Originally published online as doi:10.1189/jlb.0907649 on April 3, 2008
Published online before print April 3, 2008
(Journal of Leukocyte Biology. 2008;84:27-49.)
© 2008
by Society for Leukocyte Biology
Antiviral NK cell responses in HIV infection: II. viral strategies for evasion and lessons for immunotherapy and vaccination
Alexandre Iannello,
Olfa Debbeche,
Suzanne Samarani and
Ali Ahmad1
Laboratory of Innate Immunity, Center of Research Ste Justine Hospital, and Department of Microbiology and Immunology, University of Montreal, Montreal, Quebec, Canada
1Correspondence: Center of Research, Ste Justine Hospital, 3175 Côte Ste-Catherine, Montreal, Qc, H3T 1C5, Canada. E-mail: ali.ahmad{at}recherche-ste-justine.qc.ca
ABSTRACT
As is the case in other viral infections, humans respond to
HIV infection by activating their NK cells. However, the virus
uses several strategies to neutralize and evade the host’s
NK cell responses. Consequently, it is not surprising that NK
cell functions become compromised in HIV-infected individuals
in early stages of the infection. The compromised NK cell functions
also adversely affect several aspects of the host’s antiviral
adaptive immune responses. Researchers have made significant
progress in understanding how HIV counters NK cell responses
of the host. This knowledge has opened new avenues for immunotherapy
and vaccination against this infection. In the first part of
this review article, we gave an overview of our current knowledge
of NK cell biology and discussed how the genes encoding NK cell
receptors and their ligands determine innate genetic resistance/susceptibilty
of humans against HIV infections and AIDS. In this second part,
we discuss NK cell responses, viral strategies to counter these
responses, and finally, their implications for anti-HIV immunotherapy
and vaccination.
Key Words: ADCC • AIDS • CD94/NKG2 • chemokines • cytokines • HIV-1 • HLA • KIR • KIR haplotypes • MHC class I • MICA • MICB • NK cell receptors • NKG2D • ULBP
INTRODUCTION
This is second part of a review article on NK cell responses
in HIV infections. The first part gives an overview of our current
knowledge about NK cell immunobiology, receptors, and their
ligands. The part also describes how polymorphism in the genes
encoding killer-cell Ig-like receptor (KIR) and their HLA ligands
determines innate genetic resistance/susceptibility to HIV infection
and development of AIDS. This second part of the article deals
with functional defects that occur in NK cells in the course
of HIV infection, viral strategies to counter host’s NK
cell responses, and their implications for anti-HIV immunotherapy
and vaccination. We recommend that this article be read in conjunction
with its first part.
NK CELL ACTIVATION IN HIV INFECTION
As mentioned earlier, NK cells are present in the circulation,
bone marrow, lymph nodes, spleen, lung, liver, omentum, etc.,
and can reach almost any place in the body where a viral infection
occurs and induces an inflammatory response. Viral infections
generally activate NK cells, especially in early stages of the
infection. Studies from animal models as well as in individuals
in acute stages of the infection suggest that HIV is no exception
to this rule. The infection also causes activation and expansion
of NK cells. NK cell activation and expansion have been observed
in humans in primary HIV infections and precede the appearance
of virus-specific CTL responses. The expansion usually occurs
in the highly cytotoxic CD56
dimCD16
+ subset of NK cells [
1
].
Increased NK cell activities were also observed in monkeys after
experimental infection with SIV [
2
]. This initial NK cell expansion
and activation probably result from direct and indirect effects
of the infection. Virus-induced cytokines, e.g., type I IFN,
IL-12, IL-15, IL-18, etc., are usually responsible for early
NK cell activation and expansion. Viral proteins and nucleic
acids may bind to TLRs and/or other receptors on a variety of
host cells including NK cells themselves, resulting in their
activation. As mentioned in the first part of this review, to
become functionally competent, TLRs expressed on NK cells seem
to require help from accessory cells [
3
,
4
]. Thus, it is not
surprising that a uridine-rich ssRNA derived from HIV-1 long-terminal
repeat has been shown to activate NK cells but requires the
presence and activation of plasmacytoid DC or CD14
+ monocytes
[
5
]. Activated NK cells activate DC, secrete IFN-
, and act
as adjuvants by killing virus-infected cells and by causing
release of intracellular proteins from the killed cells. NK
cell activation has been shown to be important in inducing an
effective adaptive immune response against intracellular pathogens
in several animal models. In the context of HIV infection, NK
cells may control the infection, not only by killing virus-infected
cells directly as well as indirectly by antibody-dependent,
cell-mediated cytotoxicity (ADCC), but also, they serve as an
important source of β-chemokines (MIP-1
, MIP-1β, and
RANTES) and undefined soluble factors, which can suppress replication
of M- and T-tropic HIV viruses [
6
7
8
]. NK cell-secreted cytokines,
especially IFNs, may induce the antiviral state in host cells
and cure HIV-infected cells via noncytolytic mechanisms.
Many studies have shown that NK cells play an important role in controlling HIV replication. The presence of NK cells suppresses HIV replication in cell cultures [9
10
11
]. It has been demonstrated that i.v. drug users, who are at high risk of contracting HIV infection, resist infection, as long as they have elevated NK cell activities. In this regard, researchers have shown that these uninfected but highly exposed drug users have NK cells, which produce more chemokines and cytokines in vitro with or without simulation and whose KIR repertoire is predominantly of an activating type. They have high ratios of KIR3DS1+/KIR3DL1+ and NK cell group 2C+ (NKG2C+)/NKG2A+ NK cells and coinherit the weakly inhibiting KIR-MHC gene pair (KIR2DL3/HLA-C of group I). They also have low expression of KIR3DL1 and an increased expression of CD107a and CD69 on their NK cells [12
, 13
]. Apart from protecting from HIV infection, high NK cell activities also delay progression of the infection toward AIDS [14
, 15
]. It has been demonstrated that decreases in NK cell cytotoxicity as well as in NK cell counts in the circulation of the infected persons were associated with their rapid CD4+ T cell depletions and rapid progression toward AIDS [14
, 16
]. However, the infected persons who are able to maintain their NK cell functions remain healthy, despite having decreased CD4+ T cell counts [15
]. Animal models of HIV infection also support a role of NK cells in controlling this infection. It has been shown that our closest relatives, chimpanzees (Pan troglydytes), can be infected with HIV-1 and SIVcpz. The viruses replicate in this species but cause no AIDS-like disease. It is noteworthy that NK cells are more abundant in this species than in humans; they remain fully functional throughout the course of infection and unlike humans, can up-regulate certain natural cytotoxicity receptors (NCR; NKp30) in response to the infection. As mentioned above, this receptor plays a role in NK cell–dendritic cell (DC) interactions. Higher NK cell responses in chimpanzees are thought to be a factor in their resistance to progression to an AIDS-like disease [17
, 18
].
Several workers have investigated NK cell responses in HIV-infected humans. An exhaustive list of these studies, along with their major findings, is given in Table 1
. It is quite evident from this table that NK cell functions (cytolytic and secretory) become compromised in HIV-infected persons; depletion of functional NK cell subsets and expansion of nonfunctional NK cells occurs; the infection causes changes in the expression of NKRs and their ligands; HAART tends to normalize changes in the number and functional capabilities of NK cells, but they never become normal. Few studies have been undertaken to translate our current knowledge into ways and means to invigorate NK cells and develop novel, anti-HIV vaccines.
ADCC
NK cells not only can kill virus-infected cells alone, they
can also do so in combination with antibodies for which the
antigen is expressed on the surface of the infected cells. The
process is called ADCC. The antibodies bind through their variable
antigen-binding sites to the viral antigen on the surface of
the virus-infected cells and through their so-called crystallizable
fragments (Fc) to CD16 on NK cells [
63
,
64
]. The antibodies
cross-link CD16 on NK cells and consequently, trigger their
cytolytic functions. This results in killing of the virus-infected
cells and secretion of cytokines and chemokines from NK cells
(
Fig. 1
). The ADCC is a classical example of cooperation between
innate and adaptive immune responses in protecting host from
viral infections and malignancies. CD16 is a type I Ig-like
integral membrane glycoprotein, which is expressed on the surface
of NK cells, monocyte-macrophages, Langerhan’s cells,
DC, etc. It is a low-affinity type III receptor for the Fc part
of IgG (Fc
RIII; CD16). It binds aggregated but not monomeric
human IgG1 and IgG3. The aggregated Ig are present in immune
complexes. NK cells express the CD16A or Fc
RIIIA form of the
receptor. This form associates noncovalently via its transmembrane
region with signaling adaptors (
and/or
chains) and can transmit
signals intracellularly. The receptor plays a predominant role
in NK cell-mediated ADCC. Therefore, it is also commonly referred
to as the "ADCC receptor." Another form of the receptor (CD16B
or Fc
RIIIB) is anchored in the plasma membrane via GPI and cannot
transmit intracellular signals. This form acts as a sink for
antigen/antibody complexes and is expressed on neutrophils and
eosinophils [
64
]. The level of expression of CD16 on the surface
of NK cells correlates with their functional ADCC activity.
CD16 interacts physically with CD38 on the surface of NK cells.
CD38 is a surface glycoprotein with ADP ribosyl cyclase/cyclic
ADP-ribose hydrolase activities. It regulates cytoplasmic calcium
and also acts as a receptor modulating cell–cell interactions.
It binds CD31 (PECAM-1), which is a transmembrane Ig-like glycoprotein
expressed on human vascular endothelial cells, and plays a role
in angiogenesis, cell adhesion, and diapedesis. When cross-linked,
CD38 transmits activating signals to NK cells via CD16 [
65
].
