HIV-1 Vpu interference with innate cell-mediated immune mechanisms.
ABSTRACT The HIV-1 accessory protein Vpu is emerging as a viral factor with a range of activities devoted to counteracting host innate immunity. Here, we review recent findings concerning the role of Vpu in hampering activation of cellular immune responses mediated by CD1d-restricted invariant natural killer T (iNKT) cells and natural killer (NK) cells. The two key findings are that Vpu interferes with CD1d expression and antigen presentation, and also with expression of the NK cell activation ligand NK-T and B cell antigen (NTB-A). Both these activities are mechanistically distinct from CD4 and Tetherin (BST-2) down-modulation. We summarize the mechanistic insights gained into Vpu interference with CD1d and NTB-A, as well as important challenges going forward, and discuss these mechanisms in the context of the role that iNKT and NK cells play in HIV-1 immunity and immunopathogenesis.
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ABSTRACT: The clinical successes of proteasome inhibitors for the treatment of cancer have highlighted the therapeutic potential of targeting this protein degradation system. However, proteasome inhibitors prevent the degradation of numerous proteins, which may cause adverse effects. Increased specificity could be achieved by inhibiting the components of the ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a multitude of processes at the cellular and organismal levels, and their dysregulation is implicated in many pathologies. SCF ubiquitin ligases are characterized by their high specificity for substrates, and these ligases therefore represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This Review explores and discusses potential strategies to target SCF-mediated biological processes to treat human diseases.dressNature Reviews Drug Discovery 11/2014; · 37.23 Impact Factor
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ABSTRACT: The chemokine receptor CCR7 plays a crucial role in the homing of central memory and naive T cells to peripheral lymphoid organs. Here, we show that the HIV-1 accessory protein Vpu downregulates CCR7 on the surface of CD4(+) T cells. Vpu and CCR7 were found to specifically interact and colocalize within the trans-Golgi network, where CCR7 is retained. Downmodulation of CCR7 did not involve degradation or endocytosis and was strictly dependent on Vpu expression. Stimulation of HIV-1-infected primary CD4(+) T cells with the CCR7 ligand CCL19 resulted in reduced mobilization of Ca(2+), reduced phosphorylation of Erk1/2, and impaired migration toward CCL19. Specific amino acid residues within the transmembrane domain of Vpu that were previously shown to be critical for BST-2 downmodulation (A14, A18, and W22) were also necessary for CCR7 downregulation. These results suggest that BST-2 and CCR7 may be downregulated via similar mechanisms.Cell reports. 06/2014;
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ABSTRACT: BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins.DOI: http://dx.doi.org/10.7554/eLife.02362.001.eLife Sciences 04/2014; 3:e02362. · 8.52 Impact Factor
Current HIV Research, 2012, 10, 327-333 327
HIV-1 Vpu Interference with Innate Cell-mediated Immune Mechanisms
Johan K. Sandberg*,1, Sofia K. Andersson1, Susanna M. Bächle1, Douglas F. Nixon2 and Markus Moll1
1Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital
Huddinge, Stockholm, Sweden; 2Division of Experimental Medicine, Department of Medicine, University of California,
San Francisco, San Francisco, CA, USA
Abstract: The HIV-1 accessory protein Vpu is emerging as a viral factor with a range of activities devoted to
counteracting host innate immunity. Here, we review recent findings concerning the role of Vpu in hampering activation
of cellular immune responses mediated by CD1d-restricted invariant natural killer T (iNKT) cells and natural killer (NK)
cells. The two key findings are that Vpu interferes with CD1d expression and antigen presentation, and also with
expression of the NK cell activation ligand NK-T and B cell antigen (NTB-A). Both these activities are mechanistically
distinct from CD4 and Tetherin (BST-2) down-modulation. We summarize the mechanistic insights gained into Vpu
interference with CD1d and NTB-A, as well as important challenges going forward, and discuss these mechanisms in the
context of the role that iNKT and NK cells play in HIV-1 immunity and immunopathogenesis.
