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Special Reviews

Innate immunity in the control of HIV/AIDS

recent advances and open questions

Ploquin, Mickaël J.-Y.a; Jacquelin, Béatricea; Jochems, Simon P.a,b; Barré-Sinoussi, Françoisea; Müller-Trutwin, Michaela C.a

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doi: 10.1097/QAD.0b013e328353e46b
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Abstract

Introduction

Since the beginning of the HIV pandemic, scientific attention has been directed at developing new affordable strategies to prevent HIV infection. Therefore, the identification of protective factors against HIV infection and/or disease is extremely beneficial in deriving rational approaches for vaccines or therapeutics. However, the field is still lacking knowledge regarding the immune correlates of protection, including the role of innate immunity (Table 1). Rare individuals displaying spontaneous resistance to infection, called ‘exposed uninfected individuals’ [1] or to progression to AIDS, such as ‘long-term nonprogressors’ (LTNPs) and ‘elite controllers’ [2,3], can help identify and elucidate natural mechanisms of protection. The majority of elite controllers display robust anti-HIV-1-specific CD8+ T-cell responses ([4], this issue). However, a large proportion of elite controllers lacks efficient T-cell responses [5]. Innate responses might be involved in HIV control in elite controllers. Furthermore, some African nonhuman primates naturally infected with simian immunodeficiency virus (SIV) (e.g. sooty mangabeys and African green monkeys) lack signs of generalized immune activation and are resistant to AIDS despite viremia as high as those observed in viremic patients [6,7] or in SIV-infected macaques. These simian models can provide crucial clues to understanding innate mechanisms associated with resistance as well as susceptibility to disease progression [8,9]. Therefore, studying all these individuals and nonhuman primate models can shed light on the role of innate immune responses, their complexity and their influence on the control of and the outcome of HIV/SIV infections. This review will emphasize in particular the role of dendritic cells and natural killer (NK) cells as examples of innate immune responses to HIV.

Table 1
Table 1:
Components of the innate immune system.

Innate immunity as a firewall sensing HIV-1 entry into host target cells

Recognition via Toll-like receptors in plasmacytoid dendritic cells

During mucosal infections, HIV must breach the robust physical barrier formed by epithelial cells to infect the deeply embedded CD4+ T cells [10,11]. On its way to the basal epithelium, resident innate target cells such as dendritic cells can capture HIV-1 upon gp120–CD4 interactions. These cells express pattern recognition receptors acting as viral sensors, notably the Toll-like receptors (TLRs) that ‘recognize’ viral intrusion (Fig. 1). HIV-1 recognition by plasmacytoid dendritic cells (pDCs) is mediated mostly by TLR7, but also by TLR9 [12–14]. This recognition is intracellular and requires virion endocytosis followed by trafficking to early endosomes [15]. PDCs can sense HIV-1-infected cells more efficiently than free virions [14,16]. Increased expression of TLR7/9 by pDCs following pDC–epithelial cell interactions in vitro[17] supports the concept that in-vivo pDCs may respond to infection to gain better HIV-1 sensing ability. Upon HIV-1-mediated TLR7 activation, pDCs do not fully mature but upregulate IRF7 expression and persistently become type I interferon (IFN)-I-producing cells [15]. IFN-I is known to inhibit early stages of the HIV-1 replication cycle [18]. It seems counterintuitive for HIV-1 to trigger a long-lasting IFN-I response, as it could hinder its replication. However, as we will discuss in further sections, HIV-1 tends to promote IFN-I and innate inflammatory responses to recruit activated target cells leading to a local amplification of infection. HIV-1 is also capable of escaping IFN-I-induced antiviral activity.

Fig. 1
Fig. 1:
Inflammatory innate responses are a two-edged sword.Early innate events either preventing viral replication (displayed in blue) or promoting viral amplification and inflammation (displayed in red) are shown here. They may occur simultaneously in vivo and the balance of these events may determine the efficiency of viral confinement at the site of entry or viral spread to lymphoid organs. HIV-1 triggers inflammatory cytokines and chemokines and thereby the recruitment of new target cells (activated CD4+ T cells, dendritic cells) at the site of entry. Activated CD4+ T cells are the highest producers of HIV locally. Type I IFN (IFN-I) and TNF-α, released by pDCs, enhance mDC maturation and increase their homing capacity to lymphoid organs, contributing to HIV-1 dissemination to lymphoid organs. Additionally, strong and harmful inflammation triggers anti-inflammatory cytokine production, i.e. IL-10, TGF-β in an unsuccessful attempt to suppress inflammation. These detrimental side effects of the innate response are counterbalanced by the capacity of innate immunity to confine HIV replication. Indeed, activated dendritic cells can lead to NK cell activation to ensure killing of virus-infected cells. The discovery of innate restrictions factors, intrinsic hindrance of HIV-1 replication in target cells in elite controllers as well as the peculiar composition of mucosal secretions in exposed uninfected individuals emphasizes the protective role of innate responses. DC, dendritic cell.

