Dendritic cells are antigen-presenting cells with the unique capacity to prime naïve T cells for efficient cellular responses against pathogens such as HIV-1 . Dendritic cells bridge the innate and adaptive immune systems, since they are important not only for the recognition of pathogens via pattern recognition receptors like Toll-like receptors (TLRs) and C-type lectins and their production of cytokines, but also for their ability to process and present antigens to T cells. Two major subtypes of dendritic cells have been identified in the human immune system: CD11c+ myeloid dendritic cells (mDCs) and CD11c− CD123+ plasmacytoid dendritic cells (pDCs). mDCs can be further classified in different subsets, including Langerhans cells found, for example, in the epidermis of skin and the submucosa. Recently, an additional subset of mDCs that expresses BDCA-3 (CD141) that specializes in cross-presentation has been described [2•–5•]. Dendritic cells are crucial for activating and conditioning virus-specific T cells, which are needed to control viral infection including HIV-1. This process is largely influenced by the innate immune responses mounted by the different dendritic cell subsets including what cytokines they produce. For comprehensive overviews of dendritic cell subsets and their specific role in HIV-1 infection and other human diseases, we refer to several recent excellent review articles [6–9]. This review focuses on recent research findings highlighting the role of dendritic cells in HIV-1 infection with respect to their function in both innate and adaptive immune responses.
HIV-1 infection of dendritic cells
HIV-1 infection is characterized by the loss of CD4+ T cells and failure to control infection. Although justly described as a T-cell deficiency, the failure to mount efficient HIV-1-specific immune responses could partially be a consequence of defects in dendritic cells. Dendritic cells express the receptors most commonly used by HIV-1 (CD4, CCR5 and CXCR4) and are indeed susceptible to infection [10–18], which may impair their ability to induce immunity . Upon sexual transmission of HIV-1, dendritic cells such as Langerhans cells may be one of the initial target cells of the virus [15,20]. After HIV-1 crosses the mucosa it eventually reaches the lymphoid tissue in which a permanent infection is established. Dendritic cells are proposed to play a crucial role in the early events of HIV-1 transmission by transporting the virus from the peripheral site to the lymphoid compartment. The dendritic cell–T-cell interaction in lymphoid tissue is critical for the generation of immune responses, but also inadvertently creates a perfect microenvironment for HIV-1 replication and transmission between cells [21–23]. The effects of HIV-1 on dendritic cell function are poorly understood yet crucial to our knowledge of the pathogenesis of disease.
Innate dendritic cell responses to HIV-1 infection
It is well documented that the numbers of both mDCs and pDCs are reduced in blood during HIV-1 infection [24–29]. The decline in circulating dendritic cells correlates with an increase in HIV-1 viral load (43), suggesting that there is a relationship between loss of dendritic cells and the individual's ability to control disease. A recent study using cross-sectional and longitudinal analyses of samples from HIV-1-infected individuals found that the reduction in blood dendritic cell numbers begins very early in HIV-1 infection [30••]. Again, there was a correlation between plasma viral load and reduced dendritic cell numbers. However, dendritic cell numbers were also reduced in HIV-1 elite controllers, infected individuals who maintain undetectable viral load even in the absence of antiviral therapy. This finding suggests that blood dendritic cell loss may be more related to the inflammatory microenvironment and chronic immune activation established during HIV-1 disease rather than to the level of viremia.
The cytokine response and maturation status of dendritic cells in response to HIV-1 have been extensively studied. These functional properties of dendritic cells play an important role in regulating both primary and secondary memory T-cell responses . Whereas dendritic cells of myeloid origin display no or modest up-regulation of co-stimulatory molecules such as CD40, CD80, CD83, CD86 or major histocompatibility complex (MHC) class II after direct HIV-1 exposure, pDCs respond by secreting large amounts of IFN-α and significantly up-regulating co-stimulatory molecules [12,17,31–33]. Consequently, cytokines secreted by pDCs efficiently mature bystander mDCs . These data would therefore indicate that HIV-1-exposed dendritic cells retain their ability to phenotypically mature, which is critical to transition into potent antigen-presenting cells. Although HIV-1 infects dendritic cells, the virus replicates poorly in these cells. This may partly explain why mDCs do not mature in response to HIV-1 despite expressing multiple receptors that can sense RNA viruses [35••]. A recent study showed that when dendritic cells of myeloid origin were infected with HIV-1 together with Vpx, an SIV/HIV-2 encoded protein that can overcome replication restrictions, HIV-1 could induce maturation in infected dendritic cells via interaction of newly synthesized viral capsid protein and the host protein cyclophilin A and subsequent activation of the transcription factor interferon regulatory factor 3 (IRF3) [35••].