Keywords: HIV-1, iNKT cells, CD1d, Vpu, NK cells, immune evasion, NTB-A, Nef, Vpr.
viral infections. Immune cells with innate characteristics
have the capacity to respond rapidly without the need for an
extensive priming phase, and such cells may therefore be
particularly important in controlling viral replication during
the first days of an infection. This group of cells includes
invariant CD1d-restricted natural killer T (iNKT) and natural
killer (NK) cells. iNKT cells are characterized by a semi-
invariant T cell receptor (TCR) that uses the TCR ?-chain
segments V?24 and J?18 preferentially paired with the
variable ?-chain V?11 segment . They have a surface
phenotype reminiscent of effector memory T cells [2, 3], and
can be subdivided into CD4+ and CD4- subsets with distinct
functional profiles [4, 5]. iNKT cells respond rapidly to two
distinct types of stimuli. First, they can recognize foreign
glycolipid antigens presented by CD1d molecules expressed
by antigen presenting cells such as dendritic cells (DCs),
monocytes and B cells [6, 7]. This mode of activation has
been observed with antigens from certain species of bacteria,
such as Sphingomonas [8, 9], and Borrelia burgdorferi .
Secondly, iNKT cells can be activated in the absence of
cognate CD1d-presented antigen through TCR recognition of
endogenous lipids in the context of inflammatory cytokines
such as IL-12 and IL-18 [11, 12]. The endogenous antigens
recognized in this way have long remained elusive, but very
identified as one such antigen . ?-GlcCer was found to
accumulate in response to infection as well as TLR agonists,
suggesting that this type of recognition may be relevant for
several pathogens including viruses.
Cellular immunity is important for host defense against
and production of cytokines and chemokines, and these
activities are regulated by a vast array of activating and
NK cells mediate their effector function through cytolysis
*Address correspondence to this author at the CIM, Department of
Medicine, F59, Karolinska Institutet, Karolinska University Hospital
Huddinge, 14186 Stockholm, Sweden; Tel: +46-8-58583298;
Fax: +46-8-7467637; E-mail: email@example.com
inhibitory receptors [14, 15]. One important activating
receptor is natural-killer group 2 member D (NKG2D) which
mediates activation upon engagement of stress-induced
MHC class I-related chain A and B (MICA/B) and members
of the UL16-binding protein (ULBP) family [16, 17].
Another activating NK cell receptor is DNAX accessory
molecule-1 (DNAM-1), which recognizes both the
poliovirus receptor (PVR) (CD155) and Nectin-2 (CD112)
. During a viral infection, the activating and inhibitory
receptors collectively have the delicate task to allow and
facilitate activation of anti-viral effector mechanisms against
infected cells, while at the same time limiting collateral
damage to uninfected host cells . Convincing evidence
for an important role of NK cells in viral infections in
humans comes from patients with NK cell defects that have
higher susceptibility to certain viruses, including herpes
viruses [20-22]. There is also evidence that several viruses
modulate expression of ligands for activating and inhibitory
NK cell receptors to evade recognition by these cells .
about the role of iNKT cells and NK cells in HIV-1 infection
with a special focus on the recent findings that the HIV-1
vpu gene-product interferes with expression of the iNKT cell
ligand CD1d , as well as the homotypic activating NK
cell receptor/ligand NTB-A .
In this paper, we briefly review what is currently known
iNKT CELLS IN HIV-1 INFECTION
of iNKT cells in peripheral blood are severely depressed in
HIV-1 infected adults [25, 26], and children  (Fig. 1).
This was subsequently confirmed by others , and similar
findings were made in non-human primate models of SIV
infection . The loss of iNKT cells appears to be rapid in
many patients, and this may be at least partly due to high
levels of CCR5 expression making them preferential targets
for HIV-1 (Fig. 1) [26, 27, 30]. Somewhat conflicting data
exist regarding the ability of antiretroviral treatment (ART)
to rescue quantitative and qualitative aspects of the iNKT
cell compartment, and the efficacy of ART in this context
In 2002, three groups independently reported that levels
1?7?-????/12 $58.00+.00 © 2012 Bentham Science Publishers
328 Current HIV Research, 2012, Vol. 10, No. 4 Sandberg et al.
may depend on timing of initiation of treatment [28, 31-34].
