ljunggren HG. 1998. Fine tuning of natural killer cellspecificity and maintenance of self tolerance in MHCclass I-deficient mice. Eur J Immunol 28: 1315–1321.

Schwartz O, Marechal V, Le Gall S, Lemonnier F, Heard JM.1996. Endocytosis of major histocompatibility complexclass I molecules is induced by the HIV-1 Nef protein.Nat Med 2: 338–342.

Shilling HG, Guethlein LA, Cheng NW, Gardiner CM,Rodriguez R, Tyan D, Parham P. 2002. Allelic polymor-phism synergizes with variable gene content to individu-alize human KIR genotype. J Immunol 168: 2307–2315.

Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E,Heitman J, Lebedeva M, DeCamp A, Li D, Grove D,et al. 2009. Induction of a striking systemic cytokinecascade prior to peak viremia in acute human immuno-deficiency virus type 1 infection, in contrast to moremodest and delayed responses in acute hepatitis B andC virus infections. J Virol 83: 3719–3733.

Stewart CA, Laugier-Anfossi F, Vely F, Saulquin X, Riedmul-ler J, Tisserant A, Gauthier L, Romagne F, Ferracci G,Arosa FA, et al. 2005. Recognition of peptide-MHC classI complexes by activating killer immunoglobulin-likereceptors. Proc Natl Acad Sci 102: 13224–13229.

Storkus WJ, Alexander J, Payne JA, Cresswell P, Dawson JR.1989a. The a1/a2 domains of class I HLA moleculesconfer resistance to natural killing. J Immunol 143:3853–3857.

Storkus WJ, Alexander J, Payne JA, Dawson JR, Cresswell P.1989b. Reversal of natural killing susceptibility in targetcells expressing transfected class I HLA genes. Proc NatlAcad Sci 86: 2361–2364.

Thibault S, Fromentin R, Tardif MR, Tremblay MJ. 2009.TLR2 and TLR4 triggering exerts contrasting effectswith regard to HIV-1 infection of human dendritic cellsand subsequent virus transfer to CD4þ T cells. Retrovir-ology 6: 42.

Thomas R, Apps R, Qi Y, Gao X, Male V, O’hUigin C,O’Connor G, Ge D, Fellay J, Martin JN, et al. 2009.HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C. NatGenet 41: 1290–1294.

Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, Lanier LL, Parham P.1997. Human diversity in killer cell inhibitory receptorgenes. Immunity 7: 753–763.

Vales-Gomez M, Reyburn H, Strominger J. 2000. Interactionbetween the human NK receptors and their ligands. CritRev Immunol 20: 223–244.

Valiante NM, Uhrberg M, Shilling HG, Lienert-WeidenbachK, Arnett KL, D’Andrea A, Phillips JH, Lanier LL, Par-ham P. 1997. Functionally and structurally distinct NKcell receptor repertoires in the peripheral blood of twohuman donors. Immunity 7: 739–751.

Vilches C, Parham P. 2002. KIR: Diverse, rapidly evolvingreceptors of innate and adaptive immunity. Annu RevImmunol 20: 217–251.

Vitale M, Sivori S, Pende D, Moretta L, Moretta A. 1995.Coexpression of two functionally independent p58inhibitory receptors in human natural killer cell clonesresults in the inability to kill all normal allogeneic targetcells. Proc Natl Acad Sci 92: 3536–3540.

Wende H, Colonna M, Ziegler A, Volz A. 1999. Organizationof the leukocyte receptor cluster (LRC) on human chro-mosome 19q13.4. Mamm Genome 10: 154–160.

Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D,Beck S, Trowsdale J. 2000. Plasticity in the organizationand sequences of human KIR/ILT gene families. ProcNatl Acad Sci 97: 4778–4783.

Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Chris-tiansen FT. 1999. Population frequencies and putativehaplotypes of the killer cell immunoglobulin-like recep-tor sequences and evidence for recombination. Trans-plantation 68: 1784–1789.

Yawata M, Yawata N, Draghi M, Little AM, Partheniou F,Parham P. 2006. Roles for HLA and KIR polymorphismsin natural killer cell repertoire selection and modulationof effector function. J Exp Med 203: 633–645.

Yokoyama WM. 2002. The search for the missing “missing-self” receptor on natural killer cells. Scand J Immunol 55:233–237.

Yokoyama WM, Kehn PJ, Cohen DI, Shevach EM. 1990.Chromosomal location of the Ly-49 (A1, YE1/48) multi-gene family. Genetic association with the NK 1.1 antigen.J Immunol 145: 2353–2358.

Yu J, Heller G, Chewning J, Kim S, Yokoyama WM, Hsu KC.2007. Hierarchy of the human natural killer cell responseis determined by class and quantity of inhibitory recep-tors for self-HLA-B and HLA-C ligands. J Immunol179: 5977–5989.

Zappacosta F, Borrego F, Brooks AG, Parker KC, Coligan JE.1997. Peptides isolated from HLA-Cw�0304 confer dif-ferent degrees of protection from natural killer cell-mediated lysis. Proc Natl Acad Sci 94: 6313–6318.

Zhang C, Zhang J, Wei H, Tian Z. 2005. Imbalance ofNKG2D and its inhibitory counterparts: How doestumor escape from innate immunity? Int Immunophar-macol 5: 1099–1111.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



March 20, 20122012; doi: 10.1101/cshperspect.a007070 originally published onlineCold Spring Harb Perspect Med

Mary Carrington and Galit Alter Innate Immune Control of HIV

Subject Collection HIV

Viral Populations and Infected CellsHIV Pathogenesis: Dynamics and Genetics of

John Coffin and Ronald Swanstrom

HIV-1 Pathogenesis: The VirusRonald Swanstrom and John Coffin

Human Immunodeficiency Virus Vaccine Trials

Corey, et al.Robert J. O'Connell, Jerome H. Kim, Lawrence

The T-Cell Response to HIVBruce Walker and Andrew McMichael

HIV TransmissionGeorge M. Shaw and Eric Hunter

HIV-1 Reverse TranscriptionWei-Shau Hu and Stephen H. Hughes

Novel Cell and Gene Therapies for HIVJames A. Hoxie and Carl H. June

HIV Pathogenesis: The Host

RodriguezA.A. Lackner, Michael M. Lederman and Benigno

Strategies for HIV PreventionBehavioral and Biomedical Combination

QuinnLinda-Gail Bekker, Chris Beyrer and Thomas C.

HIV: Cell Binding and EntryCraig B. Wilen, John C. Tilton and Robert W. Doms

HIV-1 Assembly, Budding, and MaturationWesley I. Sundquist and Hans-Georg Kräusslich

Innate Immune Control of HIVMary Carrington and Galit Alter

HIV-1 Assembly, Budding, and MaturationWesley I. Sundquist and Hans-Georg Kräusslich

HIV DNA IntegrationRobert Craigie and Frederic D. Bushman

Vaccine Research: From Minefields to MilestonesLessons in Nonhuman Primate Models for AIDS

Jeffrey D. Lifson and Nancy L. Haigwood TreatmentCurrent Issues in Pathogenesis, Diagnosis, and HIV-1-Related Central Nervous System Disease:

Serena Spudich and Francisco González-Scarano

http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

Copyright © 2012 Cold Spring Harbor Laboratory Press; all rights reserved


http://perspectivesinmedicine.cshlp.org/cgi/collection/

http://perspectivesinmedicine.cshlp.org/cgi/collection/


Documents

Innate Immune Control of HIVperspectivesinmedicine.cshlp.org/content/2/7/a007070.full.pdf · the immune system, including NK-cell recogni-tion, suggesting a role for these cells in