Blood, 15 September 2001, Vol. 98, No. 6, pp. 1667-1677
REVIEW ARTICLE
Dressed to kill? A review of why antiviral CD8 T lymphocytes fail
to prevent progressive immunodeficiency in HIV-1 infection
Judy Lieberman,
Premlata Shankar,
N. Manjunath, and
Jan Andersson
From the Center for Blood Research and Department of
Pediatrics, Harvard Medical School, Boston, MA; and the Division of
Infectious Diseases, Center for Infectious Medicine, Karolinska
Institutet, Huddinge University Hospital, Stockholm, Sweden.
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Abstract |
CD8 T cells play an important role in protection and control of
HIV-1 by direct cytolysis of infected cells and by suppression of viral
replication by secreted factors. However, although HIV-1-infected individuals have a high frequency of HIV-1-specific CD8 T cells, viral
reservoirs persist and progressive immunodeficiency generally ensues in
the absence of continuous potent antiviral drugs. Freshly isolated
HIV-specific CD8 T cells are often unable to lyse HIV-1-infected cells. Maturation into competent cytotoxic T lymphocytes may be blocked
during the initial encounter with antigen because of defects in antigen
presentation by interdigitating dendritic cells or HIV-infected
macrophages. The molecular basis for impaired function is
multifactorial, due to incomplete T-cell signaling and activation (in
part related to CD3
and CD28 down-modulation), reduced perforin expression, and inefficient trafficking of HIV-specific CD8 T cells to
lymphoid sites of infection. CD8 T-cell dysfunction can partially
be corrected in vitro with short-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a
significant causal or exacerbating role. Functional defects are
qualitatively different and more severe with advanced disease, when
interferon 
production also becomes compromised.
(Blood. 2001;98:1667-1677)
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Persistence of HIV-1-infected cells in vivo despite a
vigorous immune response |
During primary HIV-1 infection, plasma viremia
increases to peak levels of up to 109 HIV-1 copies/mL.
Viremia is thereafter partially controlled by the immune response and
stabilizes 3 to 6 months later. However, in situ hybridization for
HIV-1 RNA and quantification of cell-associated unspliced messenger and
genomic RNA and DNA indicate that HIV-replicating and latently infected
cells in lymphoid tissue increase over time.1,2 The
majority of cells replicating HIV-1 are CD4 T cells, both early and
late in disease.3
Viral replication persists in lymphoid tissue despite a vigorous immune
response. HIV-1-specific CD8 T cells, which should be able to target
virally infected cells for elimination, exist at high frequencies in
most HIV-1-infected patients. Previous limiting dilution estimates of
the frequency of HIV-specific CD8 T cells reached around one per
thousand cells.4,5 However, more sensitive techniques that
use tetramer staining, which fluorescently labels T cells whose T-cell
receptors (TCRs) recognize an antigenic peptide-major
histocompatibility (MHC) pair, have shown that up to a few percent of
circulating CD8 T cells recognize a particular HIV-1
peptide.6 The frequency of CD8 T cells producing
interferon (IFN) in response to major HIV-1 proteins expressed
by vaccinia virus ranges from 0.8% to 18%.7 In response
to HIV-1-infected primary CD4 T cells, approximately 0.3% to 3% of
HIV-seropositive donor CD8 T cells produce IFN.8 In
those studies, the frequency of circulating HIV-specific CD8 T cells is
generally above 1%. These results provide lower limits for the
frequency of HIV-specific CD8 T cells because, as discussed below, not
all specific cells are triggered to produce IFN.8
After the first week of infection when viral dissemination is
reined in by the innate immune response, viral-specific CD8 T cells
form the cornerstone of immune control for most viruses, including
HIV-1. Viral-specific cytotoxic T lymphocytes (CTLs) suppress HIV-1
replication in vitro by direct cytotoxicity and secretion of soluble
factors.9-13 Acute viremia resolves with the appearance of
HIV-specific CTLs.14,15 Moreover, the likelihood of
progressing to AIDS increases in patients who lack
gag-specific CTLs.4,16 This finding, together
with the rapid disease course in neonates whose overall T-cell immunity
is immature,17 suggests that CTLs are important in
controlling HIV-1. Direct evidence was provided in rhesus macaques in
which elimination of CD8 T cells results in a dramatic increase in
simian immunodeficiency virus (SIV) load.18,19
If there are so many HIV-1-specific CD8 T cells, why are these cells
not doing a better job? In the absence of antiviral drugs, the immune
response fails to halt progressive immunodeficiency in all but a small
minority of long-term nonprogressor (LTNP) patients. A persistent viral
reservoir might be explained by the fact that HIV-1 can establish
latent cellular infection in which HIV-1 provirus is integrated into
the host genome, but no viral proteins are produced to signal to roving
T cells. However, the progressive nature of the disease suggests that
antiviral CD8 T cells do not always efficiently destroy cells
replicating HIV-1. As many as 10 billion virions are produced each day
in asymptomatic, untreated individuals.20,21 The failure
of CD8 T-cell function is clear when one compares the frequency of
HIV-specific CD8 T cells with the numbers of HIV-1-infected cells
replicating virus, generally substantially below one per thousand and
frequently on the order of one per million mononuclear cells. Because
