role of natural killer cells in hiv pathogenesis

Role of Natural Killer Cells in HIV Pathogenesis

Jeffrey Ward, BS, BA, and Edward Barker, PhD

Corresponding authorJeffrey Ward, BS, BADepartment of Microbiology/Immunology, SUNY Upstate Medical University, 766 Irving Avenue, Weiskotten Hall, Room 2204, Syracuse, NY 13210, USA.E-mail: [email protected]

Current HIV/AIDS Reports 2008, 5:44–50Current Medicine Group LLC ISSN 1548-3568Copyright © 2008 by Current Medicine Group LLC

Although the majority of research on immune cell rec-ognition of HIV-infected cells has focused on CD8+ T cells with an eye towards vaccine development, innate immune recognition by natural killer (NK) cells has become a focus in recent years. Genetic and mecha-nistic data indicate that NK cells play a role during pathogenesis, and research on NK biology in the context of the broader immune response shows that NK cells are required to mount an effective antiviral response. HIV is able to escape cytotoxic T lymphocyte recognition by downmodulation of major histocompatibility complex class I receptors, which should enhance NK cytotoxicity against infected targets. However, the virus has evolved elaborate mechanisms to evade NK cell responses. Moreover, NK cell function as a whole is compromised through poorly understood mechanisms as a result of viremia. Further work on the role of NK cells during all stages of disease will further our understanding of the immune response against HIV.

IntroductionDespite the tremendous amount of knowledge gained about HIV from active research over the past 25 years, HIV infection is still a major international health crisis, with an estimated 40 million people living with the dis-ease in 2005 [1]. As such, much more research is needed to better understand the virus and HIV-related pathology in order to develop effective preventive measures, thera-pies, and vaccines. One avenue of research that has seen a resurgence of interest in recent years surrounds the study of natural killer (NK) cells in HIV disease. The NK cell population was initially identified purely in functional terms as lymphocytes able to kill tumor cells, in vitro,

without prior tumor-cell antigen stimulation as is neces-sary for cytotoxic T lymphocytes (CTLs). This killing event is contact-dependent and a nonphagocytic process. This review summarizes some exciting new findings in NK cell biology over the past decade, which has impacted our understanding of the role NK cells play in host defense against HIV.

NK cells are large granular bone marrow–derived lymphocytes and make up about 10% of total blood lym-phocytes in healthy donors. They can largely be divided into two subsets based on the overall intensity of cell-sur-face expression of neural cell adhesion molecule (CD56). One such population is CD56bright, which make up roughly 10% of blood NK cells and are the predominant popu-lation in lymph nodes (LNs). The other population is CD56dim, which are the major subset in the blood and the minor subset found in LNs of normal, healthy individuals [2]. In addition to phenotypic differences, these two popu-lations differ with respect to their function. CD56bright NK cells tend to be regulatory and less cytotoxic in nature. They can secrete cytokines such as interferon (IFN)- and tumor necrosis factor- . In contrast, CD56dim cells are highly cytotoxic. Although the CD56dim NK cell popula-tion can secrete cytokines, they do so to a lesser extent than the CD56bright NK cells. Upon exposure to the cyto-kines interleukin (IL)-2, IL-12, or IL-15, CD56bright can take on the character of CD56dim and upregulate cytotoxic molecules such as granzymes, as well as the CD16 recep-tor, which allows NK cells to kill antibody-coated target cells in a process known as antibody-dependent, cell-mediated cytotoxicity (ADCC) [3•].

NK cell function is governed by a balance of intracel-lular signals that are received through invariant activating and inhibitory receptors. The activating receptors rec-ognize a wide range of ligands from hematopoietic cell markers to genotoxic stress-induced molecules. Several NK activating receptors have been identified in recent years and can be broken down into the major activat-ing receptors NKp30, NKp44, and NKp46 (or natural cytotoxicity receptors [NCR]) and the stress ligand recog-nition receptor, NKG2D [4]. A series of other molecules have been termed “NK coreceptors” due to their ability to augment activation of NK cells when coupled with stimulation of a major activating receptor [4]. The NK

Role of Natural Killer Cells in HIV Pathogenesis Ward and Barker 45

cell coreceptors identified to date include 2B4, NTB-A, CD2, CRACC, DNAM1, and NKp80.