Previously, pDCs isolated from HIV-1-infected individuals have been demonstrated to secrete less IFN-α after stimulation in vitro than pDCs isolated from healthy donors [27,36]. However, a recent study showed that the blood dendritic cells from HIV-1-infected patients are hyper-responsive to stimulation with TLR7 agonists and produce higher levels of cytokines compared to dendritic cells isolated from uninfected controls [30••]. This correlated with elevated transcription of TLR7 and IRF7 in dendritic cells from patients with primary HIV-1 infection. HIV-1 likely stimulates pDCs via TLR7  and, due to their constitutively high expression of IRF7, the pDCs rapidly secrete large amounts of IFN-α. A frequent functional TLR7 polymorphism has been associated with accelerated HIV-1 disease progression , whereas polymorphisms in IRF7 have been shown to affect IFN-α responses to HIV-1 in pDCs from healthy donors . Furthermore, activated pDCs from HIV-1-infected women produce more IFN-α than pDCs from HIV-1-infected men . This was suggested to contribute to the increased likelihood for HIV-1-infected women to develop AIDS compared to men with similar viral load; however, this remains to be proven. In combination, these observations support the notion that HIV-1 signals via TLR7 in pDCs and the magnitude of the subsequent IFN-α response is important for disease outcome. It was recently suggested that HIV-1 pulsed pDCs, in contrast to influenza virus pulsed pDCs, have persistent IFN-α production due to trafficking of HIV-1 to early endosomes. This low but persistent IFN-α production was associated with a semi-mature phenotype, which when combined may result in chronic inflammation and pathogenesis rather than promoting the development of anti-HIV-specific immunity [41••]. The differing data on whether pDCs from HIV-1-infected individuals produce less or more IFN-α upon stimulation in vitro than pDCs from healthy controls may depend on different TLR agonists used for stimulation, kinetics, cell isolation protocol, maturation status of the cells and/or a difference depending on whether isolated pDCs vs. total peripheral blood mononuclear cells (PBMCs) (in which the HIV-1+ patients have fewer pDCs and possibly therefore secrete less IFN-α) were used. Taken together, these studies underline the need for side-by-side comparisons of these parameters to be able to make solid conclusions on this matter and merit further investigation.
Influence of HIV-1 on dendritic cells for the initiation of adaptive immune responses
The potency of the innate immune responses likely determines the quality of subsequent adaptive anti-HIV-1 immunity. CD8+ cytotoxic T cells are central to control the HIV-1 levels in infected individuals. However, the efficiency of these responses is highly compromised due to the extreme antigen escape variants of HIV-1 . As dendritic cells are essential to initiate cellular responses, there have been considerable efforts to determine whether HIV-1 functionally impairs dendritic cell function. The reduction of blood dendritic cell numbers in HIV-1-infected individuals is well established and this depletion has been shown to correlate with disease progression . However, although there are several innate dendritic cell functions described above that are affected in HIV-1-infected individuals or after HIV-1 exposure in vitro, there is no consensus as to whether the antigen-presenting capacity of dendritic cells is impaired to a degree that would affect the generation of antigen-specific immune responses. Several studies show that dendritic cells maintain their ability to stimulate T-cell responses after HIV-1 exposure [30••,44–49]. However, there are also studies that demonstrate a reduced allogeneic T-cell immunostimulatory function [43,50,51]. Again, differences such as the type of dendritic cell subset studied, the isolation procedure, virus strain and dose used may be reasons for these divergent data. The well documented reduction of dendritic cell numbers in blood in HIV-1-infected individuals has been proposed to be a consequence of direct infection of dendritic cells . However, the frequency of infected dendritic cells in vivo is undetectable or very low compared to CD4+ T cells, at least after the initial transmission [20,52,53]. Alternatively, the loss of dendritic cells from blood could be due to an increased migration of dendritic cells