the frequency of HIV-specific CD8 T cells is typically at least 10-fold higher and because in infected individuals there are usually more CD8 T
cells than CD4 T cells and macrophages, the inability to control viral
production is striking, especially because CTLs are "serial
killers" able to lyse multiple cells.22,23
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HIV-specific CD8 T cells do not lyse HIV-1-infected cells |
Failure to control viral replication suggests that antiviral CD8 T
cells are impaired in lysing HIV-1-infected cells and suppressing HIV-1 replication. Although early reports suggested that peripheral blood mononuclear cells (PBMCs) from 80% to 90% of HIV-1-infected donors demonstrate HIV-specific cytotoxicity above background in 6- to
16-hour assays,10,24,25 specific cytotoxicity by freshly
isolated PBMCs is generally not much above background in direct 4-hour
51Cr release assays.8,26-28 However,
HIV-specific cytotoxicity by PBMCs is dramatically enhanced after
overnight culture in an interleukin-2 (IL-2)-dependent
manner.26 The rapid increase in cytotoxicity, typically to
10% to 30% specific cytotoxicity in a 4-hour assay at an
effector/target (E:T) ratio of 25:1 to 50:1, cannot be explained
by overnight clonal expansion of viral-specific T cells. A possible
specific defect in HIV-specific cytotoxic capability was recently
demonstrated by comparing HIV- and CMV-specific lysis by freshly
isolated blood lymphocytes.28 HIV-specific lysis was
considerably less than CMV-specific lysis, despite comparable numbers
of tetramer-staining HIV-specific and CMV-specific CD8 T cells.
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Viral evasion of cytotoxic T cells |
Failure of cytolysis could arise either from resistance of
HIV-1-infected targets to CTL recognition or lysis29,30
or from a lack of effector function by the CTLs
themselves.26 Many viruses have strategies to evade CTL
recognition, especially by interfering with antigen presentation
(reviewed in Tortorella et al31). Two HIV-1 evasion
strategies have been described. Viral mutation of the epitopic sequence
recognized by HIV-specific CTL can sidestep CTL
recognition.29,32,33 Moreover, mutated epitopes (altered peptide ligands) can interfere with subsequent triggering by cells expressing wild-type sequence.34 Although such mutations
certainly exist, it is uncertain whether they play an important role.
Convincing recent evidence for a role for escape mutation comes from
the rapid emergence of viral mutations of recognized tat epitopes during acute SIV infection.35
Another viral evasion mechanism is nef-induced down-modulation of MHC
class I A and B molecules.36-40 Assays that measure T-cell functional responses to HIV-1-infected primary cells are invaluable for determining whether viral evasion significantly interferes with
T-cell immune responses.8,40-43 In fact, CD8 clones that recognize 4 different HIV-1 proteins lyse HIV-1-infected primary CD4 T
cells as well as they lyse cells infected with recombinant vaccinia
virus expressing HIV-1 genes.43 Moreover, nef is a major
antigen recognized by HIV-seropositive donor CD8 T
cells.44 In addition, CD8 T cells can recognize target
cells expressing only a few antigenic peptide-MHC
molecules45 and the HLA class I C allele is unaffected by
nef.46 Those results suggest that nef-mediated
down-modulation of class I alleles may not block immune recognition of
HIV-1-infected cells. Nef-mediated down-modulation of class I
molecules, however, might be important for CD8 T cells with
low-affinity TCRs or for antigens, synthesized at low levels or
inefficiently processed and presented.30
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T-cell anergy in HIV-1 infection |
Because lysis of HIV-1-infected cells is dramatically
up-regulated after brief exposure to IL-2 in vitro,26
there is also a functional in vivo problem with HIV-specific CTLs.
Previously activated antigen-specific T cells may be unable to
proliferate or to perform the full complement of effector functions
when they re-encounter antigen. Lack of proliferation or function is
termed anergy.47 Although anergy can be defined as
complete unresponsiveness on re-encounter with antigen, in reality
cells more often become partially anergized. For example, a CD4 T cell
may lose the ability to proliferate to antigen but may still express
activation molecules and secrete some cytokines. Anergy is important to
prevent immunopathology and autoimmunity. Anergy has been studied
extensively for CD4 T cells, but less is known about regulation of CD8
T-cell function.
HIV-1-specific CD4 T-cell proliferation is undetectable within 3 months after primary infection in most HIV-1-infected individuals, with the exception of some LTNPs and early treated
patients.48-54 However, HIV-specific CD4 T cells are not
deleted but are present in low numbers in a partially anergized
state.55 In response to HIV-1 gag p24, approximately
0.12% (range, 0%-0.66%) of CD4 T cells produce IFN by
intracellular flow cytometry analysis. The median response is higher in
nonprogressive HIV-1 disease (0.40%). However, those figures are about
an order of magnitude lower than the corresponding CD8 T-cell activity,
especially when the reduced numbers of CD4 T cells are
considered.55 Moreover, CD4 proliferation to HIV-1 p24 can
be induced in vitro by adding CD40L-trimer and IL-12, providing further
support for persistence of anergized HIV-specific CD4
cells.56
CD4 T cells are important to maintain effective antiviral CD8 CTLs.