Alternative sensors of HIV-1

Additional sensors of HIV may exist and remain to be clearly identified. Notably, activation of unknown innate sensor(s) was proposed in myeloid dendritic cells (mDCs) upon viral capsid–cyclophilinA interactions [19,20]. Other, but yet unidentified, innate nucleic acid sensors act in T cells and TREX1 has been shown to counteract their effects in HIV-1 infection [21,22]. In vitro, epithelial-like cells can sense HIV-1 in an IRF3-dependent manner [16] and secrete chemokines in response to HIV to recruit dendritic cells [23]. PDCs die due to apoptosis [24] and at later stages of HIV/SIV infections pDCs seem to be no longer the major producers of IFN-I [25]. Understanding HIV-sensing mechanisms in dendritic cells is currently an important area of research [20,26].

Nod-like receptors (NLRs) have been proposed as an alternative to TLRs in other infections [27,28]. The NLR family pyrin-domain-containing-3 (NALP3, also known as NLRP3) has been recently proposed as a novel cytoplasmic sensor for cytidine-phosphate-guanosine DNA motifs present in bacteria and viruses and for viral ssRNA and dsRNA [27]. NALP3 interacts with coadaptor proteins to form molecular complexes known as inflammasomes. The inflammasome triggering leads to the production of proinflammatory interleukins (IL) such as IL-1β and IL-18 [28]. The latter are released in substantial amounts during HIV/SIVmac infections [29–31]. Although no data clearly show that HIV-1 genetic material can activate the inflammasome, polymorphisms in NALP3 and in IL1B are associated with a higher risk for HIV-1 infection [32,33]. Inactivated HIV-1 also induces an important NALP3 RNA expression within 4 h in monocyte-derived dendritic cells accompanied by an increased release of IL-1β [34]. Notably, dendritic cells from HIV-1-positive individuals, independent of the presence of antiretroviral therapy (ART), failed to increase NALP3 expression due to already elevated basal expression. This finding suggests a chronic state of activation of dendritic cells in HIV-1 infection [34].

HIV/SIV transmission occurs at higher rates during coinfection notably with herpes simplex virus 2 [35]. More studies [35,36] are required on the impact of such coinfections on the innate immune responses, such as TLR, inflammasome triggering and consequences for adaptive responses controlling the outcome of HIV/SIV infections.

In conclusion, dendritic cells are critical protagonists during the first steps of HIV-1 infection, as they detect viral intrusion. More investigations are needed regarding the mechanisms of recognition, the role of sensors other than TLRs and on the consequential processes following the sensing of HIV. These responses are important either to confine infection at the site of entry or to promote inflammation and viral dissemination.

Innate immunity controlling HIV-1 infection and promoting viral dissemination

Intrinsic cellular hindrance of viral replication

Innate restriction factors, such as ‘tripartite motif-containing protein 5 alpha’ (TRIM5α), APO lipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC-3G) and tetherin, can inhibit HIV replication at different stages of the replication cycle [37,38]. Although not generally considered part of the innate immune system, these intrinsic factors represent a natural activity against HIV infection. Moreover, several of them are produced by cells of the innate immune system and/or triggered by IFN-I, which is released predominantly by pDCs in the case of HIV, as described above.

SAM domain-containing and HD domain-containing protein 1 (SAMHD1) is the most recently discovered restriction factor with its activity specifically confined to differentiated uncycling cells like macrophages and mDCs [39,40]. Polymorphisms in genes encoding for restriction factors such as APOBEC3G and TRIM5α have been associated with the rate of disease progression [41]. In most cases, HIV-1 has evolved to counteract these innate antiviral factors: the viral capsid for TRIM5α, Vpu/Nef/Env for tetherin, Vif for APOBEC3G and Vpx for SAMHD1 [26]. These instances of viral escape demonstrate that such restriction factors potentially are important components of defense.