Inhibitory receptors (iNKRs) recognize mainly major histocompatibility complex (MHC) class I molecules (although non-MHC class I–specific inhibitory receptors have recently been described) and belong either to the immunoglobulin superfamily of receptors or c-type lectin receptors [5]. The immunoglobulin superfamily of recep-tors can be further classified as killer immunoglobulin-like receptors (KIR) or immunoglobulin-like transcripts [5]. iNKR expression on NK cells is variegated and, with the exception of immunoglobulin-like transcripts, is specific for certain HLA class I molecules. KIR2DL1-3 recognizes specific HLA-C alleles, KIR3DL1 recognizes HLA-A and -B molecules belonging to the HLA-Bw4 serotypes, KIR3DL2 recognizes HLA-A3 and -A11, and the heterodimer of NKG2A/B and CD94 recognize the non-classical MHC class I molecule, HLA-E.

The two major NK cell subpopulations not only differ with respect to CD56 surface expression and func-tion but also with respect to expression of the activating receptors and iNKRs. CD56bright are CD94/NKG2A+,KIR-/lo, and CD16-/lo. CD56dim are CD94/NKG2A+/-,KIR+/-, NCR+, and CD16+.

Impact of HIV on NK Cell FunctionEven before the realization that HIV was the causative agent of AIDS, it was recognized that NK cells from AIDS patients with opportunistic infections had decreased ability to lyse the MHC class I–negative K562 cell line compared with NK cells from healthy controls [6]. After looking at acutely and chronically infected patients, Alter et al. [7••] found that total NK cell numbers expand early following infection and then decline to baseline soon afterwards [7••] with a decrease in the CD56 express-ing NK cells accompanying accumulation of a NK cell population lacking CD56 but possessing CD16 and KIRs (CD56-CD16+KIR+) [8]. These CD56-CD16+KIR+ NK cells are highly dysfunctional in terms of cytotoxicity and cytokine secretion following exposure to NK-sensi-tive cell lines. The decreased cytotoxic function of the CD56-CD16+KIR+ NK cells is most likely related to decreased perforin expression [9]. Not only is there a change in NK cell subpopulations associated with HIV infection that is related to loss of function, there are also marked changes in NK cell surface receptor expres-sion. With HIV viremia, there is an overall decrease in surface receptor density of NKp46 and NKp30 found on freshly drawn NK cells, and a dysfunction in NKp44 upregulation upon stimulation in vitro resulting in what has been termed an NCRdull phenotype [10]. Moreover, a concomitant increase in KIR density is also observed [8]. The downmodulation of activating receptors and upregu-lation of iNKRs result in measurable functional defects in NK cell–mediated cytotoxicity regardless of the NK cell

subpopulation [11••]. Although the alteration in activat-ing and inhibitory receptor expression may explain the decrease in NK cell activity during disease progression, there is an opposite effect that occurs with HLA-E–spe-cific receptors with progression to disease. Specifically, during chronic HIV infection, there is a decrease in the expression of NKG2A accompanied by an increase in NKG2C expression [12]. NKG2C, together with CD94, is an activating receptor that recognizes HLA-E [13]. What impact increased NKG2C and decreased NKG2A expression will have on overall ability of NK cells to con-trol HIV is not clear especially because HLA-E is present on HIV-infected T cells. In healthy individuals, surface expression of NKG2C is quite low and is increased dur-ing cytomegalovirus (CMV) infection [14]. Thus, the enhanced NKG2C+ NK cells seen in patients with HIV may also be dependent on CMV [15].

At this time, the overall cause of NK cell dysfunc-tion during HIV infection is poorly understood. HIV infection of NK cells has been described as one cause [16]. However, HIV has not been universally shown to be present in NK cells of viremic individuals with HIV infection [8]. In a few cases where infected NK cells have been found, the percentage of infected cells observed was very low relative to CD4+ T cells. Thus, direct infection of NK cells is not likely to explain the dysfunctional NK cells in infected individuals.

Because NK cell defects improve with highly active antiretroviral therapy (HAART) [8], it is highly likely that the high levels of plasma viremia and the accompanying immune activation are responsible for these defects. The LN is a site of high-level HIV replication and is also a predominant location for human NK cell development [17]. Moreover, direct interactions between NK cells and HIV gp120 have been shown to upregulate genes related to cell-death pathways and may help explain why NK cell function returns as viral loads decrease [18]. Hence, in the LN, where productive infection takes place, there is a possibility that viral gene products would alter the various NK cell populations and their function. Recent studies seem to indicate that CD56bright NK cells leave the LN and mature into the CD56dim subset, with peripheral fibroblasts possibly playing a role in the process [19]. Inter-estingly, a recent report has described increased amounts of IL-2, IL-12 and IL-15, among other cytokines, in the LN of patients with HIV infection [20•]. Increased lev-els of these cytokines would be expected to increase NK cytotoxicity and differentiation of CD56bright into CD56dim

NK cell subsets. To date, the impact of increased cytokine levels together with the effects of viremia has not been studied in the context of NK cell development.