They secrete IL-2, an important growth factor for CD8 cell survival.
However, high concentrations of IL-2 facilitate T-cell
activation-induced apoptosis. The high frequency of HIV-specific CD8 T
cells may be partly due to higher concentrations of stromal cell and
monocyte-derived cytokines, such as IL-7, IL-12, and IL-15, which
promote T-cell survival but not apoptosis, compared with CD4
T-cell-derived IL-2.57-62 CD4 T cells also express
molecules whose ligation is directly or indirectly required for CTL
differentiation. For example, ligation of CD40L on CD4 T cells
activates dendritic cells (DCs) to provide signals for development of
CD8 CTLs.63-65 Although antiviral CD8 T cells persist in
CD4 T-cell-depleted mice, their function is
compromised.66,67 In this review we argue that CD8 T-cell
anergy contributes significantly to the progressive immunodeficiency of
untreated HIV-1 infection, as was first suggested by
Miedema68 and Lewis et al.69
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Potential dysfunction of antigen presentation by macrophages
and dendritic cells |
Lack of HIV-specific CD4 proliferation and CD8 cytotoxicity is
usually not overcome by antiretroviral therapy. As was originally suggested by Macatonia et al70 and more recently by
Shearer,71 CD4 and CD8 T-cell anergy in HIV-1 infection
may be a result of changes in antigen presentation by DCs or
macrophages (Figure 1). Interdigitating
DCs bring antigen from peripheral tissues to the lymph nodes
(LNs), where they activate naive T cells. Mature DCs strongly
up-regulate MHC class II and costimulatory molecules72 such as CD40, CD80, CD86, OX40L,73 and
4-1BBL,74 required for effective stimulation of a primary
T-cell response. Although monocytes and macrophages are infected with
HIV-1, whether DCs are infected remains
controversial.75-79 HIV-1 binds to DCs through the
association of gp120 with a recently described C-type lectin receptor,
DC-SIGN. Tight binding of HIV to DCs facilitates CD4 T-cell
infection.80,81 Because DC-SIGN is important for
DC-mediated T-cell activation, HIV-1 particles or free gp120 might
interfere with primary T-cell activation. However, this is just a
conjecture. In fact, freshly isolated DCs from spleen or blood of
HIV-1-infected donors have no significant differences in MHC class II
or costimulatory molecule expression and are not defective
antigen-presenting cells (APCs) after in vitro
maturation.76,82-87 Although CD11c+ DCs are
reduced in the blood of HIV-1-infected individuals, this reduction may
be due to their migration to LNs, where they are increased.88 However, the APC function of
cytokine-activated monocyte-derived DCs may have little relation to the
function of DCs in vivo. Expression of critical costimulatory molecules on interdigitating DCs in situ in the paracortical regions of LNs needs
to be studied.
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| Figure 1.
Dendritic cells and macrophages in HIV-infected patients
may hinder antigen presentation.
(A) Binding of HIV-1 gp120 to DC-SIGN on DCs enhances infection of CD4
T cells and may interfere with their activation. (B)
Macrophages from HIV-infected patients have reduced expression of
molecules required for effective stimulation of T cells and have
increased expression of molecules that can trigger apoptosis.
Macrophages with defective APC function are not necessarily infected
with HIV. The size of the labels in this figure reflects the relative
expression level on macrophages from healthy donors and HIV-infected
donors. Part B modified from Shearer71 copyright 1998 and reprinted with permission from Elsevier Science.