Some patients retain almost normal numbers of iNKT cells
throughout untreated chronic HIV-1 infection, but those cells
express an exhausted phenotype with elevated PD-1
expression [32, 35]. The mechanisms by which iNKT cells
respond to HIV-1 infection are incompletely known,
although iNKT cell supernatants have been shown to inhibit
HIV replication in vitro . Solid, albeit indirect, evidence
for an important role of iNKT cells in immune defense
against HIV-1 comes from the recent observations that the
virus carries several mechanisms for down-regulation of the
iNKT cell ligand CD1d (Fig. 1) [23, 36, 37].
INTERFERENCE WITH CD1d-MEDIATED ANTIGEN
PRESENTATION BY HIV-1 VPU AND NEF
of lipid antigens by the immune system plays an important
role in the host defense to infectious diseases . In
humans, endogenous and exogenous lipid-antigens are
presented to T cells by four different CD1 molecules; CD1a,
CD1b and CD1c (group I), and CD1d (group II) [39, 40].
These four types of CD1 molecules have distinct cellular
expression profiles as well as different sub-cellular
distributions, indicating a sophisticated system to survey the
presence of lipid antigens [39, 40]. Expression of group I
CD1 molecules is mainly confined to professional antigen
presenting cells (APCs) such as DCs and Langerhans cells,
while CD1d is also expressed in monocytes, macrophages, B
cell subsets, and some non-hematopoietic cells .
Noteworthy, CD1d is absent from the surface of naïve T
cells but can be expressed upon T cell activation . Thus,
CD1 molecules have an expression pattern that largely
overlaps with the host cell range of HIV-1.
Over the last decade is has become clear that recognition
accessory HIV-1 proteins Nef and Vpu inhibit the surface
expression of CD1d in a concerted action by intervening
with the intracellular trafficking of CD1d. Under normal
In recent years it has become evident, that the two
conditions, CD1d molecules, after initial trafficking to the
cell surface, constitutively recycle between the surface and
endosomal compartments to survey the endocytic system for
the presence of lipid antigens . Nef tends to retain CD1d
in the trans-Golgi network and increases its rate of
internalization from the cell surface . Vpu on the other
hand decreases the recycling of CD1d from endosomal
compartments to the cell surface, and co-localization of Vpu
and CD1d in early endosome antigen 1 (EEA-1) positive
structures indicates retention of CD1d in the early endosome
. Putting these observations together, we suggest a model
where Nef and Vpu in a synergistic fashion achieve the
efficient inhibition of CD1d cell surface expression in
productively infected DCs (Fig. 2). This model is supported
by the finding that virus mutants lacking the expression of
either Nef or Vpu still partially down-regulate CD1d
whereas a Nef/Vpu double-defective virus completely lacks
this activity . Whereas the detailed molecular
mechanisms and structural requirements remain to be
elucidated, physical interaction between CD1d and Nef as
well as CD1d and Vpu has been detected [23, 37]. It is,
however, unclear if the observed interactions are of direct
nature or if other cellular co-factors are involved in complex
formation and down-regulation. In addition to the effects of
Nef and Vpu, a single report suggested that adding soluble
HIV gp120 protein to U937 cells reduced surface CD1d
expression on these cells . The potential mechanisms
involved and relationship to the Vpu- and Nef-mediated
effects on the CD1d antigen presentation pathway remains to
interaction of a tyrosine-based motif in its cytoplasmic tail
with adaptor protein complex-2 (AP-2) . Mutation of the
known AP-2 binding sites in Nef strongly affected CD1d
down-regulation, indicating that Nef enhances CD1d
internalization by subverting the regular AP-2 mediated
trafficking of CD1d [36, 44]. Although Vpu contains three
potential AP-binding motifs in its cytoplasmic domain, Vpu
CD1d internalization from the cell surface requires
Fig. (1). HIV-1 impacts iNKT cells at three levels. Figure illustrates the three known ways that HIV-1 infection interferes with the function
of iNKT cells. iNKT cells are susceptible to direct HIV-1 infection. The residual iNKT cells that persist in chronic infection are functionally
impaired and display signs of exhaustion, with poor IFN? production, low proliferative capacity, and frequent PD-1 expression. Finally,
HIV-1 carries two independent mechanisms to interfere with CD1d-mediated antigen presentation via the action of the Vpu and Nef proteins.