More recently, evidence shows that exposed uninfected individuals have an unappreciated molecular mucosal composition [42]. Characterization of cervical mucosa protein expression showed an overabundance (>40%) of protease inhibitors, including serpins, cystatins and A2ML1, among 360 unique proteins identified as compared with HIV-1-positive controls. It is not known, however, whether these factors cause HIV-1 resistance, or are merely associated with this phenotype [42]. Previously described anti-HIV-1 factors, elevated in mucosal secretions from exposed uninfected individuals, such as regulated upon activation, normal T-cell expressed and secreted (RANTES) [43], chemokines, secretory leukocyte protease inhibitor (SLPI) and macrophage inflammatory protein alpha/beta (MIP-α/β) [44] and elafin [45], have also been suggested as factors associated with resistance to HIV-1.

Additional intrinsic resistance of target cells, especially in macrophages, equally leads to host inhibitors of HIV-1 replication [46]. Macrophages are one of the HIV-1 cell targets and may play a role in the reservoir and pathogenesis of HIV-1 infection. On one hand, aggregation of activating immunoglobulin G Fc receptors by immune complexes inhibits reverse transcript accumulation and integration of HIV-1 in macrophages via the induction of the cyclin-dependent kinase inhibitor p21 (Cip1/WAF1) [47]. On the other hand, HIV-1 is blocked in macrophages activated via TLR3, TLR4 or TLR8 ligands [48]. The TLR4-activated primary macrophages were reported to downregulate CCR5 expression and acquire resistance to R5 HIV-1 entry and replication [49]. This response might be important once the infection is established and particularly during HIV-1-induced bacterial translocation. Macrophages derived in vitro and CD4+ T cells from elite controllers dramatically restrict HIV-1 replication during reverse transcription in contrast to macrophages from HIV-1-seronegative donors [50]. This reduced susceptibility to infection is not due to increased expression of the known innate restriction factors (TRIM5α, APOBEC3G, tetherin). It may be SAMHD1. Nevertheless, the degree of restriction observed in vitro correlated with the size of the viral reservoir in vivo[50].

Control of HIV-1 infection by natural killer cells

Exposure to IFN-I and contact with activated dendritic cells producing IL-12 and IL-15 enhance proliferation, IFN-γ production and cytotoxic activity of NK cells against infected cells [51–54]. NK cells in mucosa [55,56] are among the first lines of defense against HIV-1-infected cells. NK cell subset distribution is tissue-specific [57]. NK cells represent up to 70% of leukocytes in the decidua [58] and may participate [59] along with local decidual soluble factors [60] in the innate control of HIV-1 infection at the materno–foetal interface. During HIV-1 infection, NK cells may control the virus, especially at the early stages of HIV-1 infection before adaptive immunity is initiated [61]. A balance between activating and inhibitory signals explains the fine tuning of NK cell activation [62,63]. The expression of NK cell surface receptors can be modified by specific cellular ligands expressed on HIV-1-infected cells. For instance, HIV-infected mDCs promote the downregulation of CD85j expression on NK cells, whereas CD85j+ NK cells highly protect mDCs from HIV-1 infection [64]. Association of killer cell immunoglobulin-like receptor (KIR) polymorphism with a different outcome of HIV-1 infection [41,62,65] emphasizes the fundamental role of NK cells [66,67]. In line with this observation, exposed uninfected individuals exhibit higher ex-vivo NK cell cytotoxic activity and cytokine production (IFNγ) [68,69]. This finding was made in association with the expansion of particular NK cell subsets bearing a high KIR3DS1/KIR3DL1 ratio, along with downregulated KIR3DL1 transcript levels, or an enhanced NKG2C/NKG2A ratio.

HIV-1 seems to have the ability to escape from active NK cell immune surveillance by adapting the Vpu-Env region to host KIR genotypes, especially KIR2DL2[70]. These ‘KIR footprints’ in Vpu-Env result in enhanced binding of inhibitory KIRs to HIV-1-infected CD4+ T cells in vitro.