Interestingly, cells may shed CD16 upon activation, and cleaved
sCD16 interferes with the ADCC process. Increased concentrations
of sCD16 have been reported in the sera of HIV-infected persons,
which correlate with disease progression. Interestingly, sCD16
seems to be shed from non-NK cells in these patients [
66
].
In addition to CD16, NK cells express an activating version
of the Fc
RIIC (CD32C), which also takes part in ADCC [
67
].
However, only 40–45% humans express this receptor on their
NK cells. It is noteworthy that CD32 is encoded by three diferent
genes:
CD32A,
-B, and
-C. CD32A is an activating receptor expressed
on neutrophils, monocytes, and DC. CD32B is an inhibitory receptor
expressed on DC, monocytes, neutrophils, and B cells. An allelic
variant of CD32A expresses arginine at position 131 (R131) instead
of histidine (H131). The R131 variant responds vigorously to
IgG and has been implicated in the development of systemic lupus
erythrematosus (for details, see ref. [
67
]).
The major FcR involved in ADCC may be mutated and nonfunctional in some individuals. This happens as a result of a deletion of a single base (adenine) in exon 4 at nucleotide 550, resulting in a premature stop codon and truncated protein [68
, 69
]. Another mutation has been described that results in polymorphism at position 158 in the amino-acid sequence. The amino acid at this position could be valine (V) or phenylalanine (F). The V allotype has higher affinity with IgG than the F one. The individuals with the V/V genotype are more efficient in mediating ADCC [70
]. Few studies have investigated the impact of these mutations on the clinical course of HIV infection. In this regard, one group of researchers has demonstrated that HIV-infected persons bearing the FcRII RR genotype progress more rapidly toward AIDS than those bearing HH or HR genotypes [71
].
The ADCC-mediated destruction of tumor cells as well as of virus-infected cells can be readily demonstrated in vitro in the presence of NK cells and tumor or virus-specific antibodies of the appropriate IgG isotypes. The process also occurs in vivo. Although macrophages and neutrophils can also mediate ADCC, NK cells are the main cell type that mediates this process. Their depletion, therefore, abrogates the ADCC-mediating ability of PBMC [64
].
ADCC IN HIV INFECTION
NK cells may eliminate HIV-infected cells in combination with
HIV-specific antibodies via ADCC. The destruction of HIV-infected
cells can be readily demonstrated in in vitro ADCC reactions
in which HIV-infected cells are incubated with NK cells in the
presence of HIV-specific antibodies. The phenomenon has been
demonstrated to occur in vivo in these infections [
26
]. The
antibodies specific to the viral envelope protein gp120/41 have
been shown to mediate ADCC against the virus-infected cells.
A prerequisite of the ADCC against HIV-infected cells is that
the virus must be replicating in the cells, and the viral envelope
proteins must be expressed on the surface of these cells. Anti-HIV,
ADCC-mediating antibodies have been demonstrated in the sera
of HIV-infected persons in several studies [
9
,
33
,
63
].
Although HIV-specific ADCC eliminates HIV-infected cells, it also has the potential to contribute to AIDS pathogenesis (Fig. 1)
. In in vitro experiments, uninfected CD4+ T cells may bind exogenous recombinant gp120 and be killed by NK cells in the presence of gp120-specific antibodies of the IgG isotype [72
, 73
]. Furthermore, anti-gp120 antibodies may complex with the virus and facilitate uptake of the virus by monocytes. They may also cause NK cell activation and hence, excessive production of chemokines and cytokines. In fact, a group has demonstrated a correlation between the presence of HIV-specific ADCC antibodies and the development of AIDS [74
]. However, these studies have not been corroborated. On the other hand, several researchers have demonstrated that these antibodies correlate with better clinical condition and better prognosis in HIV-infected children and adults [63
, 75
76
77
]. The protective nature of anti-HIV ADCC antibodies could also be demonstrated in in vitro experiments in which HIV-specific antibodies or NK cells alone are not able to inhibit replication of primary isolates of HIV-1 in human PBMC. However, they do so efficiently via ADCC when added together to these cultures [9
]. Studies in animal models of HIV infection have also shown a protective effect of ADCC against disease progression [78
]. Many researchers regard anti-HIV ADCC as a reliable correlate of immune protection from HIV infection [17
, 63
]. However, it remains to be tested in HIV vaccination studies. It has been demonstrated that vaccines may elicit ADCC antibodies, which could inhibit replication of clinical strains of HIV in the presence of NK cells [9
].
Although anti-HIV ADCC antibodies can be demonstrated in HIV-infected individuals, even in late stages of the infection, the full host beneficial potential of this ADCC cannot be realized in vivo, as NK cell functions become compromised in a majority of these individuals [14
, 27
, 79
, 80
]. The decreased ADCC effector function of NK cells in HIV-infected persons could be a result of several reasons: decreased number of CD16+ NK cells, decreased expression of the signaling partner chain in NK cells, and overall decreased cytolytic capacity of NK cells (see Table 1
). It is noteworthy that the engagement of CD16 alone cannot mediate killing of the target cells. For this purpose, it needs simultaneous engagement of LFA-1 or 2B4 (reviewed in ref. [81
]). The receptor activities may be neutralized by increased concentrations of ICAMs and sCD16 in the circulation of HIV-infected patients [66
, 82
]. Interestingly, these concentrations increase with disease progression and serve as prognostic markers. Increased expression of HLA-C and -E on the surface of HIV-infected T cell blasts also interferes with their killing by autologous NK cells via ADCC. The blockage of interactions between KIR and HLA-C and between NKG2A and HLA-E with specific antibodies enhances this immune effector mechanism against this virus [83
].
Attempts to control HIV replication in HIV-infected patients via passive immunotherapy (infusion of anti-HIV antibodies or i.v. Igs) have not yielded desired results. Passively infused i.v. Igs are known to have immunosuppressive effects (reviewed in ref. [84
]). The infused antibodies form multimeric IgG complexes on DC. Such DC are killed by NK cells via ADCC or become defective for their ability to activate NK cells and to prime T cells. They decrease the expression of NKp30 and KIR on interacting NK cells [85
]. Therefore, they may aggravate the defects, which already exist in an NK cell compartment in HIV-infected patients. HIV-1 has developed myriad strategies to evade a neutralizing antibody response of the host, e.g., mutation of epitopes, masking of epitopes by glycosylation and trimerization of gp120/41 spikes, shedding of envelope proteins, etc. (reviewed in ref. [86
]). Nevertheless, the infusion of a combination of HIV-specific neutralizing antibodies does provide protection from infection in the animal models. However, it has been demonstrated that the antibodies require binding to FcR for full efficacy [87
, 88
]. These results highlight a beneficial role of ADCC for the host. FcR can also mediate uptake of antibody-coated viruses by monocytes and macrophages. The potentials and limitations of the i.v. use of neutralizing antibodies in HIV-infected patients have been demonstrated by the results of a small trial, in which a combination of HIV-neutralizing antibodies was infused into HIV-infected persons. Their HAART treatment was stopped 1 day after the infusion, and HIV rebound was measured [89
, 90
]. The virus rebound was delayed in acutely infected persons. However, this delay in the virus rebound was seen only in two of the chronically infected persons. Escape mutants also appeared for one of the three antibodies in the rebound viruses.
As mentioned above, the CD16+ NK cell subset is mainly involved in mediating ADCC. NK cell therapy with or without anti-gp120/41 antibodies may be more effective in restoring ADCC and controlling HIV replication in HIV-infected patients. Finally, several cytokines are known to increase ADCC against HIV-infected cells (reviewed in ref. [80
]).
HIV STRATEGIES TO EVADE NK CELL RESPONSES OF THE HOST
Viruses generally use multiple strategies to counter NK cell
responses of the host. HIV is no exception. The strategies aimed
at evading antiviral effects of the host’s NK cell responses
are listed in
Table 2
and are discussed below.
Changing the expression of MHC and non-MHC ligands for NKRs
The down-regulation of MHC class I antigens on the surface of
infected cells is a common strategy used by a variety of viruses
to evade antiviral CTL responses of the host, as CTL recognize
viral peptides in association with these antigens (reviewed
in refs. [
91
92
93
]). A global decrease in the expression of
MHC antigens, however, makes virus-infected cells susceptible
to NK cell-mediated killing. Therefore, viruses have developed
various strategies to evade this NK cell-mediated killing. Two
HIV proteins have been shown to affect expression of MHC class
I antigens: Tat represses promoters of the MHC class I and the
β-2 microglobulin genes, and viral protein U (Vpu) interferes
with an early step in the biosynthesis of MHC antigens [
94
,
95
]. However, a global down-regulation of MHC class I antigens
has rarely been observed in HIV-infected cells. Instead, several
studies have documented that HIV differentially down-regulates
the expression of MHC class I antigens on the surface of the
infected cells. The viral protein Nef recognizes certain motifs
present in the cytoplasmic tails of MHC class I antigens and
causes their degradation. These motifs are present mostly in
the cytoplasmic tails of HLA-A and -B but not of HLA-C and HLA-E
antigens. Consequently, the expression of HLA-A and -B but not
of HLA-C and -E is decreased on the surface of HIV-infected
cells [
96
97
98
]. It is noteworthy that HLA-A and -B predominantly
present viral peptides to CTL. Of these, only Bw4-serospecific
HLA-A and HLA-B allotypes act as ligands for KIR3DL1. On the
other hand, HLA-C and HLA-E present relatively fewer HIV-derived.
immunodominant peptides to CTL. Nevertheless, all known HLA-C
and HLA-E allotypes act as ligands for KIR and CD94/NKG2, respectively.