by Vpu and Nef
Vpu Interference with Cell-Mediated Immunity Current HIV Research, 2012, Vol. 10, No. 4 329
interaction with AP-2 or other adaptor protein complexes has
so far not been demonstrated , making involvement of
AP-2 in Vpu-mediated inhibition of CD1d expression
unlikely. Down-regulation of CD4 and tetherin involves
association of Vpu with the cellular co-factor ?-TrCP to
mediate ubiquitination and proteasomal degradation, and
phosphorylation of Vpu at serine residues 52 and 56 may be
important in this process . The contributions of
proteasomal and lysosomal degradation in down-regulation
of tetherin from the cell surface are, however, controversially
discussed [46, 47]. Moreover, enhancement of virus particle
release by Vpu may occur in the complete absence of
tetherin degradation suggesting that the two processes are
not related . However, because CD1d down-regulation
from the cell surface does not require Vpu phosphorylation
(our unpublished observation), involvement of ?-TrCP-
mediated ubiquitination and proteasomal degradation is
unlikely to be involved in this process. These results
collectively prompt the search for cellular co-factors binding
Vpu and contributing to the Vpu-mediated retention of CD1d
in early endosomal compartments.
assessed in different experimental systems and comprise
early and late events of iNKT cell activation. HIV-1 infected
DCs, as well as Vpu-transfected cell lines, loaded with the
model lipid antigen ?-galactosylceramide
significantly reduced capacity to induce the formation of an
immunological synapse with iNKT cells . Likewise, the
activation of iNKT cells is reduced when either Nef- or Vpu-
transfected cell lines or HIV-1 infected DCs are used for
stimulation, demonstrating the potency of viral interference
with CD1d expression [23, 36, 37]. Reversion of the
phenotype by deleting functional expression of Nef and Vpu
fully restores the capacity of DCs to induce iNKT cell
activation, indicating that HIV-1 infected DCs are not unable
per se to activate iNKT cells .
The consequences of CD1d down-regulation have been
T cell responses to antigens presented by these CD1
molecules has not been much studied. The effect of HIV-1
on group I CD1 proteins was described in only a single
report, where CD1a down-regulation from the cell surface
was observed in DCs infected with recombinant HIV-1
pseudotyped with VSV-G . In that study, expression of
CD1b and CD1c was unaffected, and even down-regulation
of CD1d was not observed. Mechanistically, down-
regulation of CD1a appeared to be linked to the
redistribution of this molecule from the cell surface to
LAMP-1 positive compartments, an effect mediated by the
Nef protein. The biological consequences of HIV-1
interference with CD1a expression remain unclear and need
Interference of HIV-1 with the group I CD1 system and
NK CELLS IN HIV-1 INFECTION
control of HIV-1 infection and replication . NK cells can
fight HIV-1 via direct cytolysis of infected cells [51-53], and
production of chemokines and cytokines that directly or
indirectly inhibit viral entry and replication [54, 55]. In
addition, HIV-binding antibodies allow NK cells to mediate
antibody-dependent cellular cytotoxicity (ADCC), which
probably also contributes to control of virus [56, 57].