Another role for NK cells in the shaping of the immune response during HIV infection is through the “editing” of immature dendritic cells (DCs) by cytolysis [21]. Activated NK cells, taken from acutely and chronically infected patients, have demonstrated a dysfunction in their ability

46 The Science of HIV Medicine

to lyse monocyte-derived DCs. [22]. A more in-depth study has demonstrated decreased secretion of IL-12 by mature DCs derived from viremic compared with aviremic donors [23••]. A diminished ability of mature DCs from viremic donors to trigger IFN- secretion by autologous NK cells compared with cells from normal controls was also seen. Severe dysfunction in immature DC killing by NK cells from viremic patients, but not aviremic patients, was docu-mented and is tied to diminished TRAIL expression on NK cells [23••]. This decreased cytokine production in vitro is in contrast to what has been found in LN tissue in vivo, and whether this is due to the inflammatory environment or a virus specific defect is currently unclear [20•].

Genetic Evidence for a Role for NK Cells in HIV PathogenesisThere is genetic evidence for a role of NK cells in a longer time to acquisition of AIDS. An early study revealed that homozygosity for HLA-B alleles that contain the Bw4 epi-tope are associated with a longer time to the development of AIDS compared with HLA-B alleles containing the Bw6 epitope [24]. Further studies have shown that posses-sion of the activating KIR3DS1 receptor with Bw4 alleles with isoleucine at position 80 (Bw4-80I) are most protec-tive in terms of lengthening the time from seroconversion to development of AIDS [25]. In the absence of KIR3DS1, Bw4-80I alleles were not protective, and the presence of KIR3DS1 alone was detrimental in this study [25].

The above findings appear to point to Bw4-80I mol-ecules as ligands for KIR3DS1, especially considering that Bw4 alleles with a threonine at position 80 are not protective [25]. However, efforts to stimulate KIR3DS1 expressing cell lines with cells expressing HLA-Bw4alleles have been unsuccessful [26]. In addition, efforts to demonstrate that Bw4-80I is a ligand for KIR3DS1 using tetramers loaded with HIV-derived peptides have also failed, and the KIR3DS1 ligand is still unknown [27]. In contrast to KIR3DS1, KIR3DL1 has been shown to bind to Bw4 containing HLA-A and -B alleles [28]. It has been suggested that the binding of KIRDS1 to Bw4-80I may be dependent upon the presentation of a specific HIV peptide as has been proposed for KIR3DL1/Bw4 interactions. The ability of KIR3DL1 to bind to different HLA-Bw4–con-taining alleles in a peptide-dependent manner using MHC class I tetramers has been implied; however, functional data showing that this is the case are still lacking [28].

The interpretation of the KIR3DS1/HLA–Bw4-80I interaction is complicated by a recent finding that alleles of iNKR KIR3DL1 with higher surface expression corre-lated with an increased time to the development of AIDS and higher CD4+ T-cell counts in the presence of Bw4-80I [29•]. Moreover, a study done in Australia concluded that KIR3DS1 plus Bw4-80I possession showed more rapid progression to AIDS [30]. The fact that possession of multiple KIR3DS1 alleles is detrimental when Bw4-80I

possession is not considered also implies a role for this receptor in disease progression by binding a non-Bw4 ligand; however, without functional studies, further con-clusions are difficult to make.

Because NK cells are part of the innate immune response to HIV, it should be considered if NK cells play an active role in preventing infection. Analysis of exposed, uninfected (EU) populations in Vietnam showed that these individuals had higher NK cell responses in terms of cytotoxicity and cytokine secretion in response to NK-sensitive cell line challenge compared with healthy controls or, most interestingly, HIV-infected donors who were tested both before and after seroconversion [31]. In EU individuals, there was a high KIR3DS1:KIR3DL1 ratio that was associated with downregula-tion of KIR3DL1 transcripts [32]. In addition, elevated KIR2DL3 expansion was associated with EUs. However, there was no correlation with the type of KIR expressed and whether the particular HLA class I molecule would have the capacity to recognize the receptor. This finding was similar to another study of EU female sex workers in Côte d’Ivoire. Here, it was demonstrated that a higher proportion of NK cells that possesses inhibitory KIR genes in the absence of the corresponding MHC class I ligand, such as KIR3DL1 homozygosity in the absence of a Bw4 containing HLA-B allele, could be seen in the EU population compared with seropositives [33•].