From the perspective of NK cell functions, HLA-C and HLA-E are
more important. The maintenance of these HLA molecules on the
surface of HIV-infected cells protects them from NK cell-mediated
lysis. A decreased expression of HLA-A and -B makes them invisible
to most of the virus-specific CTL. However, it comes with some
price. The infected cells become susceptible to killing by the
NK cells expressing HLA-Bw4-specific KIR. By a differential
modulation of HLA antigens on the surface of infected cells,
virus evades most if not all CTL and NK cell-mediated killing.
Indeed. autologous NK cells do not kill HIV-infected T cell
blasts despite decreased HLA-A and -B antigens on their surface
[
99
].
In addition to classical MHC class I antigens, HIV modulates expression of nonclassical MHC antigens. The infection increases the expression of HLA-E on the surface of CD4+ T cells in in vitro experiments [55
]. At least one potential mechanism of this increase is a peptide from the viral protein p24 (residues 14–22), which can bind and stabilize HLA-E on the surface of HIV-infected cells [100
]. In line with these results, increased expression of HLA-E has been reported on the surface of CD4+ T cells in HIV-infected persons. The increase was more pronounced in advanced stages of the infection and correlated with peaks in viremia [55
].
Conflicting results have been reported concerning the effect of HIV infection on the expression of HLA-G. The infection was reported to cause down-regulation of HLA-G on the surface of HIV-infected cells in a Vpu-dependent manner [96
, 101
]. However, the molecule is expressed on monocytes and T lymphocytes in HIV-infected persons, probably as a result of HAART and increased concentrations of IL-10 in the circulation [102
, 103
]. HLA-G is normally expressed on certain immune-privileged sites, e.g., cornea, and on invading cytotrophoblasts in pregnancy and is believed to protect a developing fetus from the mother’s immune responses (reviewed in ref. [104
]). Increased expressions of HLA-E and -G on the surface of HIV-infected cells would increase their resistance to NK cell-mediated killing as well as to macrophage activation.
Although exact ligands for NCR are not known, Vieillard et al. [105
] have reported increased expression of NKp44 binding to HIV-infected CD4+ T cells. They have shown that a peptide (SWSNKS) derived from the transmembrane unit (gp41) of a viral envelope protein induces the unknown NKp44 ligand on CD4+ T cells. It also suggests that the unknown ligand for this receptor could be a peptide-binding MHC or MHC-like molecule. The induction of NKp44 ligand on the HIV-infected cells may promote their killing by cytokine-activated NK cells. The increased expression of NKp44 ligands on the surface of HIV-infected cells has been corroborated by Ward et al. [83
], who also reported increased expression of MHC class I chain-related protein A (MICA), MICB, and the human CMV (HCMV) glycoprotein UL16-binding protein 1 (ULBP-1), 2, and 3 on T cell blasts infected with HIV. They also reported a decrease in the expression of CD48 and NK-T-B antigen, and no change was observed in the expression of NKp30 and NKp46 ligands. As mentioned earlier, MICA, MICB, and ULBPs serve as ligands for NKG2D, which is an activating receptor expressed on all NK and CD8+ T cells in humans. It is not in the interest of a virus to induce expression of these ligands on the surface of infected cells, as the virus-infected cells would be killed by NK cells as well as by CD8+ T cells via NKG2D. Therefore, viruses have developed different strategies to evade this NKG2D-mediated killing. For example, HCMV encodes a glycoprotein UL-16, which can bind ULBPs intracellularly and prevent them from reaching cell surface and interacting with NKG2D [106
]. Another protein from this virus, UL142, binds MICA and prevents its interaction with NKG2D [107
]. Tumors may cleave and shed soluble MICA and MICB to interfere with NKG2D-mediated killing of tumor cells [108
, 109
]. HIV uses its Nef protein to evade NKG2D-mediated killing. The protein, in addition to down-regulating the expression of HLA-A, -B and CD1d, also binds to and degrades MICA, and ULBP-1 and -2 [110
].
It is noteworthy that NKG2DL are usually induced in human cells upon genotoxic stress, which activates DNA damage response (reviewed in ref. [111
]). The response arrests cell cycle until the damage is repaired. If the damage is not repairable, the response induces apoptosis in the cells. The response is initiated by two PI-3K-like kinases: ataxia telangiectasia mutated (ATM) and ATM and RAD-3-related (ATR). The two kinases are activated by dsDNA and ssDNA breaks, respectively. Stalled replication forks also activate ATR. The induction of NKG2DL by HIV implies that the infection causes genotoxic stress in the infected cells. It could be an unintended consequence of the functional activities of the viral protein R (Vpr). The protein is known to induce cell-cycle arrest by recruiting DCAF-1/VprBP and an E3 ligase Cul4-DDB1 in eukaryotic cells and activates ATM and ATR, which may result in the induction of NKG2DL [112
]. Figure 2
summarizes HIV-induced changes in the expression of MHC ligands in HIV-infected persons.
Changing the expression of NKRs
Viruses may evade NK cell-mediated killing by increasing the
expression of inhibitory and/or by decreasing the expression
of activating receptors on the surface of NK cells of the infected
host. There is sufficient evidence to suggest that HIV uses
this strategy to counter antiviral NK cell responses of the
host. Several workers have documented an increase in the expression
of inhibitory receptors (e.g., iKIR) and a decrease in the expression
of activating receptors (e.g., NCR) in HIV-infected individuals.
Interestingly, these dichotomous effects on inhibitory and activating
NKRs were mainly observed in viremic patients and correlated
with viral load. Only a transient decrease was observed in the
expression of 2B4, whereas no effect was observed on the expression
of NKG2D on NK cells from HIV-infected persons. These changes
in receptor expression were often accompanied with decreased
cytolytic activities of NK cells [
1
,
16
,
49
,
51
] (reviewed
in ref. [
113
]). The occurrence of these changes in viremic
patients as well as their correlation with viremia suggest that
the virus might have caused the receptor modulations. This is
further supported by the fact that a stabilizing effect of the
HAART treatment on the receptor expression was observed. However,
the treatment was able to restore the expression to normalcy
after a long period of administration, when it resulted in undetectable
viral loads in the patients [
51
,
56
]. In addition to direct
effects of the virus, chronic activation of the immune system
via antigens from HIV-1 and/or from other coinfecting pathogens
may have caused perturbations in the expression of NKR. Repeated
antigenic stimulations are known to induce expression of several
inhibitory receptors including KIR on immune cells [
114
].
With respect to the NKG2/CD94 family receptors, an expansion of CD94/NKG2C+ and a marked depletion of CD94/NKG2A+ NK cells have been described in the peripheral blood of HIV-infected persons [53
]. HAART did not reverse these changes despite reducing viremia to undetectable levels in these patients. These changes are also not observed in the individuals infected with HIV alone. It is noteworthy that similar changes in the expression of the CD94/NKG2 family of receptors have been reported in humans suffering from chronic infections with HCMV. It seems more likely that HCMV infection may be the real cause in driving these changes in HIV- and HCMV-coinfected patients. Indeed, HCMV-infected fibroblasts cause proliferation of NKG2C+ human NK (HNK) cells in in vitro studies. However, the changes seem to be more pronounced in the coinfected individuals [53
, 115
, 116
]. These observations suggest a possible role of HIV infection in these NKR perturbations. It may be relevant to mention here that NKG2A is an inhibitory and NKG2C is an activating NKR. Both of them bind to HLA-E on target cells and regulate NK cell functions. The two receptors usually occur on the CD56highCD16low subset of NK cells, which express low levels of KIR. It is believed that NKG2A may be important in maintaining self-tolerance in NK cells that do not express self-reactive KIR. It is noteworthy that a HCMV-encoded protein UL40 provides a peptide, which binds and stabilizes HLA-E. The HLA-E is also stabilized by a peptide derived from the HIV p24 protein [100
, 117
]. An increased expression of HLA-E on CD4+ T cells in HIV-infected individuals has also been described [55
]. The enhanced HLA-E expression may have caused proliferation of NKG2C+ and/or an early depletion of NKG2A+ NK cells. It is not clear how these receptor changes could affect progression of HIV infection. The fact that persons coinfected with HIV and HCMV progress more rapidly toward AIDS [118
] suggests that NKG2C+ NK cells may be involved in immunopathology. We speculate that these CD56+NKG2C+ NK cells may kill many different types of cells including mature DC and CD4+ T cells, which express HLA-E [100
, 117
,119]. However, it must be emphasized that there is no direct experimental evidence at this point in time to support this notion. The modulation of NKRs by HCMV provides an example of how this herpesvirus may affect the natural course of HIV infection in coinfected individuals.
NKp44 is an activating receptor, which is not expressed on resting NK cells. The receptor is induced on cytokine-activated NK cells. A group of researchers has shown that freshly isolated NK cells from HIV-infected viremic persons are aberrantly activated: They are CD69+, HLA-DR+ but do not express NKp44. Furthermore, they express relatively low levels of other NCR [52
].
As mentioned above, HIV or its products have been implicated in the induction of changes in the expression of NKRs in HIV-infected patients. It is noteworthy that the infection causes a dysregulated production of many cytokines in the human body. It is not surprising that these cytokines have been implicated in this process. Two groups of researchers have suggested the involvement of IL-10. This immunosuppressive cytokine induces changes in the expression of NKRs in vitro similar to those seen in HIV-infected patients in vivo, i.e., increased expression of CD94, CD161, and CD158a or KIR2DL1 [41
, 48
]. It is noteworthy that concentrations of IL-10 are increased in the circulation of HIV-infected persons. The changes observed in the expression of NKRs in HIV-infected persons are summarized in Figure 2
.