NK cells play a very important and multifaceted role in
immunoglobulin-like receptors (KIRs) and their HLA class
ligands are of particular interest in the HIV field, since the
observation that individuals expressing the activating
receptor KIR3DS1 together with certain HLA-Bw4 alleles
show slower progression to AIDS than people lacking either
one or both of these receptors . In addition, individuals
carrying some alleles of the inhibitory KIR3DL1 receptor
also display slower HIV disease progression . The
importance of the KIR3DL1/DS1 interaction with HLA-Bw4
has been substantiated by the observation that KIR3DS1+
NK cell activity is balanced by signals from activating
inhibitory receptors [14, 15]. Killer-cell
Fig. (2). HIV-1 Vpu and Nef interfere with CD1d-mediated antigen presentation. A) The normal AP-2 dependent trafficking of CD1d
through early and late endosomal compartments for antigen loading and presentation to iNKT cells. B) In HIV-1 infected cells this process is
disrupted by Nef that enhances internalization, and by Vpu that inhibits recycling of CD1d back to the cell surface. Possible co-factors in the
Vpu-mediated inhibition of recycling remain to be identified.
330 Current HIV Research, 2012, Vol. 10, No. 4 Sandberg et al.
NK cells are more effective in killing HIV-infected HLA-
Bw4+ target cells . Furthermore, KIR3DL1/DS1+ NK
cells expand in infected subjects carrying HLA-Bw4 [61,
62], and this NK cell expansion correlates with viral load in
chronic infection .
to HIV-1 furthermore results in global changes in receptor
expression levels and subset distribution [63, 64]. These
changes include the relative subset redistribution with fewer
CD56dim NK cells and expansion of an aberrant CD56
negative NK cell subset. The detailed mechanisms
underlying these changes in receptor expression and subset
composition of NK cells still remain largely unknown.
Engagement of the NK cell compartment in the response
VPU INTERFERENCE WITH NK CELL CYTOLYSIS
important role in the control of HIV-1 infection, one may
speculate that the virus should have evolved means to evade
NK cell recognition and killing of infected cells. This indeed
seems to be the case. It was recently discovered that the NK-
T and B cell antigen (NTB-A) is down-regulated from the
surface of HIV-1 infected cells , in a Vpu-dependent
manner . NTB-A is a member of the signaling
lymphocytic activation molecule (SLAM) family of
receptors . It is expressed on all lymphocytes and acts in
a homotypic manner as a co-activating receptor in NK cells
. Notably, NTB-A triggering is necessary to induce
efficient lysis of target cells upon engagement of the
activating receptor NKG2D, and Shah et al. were able to
show that down-regulation of NTB-A from the surface of
HIV-1 infected cells contributes to the relatively poor NK
cell cytolytic activity against such cells (Fig. 3) . Similar
to Vpu-mediated down-regulation of CD1d, NTB-A down-
regulation does not involve ?-TrCP recruitment and
subsequent degradation of the protein, nor the enhanced
internalization from the cell surface. Interestingly, Vpu
mediates its effect on NTB-A via its transmembrane region,
and leads to accumulation of the protein in an as of yet not
described intracellular compartment.
With the mounting evidence that NK cells have an
-B class I molecules , and the vpr gene-product induces
an increased expression of some activating NKG2D ligands
(Fig. 3) [68-70]. These changes would be expected to make
cells tasty targets for NK cell killing. Vpu-mediated
interference with NTB-A expression may thus be very
important for HIV-1 to evade elimination by NK cells.
Furthermore, it was recently observed that Nef and Vpu
together act to down-regulate the DNAM-1 ligand PVR from
the surface of infected cells  (Fig. 3). Nef appears to
mediate this effect on PVR by a mechanism similar to that
used to down-regulate MHC class I molecules, whereas the
mechanism underlying Vpu’s effects on PVR is unknown
HIV-1 Nef is known to inhibit expression of HLA-A and
observation that NKG2D functions as an activating and co-
activating receptor in T cells, including iNKT cells .