The genetic studies correlating protection from AIDS progression with KIR3DS1 and HLA–Bw4-80I described above do not fit in with what is known about the biology of HIV. Specifically, HIV, through the viral product Nef, can efficiently downmodulate HLA-A and -B while leav-ing HLA-C and -E molecules on the cell surface [34]. This allows infected cells to evade HIV antigen-specific CD8+

CTL killing of infected cells expressing HIV peptides in the context of HLA-A and -B [35]. Thus, it seems that HIV modulation of HLA-A and -B may prevent the trig-gering of NK cells through KIR3DS1 even if HLA-Bw4 containing alleles can be demonstrated to bind KIR3DS1. It would appear likely that downmodulation of HLA-A and -B makes HIV-infected cells sensitive to destruction by NK cells due to decreased engagement of iNKR by their cognate ligands. In addition, new information on the development of NK cells that is rapidly becoming available shows that only NK cells expressing iNKR on the cell surface are functionally competent, which seems to indicate that iNKR are required during development for an NK cell to be fully functional [36]. This sets up a situation whereby individuals with HIV infection may have heightened NK responses if iNKR+ NK cells have developed and are relieved of inhibitory signals when HIV downmodulates HLA-A and -B. This scenario is in agreement with the genetic study showing that KIR3DL1 alleles with a higher surface expression correlated with an increased time to the development of AIDS and higher CD4+ T-cell counts in the presence of Bw4-80I [29•]


One other genetic study that is difficult to explain with regards to HIV biology showed that possession of multiple KIR2DS2 alleles results in faster disease progres-sion [30]. KIR2DS2 is an activating KIR that recognizes HLA-C alleles. This situation would appear favorable as HLA-C remains on the infected cell surface. This obser-vation is difficult to reconcile and may indicate that it is more advantageous to have a population of NK cells that are skewed toward KIRs that recognize HLA-A and -B and can be released from inhibition when these ligands are downmodulated by the virus.

As population studies have indicated NK cells as being active in the immune response against HIV, the question of where and how these interactions take place are now being raised. Work in our laboratory has shown that NK cell lysis of autologous in vitro HIV-infected cells is quite low [37], although it can be boosted by blocking the inter-action between HLA-C and -E and their corresponding inhibitory receptors or by selectively removing NK cells that express inhibitory receptors that recognize HLA-C or -E [38,39]. More recent work has confirmed the low level of lysis of unstimulated NK cells in the autologous system and has revealed that activation of NK cells by type I IFNs can enhance NK cell responses against HIV-infected cells [40].

The ability of NK cells to kill HIV-infected cells when relieved of inhibitory stimuli or when exposed to cytokines indicates that NK cell recognition of activating ligands on the infected cell surface takes place. Our recent study [41••] shows that CD4 cells upregulate the NKG2D ligands ULBP 1–3 upon infection with different HIV strains. Moreover, we demonstrate that lysis of autologous HIV infected cells by NKs can be largely abrogated by blocking NKG2D [41••]. This upregulation of an activating stimulus together with

the loss of HLA-A and -B molecules during HIV infection is offset by a downmodulation of at least two NK cell core-ceptor ligands on infected cells, NTB-A, and CD48, which bind to NTB-A and 2B4 on NK cells, respectively (Fig. 1). Therefore, HIV is able to temper the full activating potential of NK cells upon target recognition by not only inducing NKG2D ligands and decreasing HLA-A and -B but also by downmodulating the coreceptors NTB-A and CD48.

Another possible role of NK cells during HIV infection surrounds ADCC responses. ADCC has been well studied at all stages of HIV infection, and correlations between ADCC activity and viral load and CD4 cell count have been found [42]. Very recently, in the macaque model, the ability of a neutralizing antibody to provide protec-tion following simian immunodeficiency virus infection was lost if Fc receptor binding but not complement bind-ing activity was destroyed [43•]. Almost all of the ADCC studies to date use standardized cell lines to better mea-sure responses among individuals, not an autologous system where the impact of Nef-mediated MHC class I modulation can be measured. In fact, we have shown that even with ADCC responses being active against autolo-gous HIV-infected cells, NK-mediated ADCC responses are controlled by the inhibitory ligands HLA-C and -E on the cell surface [39]. Future studies using recombinant antibody-like molecules that cannot only efficiently recog-nize HIV infected cells but hyperactivate NK cells to kill HIV infected cells may show promise in the future [44].