Changing the expression of NKRs on non-NK cells
Many NKRs are also expressed on non-NK cells. CD56 is usually expressed on activated CD8+ T lymphocytes. Its expression has been associated with the acquisition of cytotoxic functions in these cells [120
]. A decrease in the expression of CD56 has been described on NK and CD8+ T cells in HIV-infected persons. Indeed, CD56+ NK and CD8+ T cell populations from HIV-infected persons express less perforin and are less cytolytic compared with their counterparts from HIV-seronegative, healthy subjects [10
, 58
, 121
].
Normally, monocytes do not express CD16; they do so upon activation. TGF-β1 has been shown to induce its expression on monocytes in humans. Monocytes from HIV-infected AIDS patients express this marker, and this expression correlates with increased concentrations of this cytokine in the circulation of these patients [122
]. This expression has implications for virus replication, as CD16+ monocytes are highly permissive to HIV replication [123
]. Furthermore, these cells may shed sCD16, which may interfere with killing HIV-infected cells via ADCC.
CD57 (Leu-7; HNK-1) is a 110-kD glycoprotein expressed on a subset of NK, CD8+, and CD4+ T cells, which plays a role in homotypic cell adhesion. It bears a sulfated carbohydrate epitope (glycotope), which is also present on several other glycoproteins and glycolipids expressed on the surface of different cell types. The epitope is regulated by two glucuronyltransferases (-P and -S) and a sulfotransferase (HNK-1; see ref. [124
] for a review). In the immune system, CD57 is expressed on terminally differentiated effector cells. These cells can neither proliferate nor circulate; however, they do migrate to nonlymphoid tissues and secrete cytokines. In the case of CD8+ T cells, CD57 expression is restricted to effector/memory phenotype. The marker is also expressed on aberrantly differentiated and clonally exhausted effector cells. Increased numbers of CD57-expressing NK and CD8+ T cells occur in chronic viral infections including that of HIV [16
, 124
]. Repeated antigenic stimulation may lead to clonal exhaustion and increased CD57 expression in HIV-infected persons. Furthermore, aberrant differentiation of these cells as a result of a lack of CD4 help and/or dysregulated production of cytokines such as IL-2, IL-7, IL-15, IL-21, IL-10, etc., may also lead to an increased number of CD57+ cells in this infection. Increased numbers of CD57+ T and NK cells represent immune dysfunction.
In the course of normal differentiation into terminally differentiated effector cells, CD8+ T cells acquire CD57 and lose CD27. However, in the case of HIV infection, they acquire relatively low levels of CD57 (compared with HCMV and EBV-specific effector CTL) and do not lose CD27 expression [125
]. This suggests that HIV-specific CTL undergo aberrant and incomplete course of differentiation. This defective differentiation of HIV-specific CTL is further supported by their decreased expression of perforin, lower cytotoxicity, and increased expression of the inhibitory marker programmed death (PD)-1 and other phenotypic markers [126
, 127
]. It has also been proposed that in HIV infection, NK cells and CTL undergo premature senescence without undergoing complete physiological differentiation. This premature senescence has been proposed as the main reason of inability of HIV-infected persons to control the virus [128
].
A subset of CTL has been shown to express KIR, NKG2/CD94, killer lectin-like receptor (KLR)-G1, and ILT-2. These markers are usually expressed at distinct stages in the course of development and differentiation of naïve CTL into effector/memory cells. For example, KLR-G1+ CD57+ CTL represent terminally differentiated effector CTL, and KLRG1+CD57– CTL represent long-lived memory CTL [129
]. Developing T cells acquire these markers after completion of their TCR gene rearrangements. Therefore, CTL with similar TCRVβ genes may have different repertoires of KIR, NKG2, and KLR-G1 receptors [130
]. The level of expression of these receptors on CTL determines their antigenic threshold for activation and is "fine-tuned" to avoid autoimmunity and to mount an effective immune response against invading pathogens [131
, 132
]. The expression of KIR in humans (and of Ly49 in mice) seems to confer survival advantage in CTL and prevents them from undergoing activation-induced cell death in response to TCR stimulation. KIR+ CTL express higher levels of the antiapoptotic protein Bcl-2 as compared with the ILT-2+ CTL [133
134
135
136
]. It appears that KIRs are expressed on long-lived memory T cells having monoclonal or oligoclonal expression of TCRVβ genes. ILT-2, on the other hand, are expressed earlier than KIR in the course of differentiation of CTL. Consequently, they are expressed on a larger percentage of antigen-specific CTL with a broader use of TCRVβ genes. Interestingly, ILT-2+ but not KIR+, HIV-specific CTL could be easily detected in HIV-infected AIDS patients, which again suggests their defective differentiation. KIR+ CTL express perforin and secrete IFN-, whereas ILT-2+ CTL can only secrete cytokines and contain little perforin [133
]. Expansions of CD8+T cells expressing these receptors usually occur in viral infections, which subside upon resolution of the infection. However, increased frequencies of the cells bearing these receptors persist in chronic infections [137
138
139
140
]. The expression of inhibitory NKRs on CTL may be essential for the development of virus-specific memory responses. This expression raises the activation threshold of CTL and prevents indiscriminate killing of host cells but still allows killing of virus-infected cells. However, coengagement of inhibitory receptors inhibits TCR-mediated activation of CTL [141
]. It has also been observed in in vitro studies that a blockage of KIR markedly increases CTL-mediated killing of HIV-infected, autologous cells [40
]. In mice, which do not have KIR genes but express their functional orthologs (LY49 genes) on their NK cells and a subset of CTL, it was also demonstrated that blockage of LY49 receptors increases anti-tumor activities of NK cells resulting in tumor regression [142
, 143
]. Interestingly iKIR, CD94/NKG2, and KLR-G1 could also be detected but sparsely on CD4+ T cells in human peripheral blood. Percentage of these cells increases with age.
It is noteworthy that many of the observations concerning the expression of inhibitory receptors on CD8+ T cells have been verified in vivo in mice infected with chronic lymphochoriomenengitis virus infection [144
].
It has been well documented that HIV infection induces a vigorous antiviral CTL response in the host (reviewed in ref. [145
]). The frequency of virus-specific CTL in the circulation of HIV-infected persons is usually higher as compared with that seen in several other viral infections. Consequently, HIV-specific CTL can be readily demonstrated in the peripheral blood of HIV-infected individuals without prior stimulation and expansion. Despite this, cellular immune response is unable to control HIV infection in humans. There could be several reasons for the inability of the antiviral CTL responses to clear HIV infections: high mutability of HIV-1, depletion of CD4+ T cells and consequent loss of CD4 help, incomplete differentiation of CTL, increased expression of proapoptotic molecule PD-1, impaired proliferative capacity of HIV-specific CTL, decreased expression of CD3 on CTL, etc. (reviewed in refs. [145
146
147
]). An increased expression of inhibitory NKR on these cells may also play a role in the ultimate failure of this antiviral immune response in controlling HIV infection in humans. This is supported by the facts that long-term, nonprogressors do not express increased levels of these receptors on their CD3+CD8+ peripheral blood cells, and in vitro blocking of these receptors causes increased killing of the CTL against autologous, HIV-infected cells [45
, 148
].
Disturbing NK cell interactions with other immunocytes
As mentioned earlier, NK cells interact intimately with DC. These interactions have important implications for the ensuing innate and adaptive immune responses against viral infections and malignancy. During these interactions, the two types of cells form an immune synapse with each other. NK cells induce polarized secretion of IL-12, IL-18, and membrane-bound IL-15 from DC. The polarized secretion from DC requires tubulin rearrangement and activation of calcium-calmodulin-dependent kinase II (CAMK-II) [149
, 150
]. These cytokines activate NK cells, which in return, secrete IFN-, TNF-, and high mobility group box-1 (HMGB1), which cause DC maturation [151
, 152
] (reviewed in ref. [153
]). It is noteworthy that HMGB1 is the most potent proinflammatory cytokine that causes DC maturation. The DC-maturing capacity of different NK cell clones depends on their ability to secrete this cytokine [154
, 155
]. The physical contact between the two cell types involves interactions among several receptor-ligand pairs, which include LFA-1, NKp30, NKp46, 2B4, DNAX accessory molecule 1 (DNAM-1), NKG2D, TNFRII, and NKG2A [150
, 156
, 157
]. NK cells also perform the task of quality control and kill immature DC if they do not undergo proper maturation. It has been demonstrated that NKp30, DNAM-1, and LFA-1 are involved in the NK cell-mediated killing of autologous, immature DC [158
]. Mature DC are not killed, as the maturation process induces expression of HLA antigens, which protect them from NK cells. It is noteworthy that it is the CD56highCD16dim NK cells that interact with and cause maturation or killing of immature DC. These NK cells express little KIR and express CD94/NKG2A as the main inhibitory receptors. It is not yet fully understood how NK cells choose between killing and causing maturation of immature DC. It probably depends on the profile of expression of several molecules on the surface of immature DC. If DC fail to express HLA antigens upon maturation, they may be killed by NK cells. The NK cell-activating potential of DC also depends on the milieu in which they differentiate. For example, immature DC, differentiated in the presence of IL-4, selectively activate NK cells but not T cells. IL-4 induces the expression of triggering receptor expressed on macrophage-2 on DC [159
, 160
]. The ratio between NK cells and their interacting DC is also a factor: A greater ratio tends to favor the killing rather than maturation.