During acute HIV-1 infection, cytotoxic CD56dim NK cells preferentially expand concomitantly with decreased numbers of cytokine-producing CD56bright NK cells [71]. In addition, an expression of inhibitory receptors begins during primary infection [71–73] and is maintained during the chronic phase in association with viremia and immune activation [74]. Chronic HIV-1 infection is associated with an expansion of the anergic CD56neg NK cell subset at the expense of both the CD56bright and CD56dim NK cells [75]. During progressive HIV-1 infection, NK cell mucosal distribution is altered [56]. In lymph nodes [15], acute HIV-1 infection does not change the numbers or distribution of NK cell subsets as compared with healthy individuals [76], with KIR NK cells being the major NK cell subset. This finding is explained by a decreased capacity of KIR+ and KIR NK cells for homing to lymph nodes. Nevertheless, lymph node KIR NK cells are highly activated and express tumor necrosis factor-related apoptosis inducing ligand (TRAIL) [76]. The decreased homing capacity of cytotoxic KIR+ NK cells offers an additional opportunity for HIV-1 to escape a control of viral replication and to establish long-term infection in lymph nodes [76]. NK cells from elite controllers and LTNP may also resist anergy [77]. However, elite controller NK cells are less robust than CD8+ T cells at killing autologous CD4+ T cells and their role in regulating the size of the reservoirs remains to be defined [78]. The existence of other innate cells with increased cytotoxic activities such as dendritic cells in LTNP and elite controllers is not excluded either [79,80].

Inflammation and viral dissemination

During viral infection, innate immunity is critical in limiting the size of the viral reservoir [81]. However, innate responses may also amplify the viral reservoir instead of limiting viral spread by attracting new HIV target cells to the sites of infection. Upon HIV/SIV mucosal infection, amplification of viral replication within the site of entry is necessary before dissemination to the lymph nodes [82]. Local inflammatory innate responses triggered upon sensing of HIV-1 may be a prerequisite for establishment of these foci [82]. Cytokines and chemokines released by innate immune cells, such as pDCs, macrophages and NK cells, can theoretically promote recruitment of other innate cells, as well as activated CD4+ T cells [83]. Thus, more target cells become available for infection. Of note, chemokines such as CXCL9/10 can also promote viral latency in resting CD4+ T cells and thus enhance the establishment of viral reservoirs capable of escaping immunosurveillance [84]. A cytokine storm, to which pDCs may contribute, is produced very early after HIV-1 infection [31,85,86]. As early as a few hours after infection, pDCs are attracted to the submucosae and have been shown to be hyperfunctional during the early stages of primary infection and to produce high levels of IFN-I and other cytokines [87,88].

IFN-I priming leads to interferon-stimulated gene (ISG) expression, including chemokines, such as CXCL9/10/11, which could further amplify recruitment of cells to sites of infection. Moreover, to date, IFN-I with ISG expression is considered one of the best inflammatory markers associated with HIV-1 pathogenesis [8,89]. In mice, IFN-I downstream signaling, especially in dendritic cells, hinders T helper 17 cell (Th17) development [90,91]. Therefore, during pathogenic SIVmac infection, chronic IFN-I priming could account for the loss of IL-17 immunity. In line with this hypothesis, natural SIV infections lack chronic ISG expression in all compartments and maintain Th17 in contrast to SIVmac infection [8,92,93]. This characteristic may result from an efficient downregulation of inflammation by the end of the acute infection in the natural primate hosts [94]. It is unclear, however, to what extent IFN-I and ISG expressions contribute directly to generalized immune activation or only represent excellent surrogate markers of inflammation.

In the future, the earliest innate responses that result either in early containment of viral replication or in harmful inflammation with viral dissemination and the mechanisms that tip this balance have to be addressed (Fig. 2). Macrophages were extensively studied in the early days of HIV research. Nevertheless, the role of HIV-1-infected macrophages in this balance should be revisited in view of the latest findings on the early events of HIV infection. A major contribution in inflammatory processes by other innate immune cells, such as neutrophils, is not excluded either and also remains to be explored.

Fig. 2
Fig. 2:
Early innate events are determinant for the degree of viral dissemination.HIV-1 triggers innate inflammatory responses leading to confinement of infection at the site of entry (in blue) versus deleterious inflammation promoting viral dissemination (in red). Understanding the precise signals that tip this balance may help to control the size of viral reservoirs.