Possible Consequences of NK Cell Dysfunction in HIV InfectionGiven the amount of data that have accumulated regard-ing the role of NK cells in regulating normal immune

NTB-A

CD48

Nef

HIV-infected cells

? ? ?

ULBPs? KIR3DS1

? KIR3DS1KIR3DL1KIR3DL2

NKG2D

NTB-A

NTB-A

NKG2D

CD94/NKG2AKIR2DL1, 2/3

NK cellinhibition

NK cell

2B4

2B4

ULBPs

HLA-C, -E

HLA-A, -B

Figure 1. HIV manipulates natural killer (NK) cell activating and inhibitory ligands to evade NK cell responses. During the course of infection, the HIV viral product Nef selectively downmodulates HLA-A and -B molecules while leaving HLA-C and -E mol-ecules on the cell surface. The lack of HLA-A and -B relieves inhibitory signals only on NK cells that express killer immunoglobulin-like receptors (KIR) specific for these receptors, while NK expressing KIR specific for HLA-C and –E are inhibited. HIV also upregulates ULBP molecules, which are ligands for the NK activating receptor NKG2D; however, the ligands for the NK activating coreceptors NTB-A and 2B4 are downregulated. This sets up a scenario whereby even while inhibitory signals are relieved (HLA-A, -B, and KIR), a full activating stimulus cannot be mounted. The ligand for the activating receptor KIR3DS1 is unknown.


responses, it is tempting to speculate on the role of NK cells in the larger immune response during HIV infection. Studies in a CMV-infected murine model have demon-strated that DC-derived IL-15 is required for proper priming of an NK response to viral pathogens [45]. For an effective CD8 immune response, NK cells are required to “tune” DC-derived IFN- levels by DC editing [46]. The inability to do so in the murine system resulted in high mortality. Given that NK cell numbers and activity increase very early in infection and then decline in the face of an increased CD8 response during HIV infection [7••], it is possible that NK cells are critical not just to mount an early innate response to the virus but also to shape the broader CD8 response. Any dysfunction in this process (ie, warped immature DC killing by dysfunctional NK cells in individuals with HIV infection) may prevent an optimal adaptive immune response.

The incidence of B-cell lymphomas and Kaposi’s sarcoma are both dramatically increased in patients with HIV. NKG2C+ NCRdull NK cells are found at an increased level in patients with late-stage Kaposi’s sarcoma [47], implying that NK cell dysfunction may have a role in tumor development. HAART therapy has diminished the incidence of non-Hodgkin’s lymphoma in patients with AIDS, but T-cell recovery seemed to be more important than NK cell reconstitution in a recent study [48]. However, this study only took NK cell num-bers into account, and we have shown that HAART therapy leads to the recovery of the CD56dim subset and a decrease in the less functional CD56- subset [49]. Long-term studies focused on the role of diminished NK cell function in HIV and, possibly, in HIV-related malignancy are needed.

ConclusionsIt is clear from a large body of work that NK cells do have a role in HIV pathogenesis both early and late during infection and that HIV likewise alters NK cell pheno-type and function. Moreover, HIV alters ligands on the infected cell surface, which changes the capacity to trig-ger NK cells while being able to evade CTLs and increase virion production (Fig. 1). Finding the source of the NK cell dysfunction during viremia and defining the HIV gene products which alter NK cell activation are the current focuses of our research. Uncovering the factors that lead to decreased ability of NK cells to control HIV may allow future treatments to augment innate immune responses in the drive to develop an effective vaccine, as has been proposed [50]. Data from EU cohorts suggest that strong NK cell activity can allow an individual to remain serone-gative despite several exposures, and replicating this with future pharmaceutical agents may prove desirable. For a cell type originally thought to be “null cells,” research has uncovered roles for NK cells in direct cell killing, cyto-kine secretion, and greater tuning of the broader immune

response through DC editing. The next phase of studies should allow the development of therapies that tap into the potential of this versatile cell.

AcknowledgmentsThe authors would like to apologize to all of those whose work could not be cited due to space and refer-ence limitations.

DisclosuresNo potential conflicts of interest relevant to this article were reported.

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role of natural killer cells in hiv pathogenesis

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