After maturation, DCs express CCR7 and migrate to secondary lymph organs, e.g., lymph nodes, where they interact with T cells as well as with activated NK cells, which control and determine T cell-priming capabilities of DC. The DC generated from monocytes in the absence of NK cells are unable to prime CD8+ T cells. The NK/DC interactions may allow DC to prime T cells without help from CD4+ T cells. The speculation is that NK cells may themselves provide this help. As mentioned earlier, properly activated NK cells express molecules that may enable them to interact with T cells. The cross-talk also involved cell–cell contact via CD161/Clr-b, 2B4/CD48, DNAM-1/Poliovirus receptor, NKG2D/NKG2DL, as well as soluble mediators, e.g., TNF-, IFN-, IL-12, and others [161
162
163
].
Depending on these interactions, DC may emerge that could prime naïve CD4+ T cells into TH1-type cells. The interactions may also lead to the generation of DC, which may favor the generation of immunosupressive regulatory T cells (Tregs).
As a result of the importance of NK/DC interactions in mediating effective antiviral immunity, viruses may target these interactions for immune evasion. For example, it has been shown that monocyte-derived DC (MDDC) from hepatitis C virus (HCV)-infected persons and their autologous NK cells fail to induce reciprocal activation. This failure results from the inability of these MDDC to express MICA and MICB in response to IFN-. The MDDC generated from the infected persons produce more IL-10 and TGF-β [164
, 165
], and TGF-β promotes induction of IL-10-secreting Tregs by inducing forkhead box P3 (FoxP3) expression in CD4+ precursor cells [166
].
The NK/DC interactions also become aberrant in HIV-infected persons. The NK cell-editing function seems to be lost in HIV-infected persons. Activated NK cells from viremic persons are unable to kill autologous, immature MDDC [51
, 167
, 168
]. This defect was more profound in the CD56–CD16+ NK cell subset, as it could not be overcome even after masking NK cell inhibitory receptors. The mature DC from HIV-infected persons produced less IL-12 and could not activate interacting NK cells. Consequently, these NK cells produce less IFN-. Defective NKp30- and TRAIL-mediated killing was blamed on the escape of the immature DC from NK cell-mediated killing in HIV-infected persons [167
]. Aberrant NK cell/DC interactions may result from overall defective NK cell functions, depletion of certain functional NK cell subsets, and changes in the expression of NKRs and coreceptors. Certain viral proteins have also been shown to interfere in these interactions. It was demonstrated in in vitro studies that LFA-1-mediated activation of CAMK-II and microtubule rearrangement are essential for NK cell activation by mature DC. Tat inhibits this activation by interfering with Ca++ influxes and activation of CAMK-II. More specifically, the C-terminal domain of Tat was found to be responsible for this interference [150
]. In another study, Nef was shown to dysregulate DC/NK interactions. Nef-pulsed DC inhibit chemokine secretory capacity as well as the cytotoxic ability of NK cells, including the CD56low CD16high subset, possibly by inducing TGF-β and IL-10 [169
].
NK cell/DC interactions determine T cell-priming characteristics of DC. For example, IFN--activated NK cells induce type 1 DC. These DC, which produce IL-12 upon stimulation via CD40, are efficient in priming TH1-type CD4+ effector T cells. IFN- is necessary for inducing this kind of helper function in NK cells [170
]. Treatment of NK cells with IL-2 or polyinosinic:polycytidylic acid has similar effects [152
, 171
]. Improperly "helped" DC may induce tolerance in the interacting T cells and/or may cause their differentiation into suppressive Tregs. The DC, which fail to prime T cells, frequently express tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (an essential amino acid) into kynurenine and other catabolites [172
, 173
]. In the absence of tryptophan, T cells cannot proliferate. Furthermore, tryptophan catabolites induce apoptosis in T cells [174
]. This results in decreased serum concentrations of tryptophan. It has also been shown that individuals with increased IDO activity are compromised in the production of 5-hydroxytryptamine in their brains. This mediator is important for signaling across neuron synapses. Its decreased production leads to decreased cognitive abilities, loss of memory, depression, and other psychiatric abnormalities. In the case of HCV-infected persons, it has been shown that decreased serum concentrations of tryptophan correlate with psychiatric symptoms in these patients. Decreased serum concentrations of tryptophan have also been reported in HIV-infected persons [175
]. These concentrations correlate with neoptrin as well as with depression, psychiatric, and neurological symptoms. Abnormal NK/DC interaction could play a role in these manifestations.
As mentioned above, NK cells also interact with macrophages. NK cell/macrophages could play an important role in protecting host from pathogens (reviewed in ref. [176
]). Nothing is known about NK cell/monocyte interactions in HIV infections.
Tregs are CD4+CD25+FoxP3+ and glucocorticoid-induced TNFR-related protein+ T cells known for their immunosuppressive properties. They can inhibit immune responses by suppressing T and NK cell functions. Enhanced numbers and functional activities of Tregs have been reported in the tissues of HIV-infected persons (reviewed in ref. [177
]). It has been demonstrated that Tregs suppress NK cell functions. Activated Tregs express membrane-bound, functionally active TGF-β. In vitro incubation of Tregs with NK cells leads to down-regulated expression, which is TGF-β-dependent, of NKG2D and other activating receptors on NK cells (reviewed in ref. [178
]). Depletion of Tregs may represent a novel way for enhancing NK cell functions in HIV-infected persons. It also leads to enhanced, HIV-specific CTL activity [177
].
Dysregulating production of NK cell-activating cytokines in HIV-infected individuals
NK cells bear receptors for a variety of cytokines, e.g., IL-2, IL-12, IL-15, IL-18, IL-21, TGF-β, type I IFNs (IFN-/β), etc. An optimum production of these cytokines is needed to maintain NK cell homeostasis and ready-to-kill state in the body. Several studies have shown that hosts (including humans) respond to a viral infection with the enhanced production of several cytokines, e.g., IFN /β, IL-12, IL-15, and IL-18 [179
, 180
]. A coordinated production of these cytokines is essential for mediating an effective antiviral NK cell response of the host. Immediate activation of NK cells following a viral infection is, to a large extent, a consequence of this virus-mediated cytokine production. Each of these cytokines plays a distinct role in NK cell activation and expansion following a viral infection. In chronic viral infections, e.g., HIV-1, this coordinated production of cytokines is dysregulated, which may be responsible, at least in part, for defective NK cell responses. Table 3
shows how these cytokines affect NK cell function and what happens to their production in this viral infection. HIV and its proteins play a role in the dysregulated production of cytokines. For example, gp120 induces IL-10, IFN-β, and TNF-, and Tat induces TGF-β1 and IL-6 but inhibits IL-12 production in human PBMC [181
182
183
]. The viral protein Nef induces IL-15 and decreases IL-18 production in the human cells [184
, 185
]. Overall, it has been well-documented that HIV-infected persons become compromised in their ability to produce IL-2, IL-12, IL-15, and IL-21 [179
, 186
187
188
189
]. Their type I IFN-producing cells (pDC) also produce less of the cytokine and are progressively depleted [190
, 191
]. A lack of these cytokines affects differentiation, survival, and cytolytic functions of NK cells. On the other hand, the concentrations of some immunosuppressive cytokines, e.g., TGF-β and IL-10, are increased in the circulation of HIV-infected patients [192
, 193
]. Parato et al. [48
] have proposed that increased IL-10 induces similar changes in NK cells as observed in HIV-infected persons. They observed a normalizing effect of HAART on IL-10 and NK cell phenotypes in a limited number of HIV-infected persons. Contrary to IL-12 and IL-15, whose production decreases in HIV-infected persons, we and others [194
, 195
] have reported increased concentrations of IL-18 in the sera from HIV-infected persons. Interestingly, the PBMC from these persons were found to produce less of this cytokine with or without stimulation with LPS. Interestingly, cells other than monocytes also produce the cytokine: Keratinocytes, adrenal cortex, and platelets also are rich sources of this cytokine. We have shown that activated platelets contribute toward increased concentrations of this cytokine in HIV-infected persons [196
]. It is noteworthy that IL-18 concentrations also increase in chronic inflammatory conditions. The cytokine increases FasL expression on NK cells, and FasL-positive NK cells may be involved in fratricidal killing of other NK cells. The cytokine appears to hasten NK cell death via Fas/FasL interactions. In constrast to the concentrations of various cytokines, little is known whether there is any change in the expression of cytokine receptors on NK cells in HIV-infected patients. In this regard, a group has shown decreased expression of the IL-7R on NK cells in HIV-infected persons [197
]. IL-7 promotes proliferation of the CD56bright subset of NK cells, which express this receptor. The viral protein Tat is known to down-regulate this receptor in CD8+ T cells [198
] and is probably also responsible for this effect in NK cells. The protein is released from HIV-infected cells and is actively taken up by other cells in the body. Another research group has documented that NK cells from HIV-infected persons do not respond to IFN- [43
]. The authors did not find out whether the lack of response was a result of a decrease in the cytokine receptor and/or a result of a defective signaling pathway of the cytokine. The decreased expression of cytokine receptors may adversely affect NK cell functions in a variety of ways: causing aberrant expression of NKRs, inducing apoptosis, etc.
Altering NK cell-secreted cytokines and chemokines in HIV infection
The profile of NK cell-secreted cytokines appears to be modified
in HIV-infected persons. As stated above, NK cells are known
to secrete several cytokines and soluble mediators: IFN-
, TNF-
,
TNF-β, GM-CSF, IL-3, IL-4, IL-5, TGF-β1, IL-10, IL-13,
etc. They do so upon interaction with the target cells, which
trigger NK cell cytotoxicity as well as upon activation with
an appropriate combination of other cytokines, e.g., IL-12 and
IL-15. Interestingly, IL-15 appears to be required by NK cells
for their production of TH2-type cytokines [
199
200
201
202
203
].