Vpr-induced expression of ULBPs may thus to some extent
counteract the activities by Vpu to inhibit activation of both
NK cells and iNKT cells. When viewed together with the
effects on tetherin and CD1d, the findings concerning down-
Yet another layer of complexity comes from the
regulation of ligands for activating NK cell receptors
indicate that Vpu may be a critical factor for HIV-1 evasion
from innate immune mechanisms .
capacity of Vpu proteins derived from the different HIV-1
groups to interfere with surface expression and function of
CD4 and Tetherin. Whereas the Vpu proteins of pandemic
group M viruses are able to induce both CD4 degradation
and antagonize Tetherin, HIV-1 group N, O and P Vpu
proteins perform only one of these functions [74, 75]. The
non-pandemic groups of viruses are geographically restricted
to West-central Africa, and acquisition of a functionally fully
competent Vpu may have contributed to the global success
of HIV-1 group M viruses . In this context it will be
important to investigate if the capacity to inhibit expression
of CD1d and NTB-A is conserved among Vpu proteins
derived from the different HIV-1 groups.
Significant effort has been put into investigating the
in the face of severe selection pressures, maintains the ability
to interfere with the lipid antigen presenting molecule CD1d.
To our knowledge, neither HIV-specific T cells restricted by
CD1 molecules nor HIV-derived lipid antigens have yet been
identified. Furthermore, viruses do not encode lipids, and the
lipid envelope of HIV is derived from host cell membranes.
The need to interfere with CD1-mediated antigen
presentation is therefore not self-evident. A possible scenario
is that iNKT cell recognition of infected cells is independent
of foreign lipid antigen. Cytokines produced by a virus
infected or exposed cell in combination with the recognition
of endogenous lipid antigens presented by CD1d may be
sufficient for iNKT cell activation. It is also possible that an
altered lipid metabolism in HIV infected cells may generate
an altered endogenous lipid antigen content in CD1
molecules. Furthermore, the recent discovery that CD1a and
CD1c are able to present lipid-modified peptides opens up
the possibility that virally derived lipopeptides may be
presented by CD1 molecules [77, 78]. Future studies may
reveal if the myristoylated HIV-1 proteins p17 and Nef give
rise to CD1-presented lipopeptide structures enabling T cells
to recognize HIV-1 infected cells.
The question arises why HIV-1 with its limited genome,
the HIV-1 life cycle . The effects that these viral proteins
have on CD1d, NTB-A, MHC class I, and PVR may
therefore vary over the life span of a productively infected
cell. Detailed studies of the expression of these viral factors
as well as their target host proteins over time in DCs and
CD4 T cells may give important insight into the complexity
of Vpu- and Nef-mediated evasion from innate cell-mediated
Nef is expressed early, whereas Vpu is expressed late in
mediated inhibition of CD1d and NTB-A expression will be
important for the basic understanding of these apparent
immune evasion mechanisms. Furthermore, this level of
understanding may allow rational design of a novel class of
anti-viral treatments. We speculate that pharmaceutical
interference with these functions of Vpu might help improve
the contribution of innate immunity to control of viral
Elucidation of the fine mechanistic detail of Vpu-
Vpu Interference with Cell-Mediated Immunity Current HIV Research, 2012, Vol. 10, No. 4 331
Council, the Swedish Cancer Foundation, the Swedish
Physicians Against AIDS Foundation, Karolinska Institutet,
Stockholm County Council, and the US National Institutes
of Health grant AI52731.
This work was supported by the Swedish Research
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Fig. (3). Vpu, Nef and Vpr modulate expression of NK cell ligands on the surface of HIV-1 infected cells. Cell surface ligands of NK
cell receptors are modulated by HIV-1 accessory proteins Nef, Vpr and Vpu resulting in the down-regulation of HLA-A and -B molecules,
up-regulation of the ULBP NKG2D ligands, inhibition of NTB-A expression, and down-regulation of the DNAM-1 ligand PVR.
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Received: January 21, 2012
Revised: March 6, 2012 Accepted: March 14, 2012