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Although no clear DC functional deficit has been demonstrated,
monocytes from HIV-infected donors aberrantly express molecules important for antigen presentation to T cells. HIV-infected macrophages are important for restimulating antigen-experienced HIV-specific T
cells. Monocyte/macrophages from HIV-infected donors have reduced MHC
class II and costimulatory CD80 and CD86 expression.89-91
Moreover, they have up-regulated fas and fasL as well as CD16,
molecules that may trigger apoptosis of HIV-specific T cells instead of activating a protective immune response.92,93 In vitro
HIV-1 infection of macrophages also up-regulates
fasL.92,94 Moreover, HIV-1 tat down-modulates
transcription of the mannose receptor, important for binding pathogens
and their efficient internalization for antigen
presentation.95
Monocyte-derived macrophages from HIV-infected donors are also likely
to be impaired in inducing TH1 and CTL responses because they produce less IL-12 and more IL-10.91,96 This may be
secondary to reduced CD4 helper function, because trimeric CD40L can
help restore IL-12 production in vitro, by substituting for CD40L on activated CD4 T cells.97 CD40L is required to activate
APCs to produce IL-12 and is required for generating functional
CTLs.63-65 Interestingly, the combination of CD40L-trimer
and IL-12 reverses CD4 and CD8 T-cell anergy in
vitro.56,98
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Granule-mediated killing of HIV-1-infected cells |
CTLs kill cells either by the granule exocytosis pathway (by
releasing cytotoxic granules that contain pore-forming perforin [PFP]
and granzyme proteases) or by engagement of death domain-containing receptors, such as fas or the tumor necrosis factor receptor (reviewed in Henkart99). The granule-mediated pathway, critical for
the immune defense against many viral infections, is absolutely
dependent on both PFP and granzymes.100 Mice genetically
deficient in PFP succumb to viral infections such as lymphocytic
choriomeningitis virus.101 Children with familial
hemophagocytic lymphohistiocytosis, linked to a defective perforin
gene, often die of overwhelming viral infections.102 Mouse
experiments have also shown that IFN production by viral-specific
CD8 T cells is important to control some viral
infections.103-105 Although HIV-1-infected CD4
T cells express twice as much fas as uninfected activated cells,
HIV-1-infected primary T cells are predominantly lysed by the
PFP-dependent granule-mediated pathway.43 This was shown
by using HIV-specific CD8 T-cell lines and clones responding to a
variety of HIV-1 proteins. Moreover, HIV-specific CD8 T cells do not
express the principal death receptor ligand fasL, even after
stimulation with HIV-1-infected CD4 cells.43
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Dysmaturation of HIV-specific CD8 T cells |
Phenotypic analysis of tetramer-stained, HIV-specific CD8 T cells
indicates that circulating viral-specific CD8+ T cells have
been previously activated, because they no longer express cell surface
markers, such as CD62L, CCR7, CD45RA, and CD28, present on
naive cells, and also express CD45RO, granzyme A (GzmA), and
bcl-2, not found in naive cells.6,8,28,106,107 (Table
1). This is not surprising, given the
high likelihood of prior encounter with HIV-1-infected cells. However,
protein expression profiles suggest that HIV-specific CD8 T cells
either have not fully differentiated into mature effector CTLs, have reverted to a memory type, or have become anergized. Another
possibility is that specific cells die before they fully mature;
however, this is unlikely, given the high frequency of HIV-specific CD8 T cells. Although no single surface marker unambiguously identifies CTLs, differentiation into effector CTLs is associated with
down-modulation of CD27 and CD28 and re-expression of
CD45RA.108-110 Although HIV-1 tetramer+ cells
are CD28
, they are uniformly CD27+ and
CD45RA in most donors.8,28,111 These
properties are distinct to HIV-specific cells, because they do not hold
for cells specific for Epstein-Barr virus (EBV) and cytomegalovirus
(CMV) in the same donors.28,107
Naive CD8 T cells have limited function on their initial encounter with
antigen; they are not cytolytic and do not produce effector cytokines
rapidly. It takes approximately 5 days to differentiate into effector
CTLs and to express cytolytic molecules.112 PFP and
granzymes are up-regulated in parallel.112 Circulating CD8 T cells in HIV-1-infected subjects, compared with healthy donors, have
an unusually high percentage of CD8 cells containing cytolytic granules, as measured by staining for the most abundant granule protease, GzmA.26 The overwhelming majority of HIV-1
tetramer+ CD8 T cells express GzmA.8,43
However, there is a disjunction between PFP and GzmA protein expression
in the LNs113 (Figure 2).
Although granzyme+ CD8 T cells are increased in
HIV-1-infected LNs compared with normal LNs, PFP+ cells
are rare. This finding holds for both acute and chronic HIV-1 samples
and is in contradistinction to acute infectious mononucleosis LNs in
which PFP and GzmA are both increased.114 Lack of LN
PFP-expressing CD8 T cells is not due to recent degranulation, because
degranulation would deplete granzymes as well as PFP. PFP is also not
expressed at high levels in circulating tetramer+
HIV-specific CD8 T cells.28 Lack of PFP seems to affect
HIV-specific cells preferentially, because about a third of all
circulating CD8 T cells (34% ± 20%) are PFP+ in a
diverse spectrum of HIV-1-infected patients.107 Moreover, in another study HIV-1 tetramer+ cells are
PFP, whereas CMV tetramer+ cells in the same
patient are PFP+.28 Because PFP is required to
lyse HIV-1-infected targets,43 lack of PFP may be
critical for impaired cytotoxicity, especially at LN sites of viral
production.
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| Figure 2.
Perforin staining is reduced
compared with staining for GzmA in adjacent LN sections from a donor
undergoing primary HIV infection.
In contrast, comparable levels of granzymes A and perforin were found
in samples from acute infectious mononucleosis. Figure taken from
Andersson et al113. Copyright 1999 and reprinted with
permission from Lippincott Williams & Wilkins.