NK cells also express constitutive, but not inducible, endothelial
NO synthase (NOS) and secrete NO. Interestingly, NOS inhibitors
can significantly inhibit functions of HNK cells [
204
]. Several
studies have shown that the profile of NK cell-secreted cytokines
depends on the milieu in which they develop and differentiate.
In analogy to TH1- and TH2-type CD4
+ T cells, NK cells could
differentiate into type 1 or type 2 NK cells (NK1 or NK2). NK1
cells predominantly secrete IFN-
, whereas NK2 cells predominantly
secrete IL-5 and IL-13 [
205
,
206
]. It is noteworthy that existence
of the two types of NK cells has been demonstrated in vivo in
humans, and they may affect the course of certain disease conditions.
For example, NK1 and NK2 cells have been associated with episodes
of relapses and remissions in multiple sclerosis, respectively
[
207
]. It has also been shown that NK2 cells play a role in
the immunopathogenesis of asthma and in the maintenance of normal
pregnancy in humans [
208
,
209
].
Surprisingly, we could not come across any study in literature about the profile of NK cell-secreted cytokines in HIV-infected persons. However, Chan et al. [210
] have shown that NK cells from these persons are of type 2. Their study relied on two cell surface markers belonging to the IL-1R superfamily, IL-18R and ST2L, which are expressed on the surface of cells producing TH1- and TH2-type cytokines, respectively [210
, 211
]. These results support earlier reports implicating TH2-type cytokine responses in the immunopathogenesis of AIDS [193
, 212
, 213
]. NK cells may be contributing to the predominance of TH2 cytokine responses in HIV-infected AIDS patients. However, studies are needed to investigate NK cell-secreted cytokines in humans in the course of HIV infection.
In addition to cytokines, NK cells produce abundant amounts of several chemokines, e.g., CCL3 (MIP-1), CCL4 (MIP-1β), and CCL5 (RANTES), which play an important role in initiating NK cell-mediated inflammation. These chemokines are also important in the context of HIV infection, as they bind to CCR5 and block entry of CCR5-using M-tropic HIV strains from entering into human cells. It is important to note that primary HIV infections usually result from M-tropic viral strains. This may also explain why persons with high-activity NK cells may be relatively protected from contracting HIV infections [12
, 13
]. It has been demonstrated that NK cells from HIV-infected individuals produce relatively less amounts of these chemokines and may be less efficient in blocking CCR5 and suppressing HIV replication [6
, 8
]. Not surprisingly, culture supernatants of NK cells from HIV-infected persons are less efficient in suppressing HIV replication than similar supernatants obtained from the cells of HIV-seronegative, healthy persons. Interestingly, viremia seems to directly suppress chemokine production from NK cells [11
].
Infecting NK cells
Infecting the very immune cells that may inhibit viral replication is a clever strategy to evade host immunity. By infecting an immunocyte, the virus could cripple its immune effector functions. HIV-1 can infect many types of immune cells, e.g., CD4+ T cells, macrophages, DC, etc. In vitro studies have shown that the virus can also infect NK cells [214
, 215
]. The CD8+ NK cell subset was found to be more susceptible to HIV infection than the CD8– subset. The two cell subsets varied in the production of cytokines: the former producing more TNF- and the latter producing more IFN-. This differential production of the cytokines was shown to be responsible for the differential susceptibility of the NK cell subsets to HIV infection [214
, 215
]. This preferential infection of CD8+ NK cells with HIV-1 may also explain why the CD8+CD16+ NK cells are frequently depleted in the circulation of HIV-infected individuals [14
, 27
, 216
]. The infected NK cells become impaired in their cytolytic functions. Remarkably, NK cells can also be infected with HIV with help from human herpesvirus 6 (HHV-6). The latter virus infects human NK cells and induces the expression of CD4 in these cells, rendering them susceptible to infection with HIV-1 [217
]. It is noteworthy that HIV-infected individuals suffer from frequent reactivations of herpes viruses, and HHV-6 infection is considered an important cofactor in the development of AIDS. Moreover, CD8-tropic HIV-1 strains have also been isolated from HIV-infected AIDS patients. Interestingly, these strains use CD8 and not CD4 as a primary receptor in human cells and infect CD8+ T cells [218
]. Little is known about these CD8-tropic HIV strains. Theoretically, they could potentially infect CD8+ NK cells. It is noteworthy that in vivo infection of NK cells in HIV-infected persons has also been demonstrated [219
]. A small percentage (0.3–6.5%) of circulating CD3–CD56+ HNK cells expresses CD4 and HIV coreceptors, CXCR4 and CCR5. Proliferative activation of NK cells causes an increase in the expression of CD4 and CCR5 on these cells. CD4+ NK cells can be infected in vitro with T- and M-tropic HIV-1 strains. A more efficient way of infecting NK cells is their coculture with HIV-infected cells. This suggests that in vivo, cell-to-cell infection of NK cells may be more important. NK cells seem to be relatively resistant to killing by HIV infection. The infected NK cells may persist in vivo despite treatment of the infected persons for several years with HAART [219
220
221
]. Thus, NK cells may provide a sanctuary to HIV, and the virus-infected NK cells may represent important viral reservoirs. The virus may persist in these cells even when HAART may have reduced viremia to very low or undetectable levels. It may be relevant to mention here that NK cells express a higher level of P-glycoprotein compared with other lymphocytes. Therefore, HIV-infected NK cells may be relatively more resistant to antiretroviral drugs, e.g., protease and RT inhibitors [219
, 222
]. These findings have implications for therapeutic strategies being used for elimination of the virus from HIV-infected persons.
Enhancing apoptosis in NK cells
NK cells from HIV-infected individuals have a reduced capacity to proliferate upon in vitro culture. It is noteworthy that the expression of a senescence marker CD57 is significantly increased on the surface of NK cells in HIV-infected persons. NK cells also undergo enhanced, spontaneous apoptosis as compared with the cells from healthy, control subjects. The enhanced apoptosis was ascribed to their relatively low expression of the antiapoptotic proteins Bcl-2 and Bcl-XL. It has been shown that Tat induces TGF-β and apoptosis in NK cells. It also down-regulates Bcl-2 expression in other hematopoietic cells [183
, 223
]. IL-10 is known to enhance serum starvation-induced apoptosis in human cells by decreasing transcription of antiapoptotic proteins Bcl-2 and Bcl-XL. As mentioned above, increased concentrations of this cytokine in the circulation of HIV-infected persons have been well documented. The viral glycoprotein gp120 from T-tropic viral strains has also been shown to increase expression of proapoptotic genes and decrease expression of antiapoptotic genes in NK cells [224
]. In this connection, another study has shown that gp120 interaction with the viral coreceptor CXCR4 induces cell death via autophagy: a kind of programmed cell death in which large chunks of cellular material and cytoplasmic organelles are degraded in lysosomes [225
]. NK cells constitutively express this receptor, and its interaction with gp120, which is present in virions and/or the circulation, may induce autophagic death of NK cells. As mentioned above, recombinant gp120 has, in fact, been shown to induce up-regulation of several proapoptotic genes in NK cells [224
]. So, it is not surprising that viremia is associated with decreased NK cell numbers as well as with decreased functional capability of NK cells in HIV-infected persons [1
].
Addition of the prosurvival cytokine IL-15 to in vitro NK cell (and T) cell cultures increases their survival by up-regulating the expression of Bcl-XL [226
]. In normal NK cells, which constitutively express high amounts of Bcl-2 and Bcl-2-like proteins, IL-15 increases NK survival by down-regulating Bim and maintaining antiapoptotic protein Mcl-1 [227
]. Bim is the only-BH-3 domain-containing, proapoptotic member of the Bcl-2 family of proteins. It binds with and inactivates Mcl-1, another member of the Bcl-2 family having antiapoptotic functions (reviewed in ref. [228
]). Recombinant human IL-15 may represent a useful immunotherapeutic tool and vaccine adjuvant for HIV-infected AIDS patients because of its prosurvival and antiapoptotic effects on NK cells, less toxicity, and minimal enhancement of HIV replication (reviewed in ref. [229
]).
A small proportion of NK cells from normal, healthy persons undergoes apoptosis when they are used as effector cells in in vitro NK cell cytotoxicity or ADCC assays [230
, 231
]. It has also been demonstrated that NK cells can undergo apoptosis after activation, as in the case of T cells. For example, IL-2 and IL-12-stimulated NK cells undergo apoptosis when they were incubated with immobilized antibodies directed against CD16, CD2, or CD94 [232
233
234
]. It was also learned that incubation of NK cells with high concentrations of certain activating cytokines, e.g., IL-15 and IL-12, induced production of TNF-, which caused apoptosis of NK cells [235
]. In fact, it is a negative-feedback mechanism by which NK cells control and limit self-activation and secretion of IFN-. As mentioned above, we and others [194
, 195
] have reported increased concentrations of IL-18 in the sera from HIV-infected persons. The cytokine induces FasL expression on NK cells, which could lead to fratricidal killing of NK cells via Fas/FasL interactions. This may explain a negative correlation between serum concentrations of IL-18 and NK cell numbers reported in patients suffering from chronic autoimmune disorders [236
]. Indeed, we have also observed a significant negative correlation between serum IL-18 concentrations and NK cell numbers in these individuals (unpublished data). These studies suggest that IL-18 may be associated with compromised NK cell functions in HIV infections. The HIV protein Tat, secreted from HIV-infected cells, has been shown to induce FasL expression on NK cells and CTL [237
]. It is tempting to speculate that Tat and IL-18 may act in concert to induce FasL expression on NK and CTL in HIV-infected persons. Fas/FasL interactions have been implicated in the immunopathogenesis of AIDS in HIV infection (reviewed in ref. [238
]).