Innate immunity and its modulatory role in shaping adaptive immunity

HIV-1 infection modulates the natural killer/dendritic cell cross-talk

In the majority of HIV-1-infected individuals, the rate of disease progression depends on the host capacity to mount efficient adaptive immune responses. This effect is well achieved in the rare elite controllers who exhibit robust CD8+ T-cell responses [2,3,95]. Dendritic cells equipped with the full antigen presentation machinery are necessary in shaping T-cell responses. HIV does not directly activate mDCs, but the IFN-I and TNF-α released by pDCs induce bystander maturation of mDCs [96,97]. Circulating mDCs from elite controllers display increased antigen-presenting properties and release less inflammatory cytokines with regard to HIV-1-infected progressors [98]. The latter exhibit numerical and functional dendritic cell deficiencies [96,99].

Activated NK cells may indirectly help to prime T-cell responses by secreting cytokines, such as IFN-γ, which promote the differentiation of activated CD4+ T cells into Th1 effector cells [83]. Dendritic cells and NK cells are both present in sites of infection and inflammation [55,56,76]. NK/dendritic cell interactions were found to be a critical checkpoint in shaping the adaptive immune response [96], which ensures an optimization of the dendritic cell differentiation process. At high NK/dendritic cell ratios, interactions lead to the killing of immature dendritic cell (iDCs) through engagement of the activating receptor NKp30. In this manner, only the mature dendritic cells survive and migrate to inductive sites to fully present HIV-1 antigens and license T cells. Conversely, at low NK/dendritic cell ratios, dendritic cells activate NK cells.

The NK/dendritic cell cross-talk during HIV-1 infection remains to be further explored. HIV-1 infection of dendritic cells may interfere with their ability to prime the appropriate NK cell response [67]. HIV-1 Vpr hinders pDC production of IFN-I and IFN-γ production by NK cells upon NK/pDC interaction [100]. Furthermore, NK cells from viremic patients show a decreased ability to kill iDCs [101,102]. The defect is associated with an increase in the proportion of rare CD56 NK cells with impaired NKp30 function during acute HIV-1 infection, early depletion of CD56bright NK cells, as discussed above, and an upregulation of the high mobility group box 1 protein (HMGB1) [102,103].

Notably, a recent report shows that the strength of the NK/dendritic cell cross-talk is greater in exposed uninfected individuals [104]. Activated NK cells from these individuals exhibit a higher ability to eliminate autologous iDCs. In turn, iDCs from these individuals produced more IL-12, which may positively feedback on the robust NK cell activity [105]. Also, iDCs from exposed uninfected individuals enhance NK cell activity (degranulation and IFN-γ production) in comparison to that observed with HIV-1-negative or other HIV-1-positive individuals [104,106]. This increased NK cell ability was not associated with higher expression of NKp30 or other NK cell surface receptors, nor with a peculiar expression of major histocompatibility complex class I molecules [104].

Protective coordination of natural killer and CD8+ T-cell responses during HIV-1 infection

Dynamics of NK and HIV-1-specific CD8+ T cells have previously been characterized [61]. NK cell responses start very early during acute HIV-1 infection and are dramatically elevated when HIV-1-specific CD8+ T-cell responses are still absent or weak. Then they decline after the emergence of HIV-specific CD8+ T cells. In contrast, both NK and CD8+ T-cell populations are substantially expanded during rebound of viral replication after ART interruption in chronic HIV-1 infection [61].

Growing evidence from studies in mice reveals an unappreciated role of NK cells as rheostat [107–109] (or competitors?) of T-cell responses. NK cell depletion improves memory CD8+ T-cell formation [110]. Of note, NK cells negatively affect both CD4+ and CD8+ T-cell expansion and effector functions during the mouse cytomegalovirus infection whose clearance depends mainly on NK cells [108]. In contrast, during the lymphocytic choriomeningitis virus (LCMV) infection in which CD4+ and CD8+ T cells are required for immune control, the presence of NK cells inhibits virus-specific polyfunctional T cells [107,109]. They, therefore, negatively impact the efficiency of viral clearance by directly suppressing activated CD4+ T cells [109]. During the natural course of HIV-1 infection, to achieve a minimal size of viral reservoirs, NK and virus-specific CD8+ T cells must cooperate in a timely manner. This coordination between NK and T-cell responses might be compromised during chronic HIV infection. Paradoxically and notably with respect to HIV infection, NK cell-mediated killing of activated CD4+ T cells prevents immunopathology and mortality in the LCMV infection model [109].

Despite the lack of knowledge regarding ways to trigger a potential-specific (and still debatable) memory NK cell responses [111,112], it is time now for rational approaches focusing on NK cells in HIV vaccine research [113]. The observations from mice studies raise exciting questions for the control of HIV-1 infection and disease progression. The clinical state in exposed uninfected individuals and the elite controllers could reflect the difference in strength in NK cell activity and NK/dendritic cell cross-talk (see model Fig. 3) [5,98,114,115].