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These results require further verification. The absence of PFP in
HIV-specific CD8 T cells compared with CD8 T cells specific for another
virus was reported in only one study. A word of caution also is
necessary before generalizing from results for HIV-1
tetramer+ cells to conclusions about all HIV-specific CD8 T
cells. HIV-1 epitopes for which tetramers are available are rarely
immunodominant.115-118 CD8 T cells responding to
subdominant or cryptogenic epitopes may have lower avidity interactions
with target cells than T cells in the immunodominant
response.119 They may revert to
CD45RAPFP memory cells if they are not
effectively activated by HIV-infected cells, especially if the viral
epitope has mutated. Low avidity interactions may alter T-cell
activation and differentiation, as has been shown for murine CD4 T
cells.120 Therefore, lack of PFP in HIV-specific CD8 T
cells needs to be confirmed by using a broader array of tetramers or
other methods.8,26-28
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CD8 T cells suppress HIV-1 replication by soluble factors |
CD8 T cells also suppress viral production by secreting cytokines
like IFN, inhibitory chemokines, such as macrophage inflammatory protein 1
(MIP-1), MIP-1
, and regulated on activation, normal T-cell expressed and secreted (RANTES), and other factors, some of which, such as CD8+ cell antiviral factor (CAF), remain
to be characterized.9-13 CAF is produced by
CD28+ CD8 T cells, which are substantially reduced in HIV-1
infection.121 The inhibitory chemokines, and perhaps other
suppressive molecules, are stored in cytotoxic granules with PFP and
granzymes.122 Leukemia inhibitory factor, also produced by
CD8 T cells, is a recently described potent HIV-1 suppressor factor,
active at concentrations 100-fold lower than the
-chemokines.123
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Reduced IFN- production by HIV-specific CD8 T cells in
late-stage patients |
IFN is important in antiviral immunity in genetically targeted
murine models.124-126 In more advanced patients, fewer
cells produce IFN in response to HIV-1, and the number of
IFN-producing cells initially increases with highly active
antiretrovial therapy.127-129 On a single cell basis,
IFN production in response to HIV-1-infected cells is impaired,
especially in late-stage patient samples.7,8,130 In one
study, IFN production was measured by intracellular staining after
stimulation with HIV-1-infected CD4 blasts in the presence or absence
of IL-28 (Figure 3). In
subjects with undetectable plasma viremia, adding IL-2 had no effect on
IFN production. In some subjects with measurable plasma viremia,
IL-2 increased the frequency of IFN-producing cells 4- to 5-fold.
IFN production was also detected after IL-2 was added to some
samples that had no IFN-producing cells without IL-2. Therefore, in
more advanced patients, IFN production is compromised. In another
approach, the numbers of HIV-1 tetramer+ CD8 T cells were
compared with the numbers of cells producing IFN after stimulation
with the tetrameric peptide. In mice, virtually every specific memory
cell produces IFN in response to antigenic peptide.131,132 In most HIV-infected subjects, however,
fewer than 25% of tetramer+ cells produce IFN after
stimulation with tetrameric peptide. Subjects with a high proportion of
IFN-producing tetramer+ cells are asymptomatic and have
well-maintained CD4 counts (> 650/µL). Most subjects with less than
25% IFN-producing tetramer+ cells have had
HIV-1-related stage B or C symptoms. Culturing tetramer+
cells in IL-15 and IL-2 converts them from nonresponsive to
IFN-producing cells.8
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| Figure 3.
The number of IFN-producing CD8 T cells in response
to HIV-1-infected CD4 T cells increases substantially in some
HIV-1-infected patient samples when IL-2 is added during the
stimulation.
Background IFN production in the presence of IL-2 but not infected CD4
T cells was low (< 0.05%) and was subtracted to get the frequency of
specific producers. Data are taken from Shankar et
al.8
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Therefore, IFN production in response to HIV-1, like cytotoxicity,
is partially impaired in vivo, especially in later-stage subjects,
because adding exogenous cytokines increases it. A few studies have not
found impaired IFN production in HIV-1 infection, but they have
either focused on donors with well-controlled or early
infection28 or measured production following stimulation with antigen plus auxiliary costimulatory agents to amplify IFN production.133 A recent study in rhesus macaques infected
with SIV mac239 confirms and illuminates the human
data.134 Although virtually all tetramer+ CD8
T cells produce IFN after vaccination or early after infection, within 6 months the proportion of specific cells that produce IFN
drops substantially. Loss of IFN production by antigen-specific CD8
T cells infiltrating melanoma tumors or circulating in melanoma patients has also been described.135-137
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Down-regulation of key signaling molecules CD3 and CD28 on
HIV-specific CD8 T cells |
The T-cell response can be dissected into a series of steps, any
of which might be impaired in HIV-specific CD8 T cells. The TCR complex
is composed of a clonotypic dimeric TCR, required for antigen
recognition, in noncovalent association with CD3, a multicomponent
signal transduction complex. CD3 consists of CD3
, CD3
, and CD3
chains and a CD3 chain-containing dimer (reviewed in Weiss
and Littman138). When the TCR encounters antigen on an
infected cell, a signal is sent into the cell via sequential tyrosine
phosphorylation of key TCR-associated signaling molecules. This signal
initiates formation of an "immunologic synapse" between the T cell
and its target. The TCR-CD3 complex, CD28 and associated signaling
molecules, such as lck, fyn, and protein kinase C
, cluster in the
center of the synapse, surrounded circumferentially by larger molecules
like CD2 and LFA-1, which stabilize the synapse. The synapse forms
within minutes of TCR engagement and lasts for more than an hour until
the entire TCR complex is internalized.139 Synapse
formation critically depends on the actin cytoskeleton to move
molecules in and out of the forming synapse.140 CD3 is
central to transmitting the TCR activation signal. It contains 3 immune-receptor tyrosine-activating motifs, which can be phosphorylated and serve as docking sites for SH2 domain-containing tyrosine kinases.