NK CELL FUNCTIONS BECOME COMPROMISED IN HIV-INFECTED PERSONS
Although humans respond to HIV infection with activation of
their NK cells, the virus uses many different strategies to
neutralize this host response. As a consequence, NK cell function
becomes compromised in these infections. Several workers have
reported that NK cell functions (killing of target cells, ADCC
effector function, editing of DC, and production of cytokines
and chemokines) become defective in HIV-infected persons [
26
,
33
,
34
,
37
,
38
,
63
,
239
,
240
]. The defects in the NK
cell compartment usually occur in early stages of the infection.
A decreased expression of LFA-1 on cells from HIV-infected persons
has been reported [
241
]. Furthermore, it has also been shown
that immune activation leads to an increase in shedding of soluble
ICAMs and CD16 in the circulation of HIV-infected persons. The
soluble forms of these molecules interfere with their membrane-inserted
forms. The role of LFA-1 and its ligands in cell adhesion, conjugate
formation, and polarization of cytotoxic granules is crucial
for NK cell-mediated killing. Thus, NK cells from HIV-infected
persons may be impaired in their ability to form immune synapses
with target cells. Furthermore, the HIV protein Tat was found
to inhibit NK cell-mediated lysis by blocking L-type Ca
++ channels
[
242
]. Ca
++ infuxes are essential for activation of CAMK-II,
rearranging microtubules and triggering degranulation of NK
cells following activation of cells via LFA-1 [
150
]. Furthermore,
gp120 binding to CD4 also inhibits LFA-1-mediated cell–cell
interactions by causing dissociation of the integrin from its
cytoplasmic partner cytohesin [
243
]. Few studies have been
undertaken to investigate functional capabilities of NK cells
from these persons for conjugate formation and triggering their
cytolytic machinery. It was demonstrated that NK cells from
the infected persons may form conjugates with target cells but
are defective in triggering their cytolytic mediators onto the
target cells [
19
,
24
]. The inability of NK cells from HIV-infected
individuals to establish and maintain an effective immune synapse
and trigger its cytolytic mediators may represent a fundamental
reason for compromised NK cell functions in HIV-infected persons.
It appears that absolute numbers and percentages of NK cells decrease over time in HIV-infected persons. CD8+CD16+ and CD56+CD16+ NK cell subsets have been reported to decrease in percentages and in absolute numbers in these individuals. These decreases are often accompanied by the expansion of a functionally defective subset of CD16+CD56– NK cells, which express KIR. It is noteworthy that it is the CD16–CD56+ subset of NK cells that expands in primary viral infections. The changes in NK cells are more severe with the onset of AIDS and correlate with clinical condition of the patients [27
, 32
, 35
, 216
]. The decreases in NK cell subsets correlate significantly with depletion of the CD4+ T cells in these patients [14
, 16
], suggesting that CD4+ T cell-secreted cytokines (e.g., IL-2, IL-21) may be important in vivo in maintaining NK cell survival. Alternatively, the declines in the numbers of these two types of immune cells may reflect immune dysfunction independently of each other. It may be relevant to mention here that CD56+ NK cells develop and differentiate in thymus and secondary lymphoid organs in T cell-rich areas. A progressive destruction of the architecture of these organs as well as depletion of CD4+ T cells in HIV-infected persons may result in depletion of this subset of NK cells. Overall, NK cells from HIV-infected persons express lower levels of perforin and higher levels of SHIP, which may be responsible for their poor cytolytic and activating potentials [58
]. As mentioned elsewhere, the envelope glycoproteins of HIV can up-regulate proapoptotic genes and reduce survivability and vigor of NK cells (see the next section). Recombinant gp120 inhibits NK cell functions when added to in vitro microcytotoxicity assays. Furthermore, certain peptides derived from the protein also have NK cell inhibitory properties [80
, 244
, 245
]. The exact mechanism of inhibition of the peptides remains unknown. Finally, stress could be a factor in suppressing NK cell functions in HIV-infected persons. Cortisol has been shown to act in synergism with HIV proteins in mediating the suppressive effects on NK cells [244
].
In vitro studies have shown that several exogenous cytokines, e.g., IL-2, IL-12, IL-15, IFN-, etc., increase cytolytic and ADCC effector function of NK cells from HIV-infected individuals. However, the responses were significantly lower in HIV-infected individuals as compared with HIV-seronegative, healthy controls [19
, 34
, 43
, 239
, 246
]. These observations suggest that NK cells from HIV-infected persons may have decreased expression of cytokine receptors and/or may have defects in cytokine-induced signaling pathways. This may explain why NK cells from these patients produce defective LAK cells when they are incubated with cytokines, e.g., with IL-2 [25
].
EFFECT OF HAART ON ANTIVIRAL NK CELL RESPONSES
HAART suppresses HIV replication to undetectable limits in the
circulation of HIV-infected persons. Over time, this leads to
improvement in the NK cell functions. However, a prolonged treatment
is needed for tangible improvements in the NK cell compartment.
In most of cases, the recovery is only partial. NK cells and
the receptor expression tend to normalize in the treated persons;
however, certain NK cell functions, e.g., their ability to produce
IFN-
in response to IL-2 and IL-15, remain compromised [
50
].
In one study, HAART reversed expression of iKIR on NK cells
after 2 years’ administration, but the reduced expression
of activating receptors persisted [
51
]. Similarly, a normalizing
effect of HAART was observed on the expression of 2B4 on NK
cells [
56
]. HAART, for more than 6 months, caused a differential
disappearance of iKIR on virus-specific CTL but usually had
no effect on ILT-2 expression [
45
]. HAART also does not have
any effect on the expansion of NKG2C on NK cells and CTL in
HIV- and HCMV-coinfected patients. As mentioned earlier, this
can be ascribed to the fact that HCMV and not HIV causes expansion
of these cells [
115
,
116
,
247
]. In primary HIV infection,
an early start of HAART may normalize changes in the NK cell
compartment within 6 months [
61
]. The baseline activation of
the immune system and viral load determines the extent to which
innate immune parameters could be reconstituted by HAART in
HIV-infected AIDS patients. Continued viral suppression and
reduction in immune activation for more than 1 year resulted
in recovery of pDC, better NK/DC interactions, and partial restoration
of NK cell numbers and functions [
248
].
If NK cells become infected, they may act as latent reservoirs for the virus, as the infection could persist in these cells even after years of HAART [219
, 221
]. Thus, immunotherapy should be considered for invigorating NK cell responses along with chemotherapy.
NOVEL APPROACHES FOR ENHANCING ANTI-HIV NK CELL RESPONSES
A better understanding of interactions between HIV and NK cell
responses of the host has led to novel, rational approaches
for boosting antiviral immunity in HIV-infected persons and
for designing more effective anti-AIDS vaccines. These approaches
are listed in
Table 4
and are discussed in the following sections.
Blocking inhibitory NKRs
As stated above, KIR, NKG2A, and ILT-2 are the main inhibitory
receptors that control NK cell activities in an individual.
They are also expressed on a subset of antigen-experienced effector/memory
CTL, in which they increase the antigen-mediated activation
threshold. Cumulative data have shown that the expression of
iKIR increases on NK cells and CTL in HIV-infected persons,
especially under viremic conditions [
16
,
40
,
148
]. Blocking
the functional activities of these receptors with receptor-
or MHC-specific antibodies or with small molecular weight inhibitors
increases cytolytic activities and cytokine secretion from NK
cells and CTL. Studies in animal models have shown that blocking
of the inhibitory NKR LY49 in vivo also augments the anti-tumor
effects of NK cells and CTL and results in tumor regression
[
143
]. This strategy may boost antiviral effects of NK cells
and CTL in HIV-infected individuals. In this regard, in vitro
studies have shown that masking of iKIR by mAb increases the
cytolytic activities of HIV-specific CTL from HIV-infected patients
against autologous, virus-infected cells [
40
]. The receptors
could also be blocked by soluble MHC antigens. However, they
are more likely to bind TCR preferentially than KIR, and hence,
they may block CTL functions. Small molecular weight chemical
compounds could be synthesized to specifically block KIR–MHC
interactions. These immunotherapies will have to be tailored
individually, as the patients may differ in their KIR–HLA
combination repertoires. As the blocking of inhibitory receptors
on NK cells and CTL may promote killing of autologous cells
and uncontrolled cytokine production, the treatment could cause
immunopathology. Furthermore, the strategy may interfere with
the development of long-term, virus-specific memory and even
may promote apoptosis of these effector/memory cells. Admittedly,
such treatments could be risky, and the treated patients will
have to be carefully monitored for any untoward effects.
Novel ways of anti-HIV cell therapy
In the past, the infusions of the in vitro-expanded, autologous, HIV-specific CTL have been used as immunotherapeutic tools in HIV-infected AIDS patients without much success [249
, 250
]. A better strategy may involve expansion and infusion of the CTL specific for HLA-C-restricted viral peptides, as the virus does not down-regulate the expression of this MHC antigen in the infected cells. Similarly, in vitro-expanded, lymphokine-activated, autologous NK cell clones that express inhibitory receptors for HLA-A or -B but not for HLA-C or -E could be considered as immunotherapeutic tools in these patients. These cells should kill only HIV-infected cells that have down-regulated HLA-A and -B but not HLA-C or -E. Similarly, lymphokine-treated, heterologous NK cells that express one or more iKIR specific for the recipient HLA-A or -B could also be beneficial. Alloreactive NK cells are known to preferentially kill hematopoietic cells in MHC-disparate recipients without causing graft-versus-host disease (GvHD). The beneficial effects of alloreactive NK cells have been well documented in leukemia patients receiving bone marrow transplants (reviewed in refs. [251
, 252
]). The potential of alloreactive NK cells as therapeutic tools for viral infections including HIV is worth investigation.