Fig. 3
Fig. 3:
Different strength in natural killer/dendritic cell cross-talk and shaping of T-cell responses: possible consequences for the outcome of HIV-1 infection.(a) In our model, exposed uninfected individuals (EUs) are characterized by the most intense NK/dendritic cell cross-talk: NK cells display ex vivo higher cytotoxic capacity against infected cells and dendritic cells. In turn, dendritic cells enhance NK cell activation. Hypothetically, in (EUs), the more intense NK/dendritic cell cross-talk secures a robust confinement of HIV-1 infection at the site of exposure and prevents viral dissemination. Killing of dendritic cells may explain poor T-cell responses [114,115]. In EUs, NK cells could be the genuine ‘viral controllers’. (b) Elite controllers (ECs) and LTNP individuals exhibit anergy-resistant NK cells with milder cytotoxic activity than CD8+ T cells. The latter are easily detected at least in blood and might be accountable for control of viral reservoirs [5]. DCs from ECs have increased antigen-presenting properties and diminished propensity to release pro-inflammatory cytokines [98]. Appropriate dendritic cell maturation and migration to lymphoid organs trigger protective T-cell responses. Hypothetically, the NK/dendritic cell cross-talk in those EC and LNTP individuals is balanced and leads to a healthy and protective cooperation between innate and adaptive immune responses. In addition, in EUs and ECs, appropriate NK cell cytotoxic activity might prevent the accumulation of unwanted activated CD4+ T cells. (c) A loss of appropriate NK/dendritic cell cross-talk might contribute to progressive HIV-1 infection. Expansion of unwanted NK cell subsets may explain this different NK/dendritic cell crosstalk. This would result in amplified inflammation at the site of entry as well as in lymphoid tissues and to the lack of appropriate killing of dendritic cells. The latter disseminate HIV-1 and license T-cell responses, which become exhausted as infection remains uncontrolled and chronic. This exhausted T-cell responses might as well come from licensing dendritic cells with functional aberrations due to inappropriate NK/dendritic cell cross-talk. Ultimately, these disorganized innate events contribute to a deleterious state of generalized immune activation and to progression to AIDS. DC, dendritic cell; NK, natural killer.

Conclusion

HIV is capable of breaching the first lines of mucosal defense to gain access to its preferred targets, activated CD4+ T cells. Innate immunity is an organized network of cells and signals that HIV dismantles, progressively and thoroughly. Innate immune responses triggered upon viral entry and sensing have a long-term impact on the outcome of HIV-1 infection. In some conditions, they promote adaptive immune responses and are associated with efficient confinement of viral replication. In others, they can help establish viral reservoirs and promote viral dissemination or chronic inflammation and thus progression to AIDS. Therefore, innate inflammatory responses appear to be a two-edged sword in HIV infection.

Understanding which early viral–host interactions lead to chronic HIV infection remains an indispensable effort. Among numerous compelling questions, knowledge on the fate and location of the virus within these first days and subsequent regulation of inflammation/dissemination is required. SIV-infected macaque models and natural hosts will provide further insights into the early protective mechanisms of control of inflammation in mucosa and in lymphoid organs. Among the many actors of the innate immune system, we focused here on the role of dendritic cells and NK cells. As we discussed, the critical impact of NK/dendritic cell interactions on the adaptive immunity, their responsiveness to the cytokine milieu (IFN-I, chemokines, other innate soluble factors) and to the mucosal environment (epithelial cells, neutrophils, innate lymphocytes) is also a missing piece in the puzzle. Eventually, pursuing the identification of specific viral determinants, which interact with these innate cell participants and their specific signaling pathways, is a mandatory prerequisite. Understanding these parameters and interactions can be selectively exploited in future rational approaches for efficient vaccine designs and therapeutic interventions.

Acknowledgements

The authors are grateful to Elisabeth Menu and Olivier Rescanière for critical reading of this manuscript. Studies referred in this manuscript are supported by ANRS (‘Agence Nationale de la Recherche sur le Sida et les hépatites virales’), SIDACTION and AREVA foundation.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

dendritic cell; HIV; innate immunity; interferon; natural killer cell; simian immunodeficiency virus

© 2012 Lippincott Williams & Wilkins, Inc.