CD3 also links TCR-CD3 to actin.141,142
In antigen-experienced CD8 T cells, cytokine secretion and cytolysis
are triggered rapidly following TCR engagement.143
Cytolytic granules, which normally contain granzymes, PFP, and some
other components, are transported toward the immunologic synapse, and the granule membrane fuses to the CTL plasma membrane, releasing its
contents. Failure of cytolysis by HIV-specific CD8 T cells could be due
to lack of recognition of HIV-1-infected primary cells by the TCR,
failure or incomplete signaling by the TCR-CD3 complex, failure of
degranulation, absence of key cytolytic components such as PFP in the
cytolytic granules, or resistance of HIV-1-infected cells to
cytolysis. Because -chemokines are also stored in CTL granules,122 viral suppression would probably also be
impaired if granule exocytosis is blocked.
HIV-specific tetramer+ CD8 T cells uniformly have
down-modulated both CD3 and the principal costimulatory molecule
CD28.26,111,144 Down-modulation of CD3 was first
described in lymphocytes infiltrating murine tumors and has since been
found in a variety of human cancers.145-148 Not
surprisingly, circulating T cells of HIV-1-infected subjects also have
signaling defects.111,149 Using immunoprecipitation and
Western blotting, Stefanova et al149 found that kinase
activities of lck, fyn, and ZAP70 were decreased in HIV-1-infected
patients at varying disease stages but not in a group of LTNPs. CD3
down-modulation was also found by Western blotting in T cells from both
acutely infected donors and AIDS patients.111,149 However,
down-modulation of CD3 and CD28 also occurs in CD8 T cells during
other viral infections and therefore, is part of normal immune
regulation.150 CD3CD28CD8 T
cells from HIV-1-infected and healthy donors have a selective defect
in activating the IL-2 axis
they neither express the -chain of the
high affinity IL-2 receptor (CD25) nor produce
IL-2.111,150 This finding may be especially critical in
HIV-1 infection in which there is a special deficit in HIV-stimulated
production of IL-2 by CD4 T cells.
Down-modulation of CD3 and CD28 on most HIV-specific CD8 T
cells almost certainly raises the activation threshold for functions induced by TCR engagement.111,150,151 The threshold for
some functions, such as cytotoxicity, may be higher than for other functions, such as IFN production. In fact, CD8 T cells with down-modulated CD3 and CD28 produce IFN but not IL-2 after TCR activation.111,150 Different activation thresholds also
characterize CD4 T-cell cytokine production. Antigen-experienced CD4 T
cells are heterogeneous in the amounts of cytokines produced and in the
signals required to activate secretion.152 Cells that do not produce cytokines may be triggered in the presence of activated APCs or of antibodies to costimulatory pathways (CD28, CD49d, and
CD5).153 Raising the threshold for cytotoxicity protects the host from immunopathogenic consequences of lysing uninfected cells
expressing the low-affinity self-antigens on which the T cell was
selected in the thymus. The requirement for participation of nearby
antigen-specific helper cells may also help ensure that the target is
indeed infected.
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Exogenous IL-2 reconstitutes CTL function |
HIV-specific cytotoxicity and IFN production are greatly
enhanced by adding more than 100 IU/mL IL-2.8,151
Cytotoxicity requires IL-2 in most patient samples; IFN secretion is
enhanced by IL-2, especially in advanced patients. Therefore,
thresholds have been raised to different levels for different
functions. A high IL-2 concentration triggers the low-affinity
IL-2R, but much lower concentrations (~1 IU/mL) trigger the
high-affinity IL-2R. Because activated CD3-down-modulated cells do
not express high-affinity IL-2R, high IL-2 concentrations are needed to
improve their function. Therefore, in vivo high-dose IL-2 therapy in
HIV infection may do more than increase CD4 T cell numbers; it may also
improve CD8 antiviral function.154 This possibility should be examined.
Correction of CD8 T-cell function with IL-2 suggests that CD4 T
help may be important for protective CD8 T-cell function, as it
is in mouse lymphocytic choriomeningitis virus
infection.67 In HIV-infected humans, who lack a
proliferative response to CMV or HIV, antigen-specific CD8 T cells
persist, as they do in CD4 T- cell-depleted mice.155 Just
as antigen-specific CD8 T cells are not protective in CD4
T-cell-depleted mice, lack of effective HIV-specific CD4 help may also
be responsible for lack of immune protection by HIV-specific CD8 T
cells.51,151,156-158 Although this hypothesis is
attractive, supporting data are mostly indirect.