Selecting epitopes for anti-HIV vaccination
As stated above, HIV-1 differentially down-regulates the expression of MHC class I antigens on the surface of infected cells for evading NK and CTL-mediated killing. The viral protein Nef causes degradation of most of the HLA-A, HLA-B, and CD1d antigens but leaves HLA-C and HLA-E to intact on the cell surface [96
97
98
]. As HLA-C and -E act as ligands for inhibitory receptors on NK cells, the virus-infected cells maintain their resistance to NK cells by maintaining their expression on the surface of infected cells. The virus, in fact, increases the expression of HLA-E by providing a peptide (within the viral protein p24) that can bind to this nonclassical MHC antigen. It is noteworthy that HLA-C is not exclusively used as ligands for NKRs. Several HIV peptides are presented to T cells via this MHC antigen [253
254
255
]. These peptides may serve as better immunogens for inducing anti-HIV CTL, as HLA-C are not degraded from the surface of the virus-infected cells, and therefore, virus may not be able to hide from the peptide-specific CTL. The notion is supported by the reported association between the presence of HLA-C-restricted viral peptides in HIV-infected individuals and their long-term nonprogression toward AIDS [256
]. Furthermore, the existence of CTL, which recognize HLA-E-restricted viral peptides, has also been demonstrated for different viruses [257
]. We could not find any study in literature about HLA-E-restricted HIV peptides presented to CTL. These HIV peptides could also be considered as immunogens for vaccination against HIV.
It is noteworthy that HLA-A and -B antigens mainly present viral peptides recognized by HIV-specific CTL. Many studies have shown that several "protective" HLA-B allotypes can present broadly reactive, immunodominant peptides to CTL [258
, 259
]. On the other hand, only a few HLA-C-restricted HIV epitopes have been described [253
254
255
]. In part, it could be a result of the fact that this HLA antigen is expressed at relatively lower levels on human cells [260
]. CTL may not be able to detect the peptide-complexed antigen. Using knowledge-based algorithms, Tong et al. [261
] have shown that HLA-C-restricted peptides could be found in most HIV proteins. Further studies are needed to evaluate the functional significance of these epitopes.
Invigorating NK cells with cytokines/anticytokines
Use of cytokines for enhancing innate and adaptive immunity of the host has been a cherished goal of immunologists since the discovery of IL-2 in the early 1980s. However, the toxicities associated with their use have always been prohibitive. Potential cytokines that can be used to enhance NK cell activity in vivo include IL-2, IL-15, IL-21, as well as ligands for c-Kit and FMS-like receptor tyrosine kinases (Flt-3). It may be relevant to mention here that IL-2 and/or IL-2-activated killer cell infusions have not been promising as therapeutic tools in cancer patients [262
, 263
]. In the context of HIV infection, these immune enhancers may pose another complication. They may increase HIV replication and act as paracrine growth factors in AIDS-related malignancies. In this regard, IL-15 has been shown to be relatively less mitogenic and less toxic and to have minimal effects on HIV replication. Furthermore, it inhibits spontaneous apoptosis in NK cells and CTL from HIV-infected patients by increasing the expression of antiapoptotic protein Bcl-XL (reviewed in ref. [229
]). The cytokine is an absolute necessity for normal development, differentiation, and homeostasis of HNK cells. IL-21 is another relatively recently discovered cytokine produced mainly from activated CD4+ T cells. It increases cytolytic potential of NK cells and is even less mitogenic than IL-15. However, no data are yet available about its effects on HIV replication and cytotoxicity.
Enhancing immunogenicity of viral immunogens
NK cell activation in the beginning of a viral infection has a strong adjuvant effect. Activated NK cells kill virus-infected cells, whose products send a "danger signal" to the host for initiating antiviral inflammatory and immune responses [264
]. The role of NK cell-secreted IFN- in this connection has been well documented. The studies about interactions between activated NK cells and DC interactions also testify to the role of NK cells in the generation of adaptive immunity. DC pulsed with tumor cell lysates are effective in mediating anti-tumor immunity in vitro and in vivo in animal models. It has been shown that these DC mediate these adjuvant effects by activating NK cells [265
]. It was also demonstrated that the presence of IL-18 in in vitro cultures of NK cells, DC, T cells, and tumor cells leads to rapid generation of tumor-specific CTL [266
]. These studies show that activating NK cells at or prior to immunization may lead to effective antiviral immunity. This activation may be achieved by cytokines and/or TLR agonists, which also cause release of cytokines. -Galactosyl ceramide has also been used as an adjuvant. It is presented by APC via CD1d to NKT cells, which in turn, activate NK cells [267
, 268
]. Based on our present understanding of NK cell biology, inhibiting KIR–MHC interactions and/or inducing expression of ligands for activating NKRs may produce better adjuvant effects than our currently used adjuvant formulations in vaccination regimens. Indeed, better antigen-specific, immune responses were induced when vectors expressing ligands for NKG2D were used along with immunogen [269
]. These novel approaches should contribute to better and more effective vaccine strategies against HIV infection and AIDS.
PERSPECTIVE AND FUTURE DIRECTIONS
Despite spectacular advances made in understanding NK cell biology,
there still remain unknown aspects of these cells, which should
be addressed in future research. For example, we are still far
from discovering all NKRs. An area that needs immediate attention
concerns finding ligands for aKIR and NCR. Furthermore, we need
to know better how the NKR repertoire of the host is shaped
and what effects the host MHC has in shaping this repertoire.
A lot has been learned about interactions between NK cells and
DC. It appears that NK cells could also interact directly with
T cells. This could be an extremely productive area of research.
It is now evident from several studies that different NKRs, particularly of the inhibitory type (e.g., KIR, ILT, KLR-G1), are expressed frequently on antigen-experienced CD8+ T cells and less frequently on CD4+ T cells. These receptors seem to be expressed at distinct stages in the course of differentiation and development of these cells. They may serve important functions; e.g., they may prevent apoptosis and increase survival of the cells and/or may increase the activation threshold of the effector cells to prevent autoaggression. These receptors could serve as important markers to distinguish different developmental stages of these cells. This knowledge may allow us to identify exact defects, which appear in these cells in viral infections and malignancy.
Activating NKRs of the KIR family have been reported to occur on CD4+ T cells under certain disease conditions. Their expression has been described on CTL in HIV-infected viremic persons [62
]. It is not known what triggers their expression and what are the consequences of this expression—how the receptor-positive cells differ from the receptor-negative cells in terms of their proliferation, cytokine production, and interaction with other cells in the body. It would also be of great interest to see if and how HIV induces the expression of their ligands on infected human cells.
In the context of HIV infections, future efforts should be directed at knowing which of the NKRs are aberrantly expressed on the surface of NK cells as well as on other immunocytes, e.g., monocyte/macrophages, DC, and B and T cells (CD4+ and CD8+ subsets). As mAb are not available for all of these receptors, and the ones that exist may not distinguish between the activating and inhibitory forms of these receptors, therefore, one may have to use alternate methods. Fortunately, the NKR genes, which have been studied so far, seem to be regulated at the transcriptional level. This suggests that real-time RT-PCR and/or oligonucleotide microarrays with appropriate controls may give a fair idea of the genes whose expression may be dysregulated in HIV-infected individuals.
As discussed above, modulation of interactions between NKRs and their ligands may represent an important tool of immunotherapy. Studies should be performed in animal models to see the long-term effects of these interventions on the resistance of the host to pathogens and development of tumors. Small, antagonist chemical molecules, peptides, and humanized receptor-specific mAb should be developed for their potential use in boosting innate and adaptive immunity in HIV-infected individuals.
We also need to develop innovative means to target NK cells toward HIV-infected cells. In this connection, fusion proteins combining intracellular chains with the extracellular region of CD4 or with HIV-specific single-chain antibody have been developed. Transduction of these fusion proteins into primary human NK cells via retroviral vectors redirects their killing toward HIV-infected cells [270
]. Another group has made a fusion protein combining gp120-specific antibodies of IgA and IgG isotypes. It is meant to kill HIV-infected cells by linking the viral envelope protein with FcR on NK and other immune cells [271
]. Finally, the potential of alloreactive NK cells as therapeutic tools in viral infections, particularly with HIV, is worth exploring. These cells have benefited leukemia patients undergoing bone marrow transplantation and do not seem to cause GvHD (reviewed in ref. [252
]). Fortunately, now, the technology exists for obtaining fully differentiated and functional NK cells from human stem cells [272
].
Invigorating and activating NK cells may benefit HIV-infected persons in controlling the infection. However, it should not be forgotten that activated NK cells are equipped with a lot of destructive potential. Their excessive activation may cause tissue destruction and contribute toward pathogenesis of the disease. Therefore, NK cell activity-enhancing treatments will have to be closely monitored for undesirable consequences.
ACKNOWLEDGEMENTS
We thank our colleagues at the Research Center for insightful
discussions, the Canadian Institutes of Health Research (CIHR),
and Fonds de recherche en santé du Quebec (FRSQ) for
support. A. I. holds a Ph.D. scholarship from the FRSQ. We regret
that as a result of space limitations, all authors on the subject
could not be cited.
Received September 24, 2007;
revised February 25, 2008;
accepted February 26, 2008.
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