| |
Inhibitory natural killer cell receptors on CD8 T
cells |
Another possible contributory factor to CD8 T-cell
dysfunction in vivo could be inhibitory signaling by natural killer
(NK) cell-inhibitory receptors (NKRs), expressed on some CD8 T cells after activation.159 The receptors belong to 2 distinct
molecular types: (1) the immunoglobulin superfamily killer inhibitory
receptors (KIRs), which recognize specific HLA allotypes with common
structural features in the -1 domain, and (2) C-type lectin
receptors in the CD94 family, which display broad specificity for HLA
class I molecules through lectin interactions.160-162
CD94/NKG2-(A-C) and NKG2D lectinlike receptors, respectively, recognize
HLA-E (not down-modulated by HIV-1 nef46) and MHC
class I chain-related A (MICA). Additional immunoglobulinlike
receptors (ILT receptors) are expressed by activated T cells
and other leukocytes, and they interact broadly with class Ia
molecules. Within the receptor families, homologues, which bind the
same ligands, have opposite inhibitory or stimulatory activity.
However, the inhibitory receptors usually have higher affinity. CD8 T
cells expressing NKRs have oligoclonal TCRs, suggesting that they
correspond to antigen-specific cell expansions. Recently, NKRs on
melanoma-specific CD8 T cells have been shown to inhibit both
cytotoxicity and IFN production.137
Large numbers of CD8 T cells express NKRs in HIV-1 infection. Moreover,
NKR expression is up-regulated by cytokines, such as IL-10, IL-15, and
tumor growth factor , which are increased in HIV-1
infection.159,163,164 In HIV-infected donor samples, blocking NKR engagement with specific antibodies augments in vitro HIV-specific cytotoxicity.165 Therefore, it makes sense to
explore a role for NKR inhibitory signaling in blocking HIV-specific
CD8 T-cell function. A first step would be to show increased expression of NKRs on HIV-1 tetramer+ CD8 T cells.
| |
Inefficient trafficking of HIV-1-specific CD8 T cells
to LNs |
Another reason for incomplete HIV-1 control by CD8 T cells
could be inefficient access to sites of HIV-1 infection in LNs. T-cell
activation in vivo is associated with changes in surface phenotype,
which reflect alterations in migration and functional capability.
Initial activation of naive CD8 T cells occurs in T-cell zones of LNs
where naive cells encounter DCs bearing the antigen, which fits its
TCR. Naive T cells continuously recirculate from blood to LNs through
specialized high endothelial venules (HEVs). Sequential engagement of
L-selectin (CD62L) and LFA-1 on naive T cells to their respective
ligands on HEVs sets into motion tethering, rolling, and firm adhesion
to HEVs, prerequisite steps for transmigration into the surrounding LN
(reviewed in Springer166). A chemokine receptor CCR7 has
also emerged as an important determinant of T-cell homing to
LNs.167-169 CCR7 on T cells interacts with the chemokine
secondary lymphoid tissue chemokine on HEVs and regulates LN homing by
delivering an activation signal for LFA-1 binding.169-171
Studies in CCR7 knockout mice suggest that CCR7 is also important for
the movement of T cells within LNs. If the naive cell encounters
antigen, it proliferates and differentiates into effector cells in the
specialized microenvironment of the LN. In keeping with the requirement
of effector/memory cells to function at peripheral sites of infection,
previously activated CD8 T cells up-regulate adhesins, including CD44
and integrins, which contribute to their preferential homing to
inflamed tissues, from which naive cells are normally
excluded.172-175 The LN homing receptors L-selectin and
CCR7 are down-modulated on effector cells but are heterogeneously
expressed on memory cells, suggesting that memory cells recirculate
through LNs as part of immune surveillance.110
In HIV-1 infection there is a marked reduction in
CCR7+ naive and long-term memory cells.107
HIV-1, EBV, and CMV tetramer+ CD8 T cells from healthy
donors and HIV-1-infected donors, even with well-controlled disease,
do not express the lymphoid homing molecules CCR7 and
CD62L.107 Exclusion of effector cells from LNs, which
normally provides efficient division of labor among CD8 T cells and may
protect LNs from damage by inflammatory cytokines and cytolytic
enzymes, may work to the detriment of the host during infections, such
as HIV-1 or EBV, that target lymphocytes by converting LNs into
immunologically privileged sites. In fact, in paired PBMC and LN
aspirate samples from HIV-infected donors, there were 3- to 4-fold
fewer EBV tetramer+ cells in the LN than in the
circulation, despite the concentration of EBV infection in lymphoid
tissues.107 In acute SIV infection in macaques,
SIV-specific CD8 T cells are also preferentially excluded from LNs;
there are proportionately 4-fold fewer SIV tetramer+ cells
in LNs than in the circulation in the first weeks after infection
(P < .007).176
Circumstantial evidence also supports selective exclusion of
HIV-specific CD8 T cells from lymphoid sites of infection. The proportion of CD8 T cells in the LNs of HIV-infected patients is about
half of what it is in the circulation.107,177,178
Moreover, the number of copies of spliced and unspliced viral RNA per
cell is much higher in LNs than in PBMCs, as is the frequency of cells carrying infectious virus, suggesting a greater failure of protective immunity in the LN.177 During primary and chronic
infection, perturbations of T-cell receptor V repertoire, indicative
of expansions of antigen-specific CTLs, are more pronounced in blood CD8 T lymphocytes than in the LN.179,180
Exclusion of CCR7 T cells from the LNs in HIV-1 infection is probably
leaky. Gene-marked HIV-specific CD8 T-cell clones infused into
HIV-1-infected subjects can be identified in LNs.181 How efficiently they traffic there is unclear, because billions of cells
are administered in these clinical studies. The requirement of CD62L
and CCR7 expression for lymphocyte homing via HEVs might also be
superseded in an inflammatory setting. Moreover, some tissue-homing
lymphocytes can enter LNs through afferent lymph. Thus, additional
human LN studies are required to determine how much lack of LN homing
molecules interferes with the ability of HIV-specific cells to get to
infection sites.
| |
Conclusions |
HIV-specific CD8 T cells have multiple properties
that might explain their inadequate immunoprotective role in HIV-1
infection: (1) they are not cytotoxic, (2) they are impaired in
trafficking to the major LN sites of viral replication, (3) they do not
produce IL-2 and cannot respond to low concentrations of IL-2, and (4) they have down-modulated key molecules for T-cell signaling (Figure 4). Moreover, CD8 T-cell function may be
compromised even more in late-stage patients, when some of the
molecular defects no longer correct in vitro with exogenous
IL-2111 or when cytokine production is impaired. We now
need to understand the relative contributions of the recently described
novel mechanisms for CD8 T-cell dysfunction and their etiology. Closer
study of the properties of HIV-specific CD8 T cells in LTNPs will help
sort out what aspects of dysfunction are especially important for
effective immune protection. Some of CD8 T-cell dysfunction is part of
normal immune regulation of CD8 T cells to prevent these serial killers
from wreaking damage by the release of cytolytic enzymes or
inflammatory cytokines. For example, down-modulation of CD3 and CD28
and of LN homing receptors on antigen-specific CD8 T cells occurs in
other infections.107,150 Although much research has
focused on how CD4 T cells are regulated to prevent autoimmunity,
regulation of CD8 T cells is largely terra incognito. Understanding CD8
T-cell regulation is critical for understanding immune pathogenesis and
formulating strategies for immune intervention for HIV-1 and other
diseases, including cancer.
View larger version (26K):
[in this window]
[in a new window]
| Figure 4.
Model of mechanisms that may contribute to lack of
protection by antiviral CD8 T cells in HIV infection.
(1) HIV-1-infected cells are not recognized because of viral escape
mutations or nef-mediated down-modulation of class I molecules, (2)
signaling is impaired because of CD3 and CD28 down-modulation, (3)
cytotoxicity is inhibited by expression of NK inhibitory receptors
(KIR), (4) cytotoxicity is ineffective because of lack of PFP
in cytotoxic granules, and (5) antigen-specific CTLs do not
efficiently reach sites of infection because of down-modulation of
homing receptors. Figure modified from Chen et
al.107
|
|
Most tetramer+ HIV-specific CD8 T cells, unlike many
EBV- or CMV-specific cells, do not have an effector CTL phenotype.
Factors specific for HIV-1 infection that might influence CTL function are the continuous presence of high levels of infectious and
noninfectious viral antigens, the paucity of functioning viral-specific
CD4 helper cells, the effect of sustained inflammation on
antigen-presenting function of macrophages and DCs, and the effect of
particular HIV-1 gene products, such as tat or nef. A possible role of
HIV proteins in blocking CD8 T-cell maturation into effector CTLs has
yet to be studied. HIV-1 infection especially targets the helper CD4 T
cells that are important in regulating effector CTLs. In mouse models
in which CD4 T cells have been eliminated, protection against infection
is lost, even though some antigen-specific CD8 T cells persist but with
compromised function.66,67 These models may provide
helpful parallels for HIV-1 infection, where CD8 T-cell protection may
well correlate with preservation of HIV-specific CD4 T-cell
function.156,182 This link needs to be studied in more
depth by moving beyond counting the numbers of HIV-specific CD8 T cells
to studying their function with assays that avoid more than a few hours
of in vitro culture. Even after overnight culture, many CD8 functional
defects correct, giving the false impression of functional
competence. Studies that show no correlation between clinical status
(such as LTNP) and numbers of antigen-specific CD8 T-cells need
to be re-evaluated in light of new findings that many HIV-specific
cells may not function in vivo.
| |
Footnotes |
Submitted March 8, 2001; accepted May 17, 2001.
Supported by grants AI-42519 and AI-45406 (J.L.) and AI-41536 (J.A.)
from the National Institutes of Health and by grant 10850 (J.A.) from
the Swedish Medical Research Council.
@ 2001 by The American Society of Hematology
Reprints: Judy Lieberman, The Center for Blood Research, 800 Huntington Ave, Boston, MA 02115; e-mail:
lieberman{at}cbr.med.harvard.edu.
| |
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Abstract
Persistence of HIV-1-infected...
production by...