to lymphoid compartments (Fig. 1) and/or insufficient repopulation of blood dendritic cells from precursor cells, although the latter has not been directly tested. Lymph nodes, tonsils and spleens from HIV-1-infected individuals have shown an accumulation of dendritic cells that exhibit a lower expression of co-stimulatory molecules than normally found in these lymphoid tissues [54,55••,56,57]. Non-human primate (NHP) models that enable more thorough characterizations of this finding have revealed, that although their numbers decline during infection, the mDCs and pDCs remaining in blood show higher expression levels of co-stimulatory molecules indicating activation, accompanied by a rapid influx of semi-mature mDCs and pDCs to lymph nodes in SIV infection [58,59••,60]. A recent study expands on this phenomenon and demonstrates that dendritic cells in lymph nodes show an increased rate of apoptosis, as characterized by elevated levels of active caspase-3 expression, in NHP with progressive SIV infection [59••]. Taken together, the data suggest that dendritic cells are depleted not only from blood but also from lymph nodes, with the net effect of an overall depletion of dendritic cells that may be predictive of the immune system's loss of disease control. The presence of dendritic cells with a semi-mature phenotype in the lymphoid tissue of HIV-1-infected individuals could potentially translate into defective or skewed stimulation of T-cell responses.
Semi-mature dendritic cells isolated from lymph nodes from HIV-1-infected individuals have been shown to support differentiation of CD4+ T cells into regulatory T cells (Tregs), and the same lymph nodes contained elevated levels of Tregs . The immunoregulatory cytokine IL-10 is elevated in peripheral circulation of HIV-1-infected individuals, which has been proposed to contribute to dysfunctional anti-HIV-1 responses. A recent study showed that dendritic cells pulsed with HIV-1 secrete IL-10 [55••,62]. Furthermore, dendritic cells cultured in vitro with IL-10 display incomplete maturation and develop tolerogenic functions [55••,62]. Dendritic cells, including pDCs, exposed to IL-10 or HIV-1 were recently shown to up-regulate programmed cell death protein ligand 1 (PD-L1) expression [55••,63•,64]. PD-L1 binding to its inhibitory receptor PD-1 on T cells leads to suppression of T-cell activation and negatively regulates cell survival [65,66,67•]. Appearance of PD-1 expression on HIV-1-specific T cells correlates with HIV-1 disease progression [68,69]. Thus, dendritic cells with elevated PD-L1 expression that present antigen to T cells may promote the differentiation of PD-1+ T cells.
It has been demonstrated that the enzyme indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan to kynurenine, is produced by pDCs upon HIV-1 gp120 binding to CD4 on these cells [63•,70,71]. Induction of IDO in pDCs causes suppression of T-cell proliferation in co-cultures , which was recently shown to occur as a result of the development of naïve CD4 T cells into Tregs that in turn suppress effector T cells [63•,71]. This can provide a mechanism by which pDCs limit potentially detrimental and excessive immune stimulation and, as a consequence, also act to limit anti-HIV immune responses.
It is well established that the interaction between dendritic cells and T cells highly facilitates HIV-1 transmission and replication [21–23]. In particular, HIV-1 is preferentially transmitted from dendritic cells to the T cells that directly interact with the dendritic cell that present their cognate antigen [44,48]. This may explain why the HIV-1-specific CD4+ T cells are preferentially infected compared to T cells with other antigen specificities in HIV-1-infected individuals . The ability of HIV-1 to interfere with different parts of peptide presentation on MHC, for example, via Vpu-mediated down-modulation of CD4 and lysosomal targeting of MHC by Nef, is thought to be an important defense mechanism against viral recognition by T cells . It is becoming increasingly clear that HIV-1 also interferes with lipid antigen presentation by HIV-1 Vpu-mediated early endosomal retention of CD1d in human dendritic cells and subsequently impaired natural killer (NK) T-cell responses [74••]. In addition, HIV-1 Nef has been implicated in affecting CD1d expression in dendritic cells . The precise role of lipid antigen presentation by CD1d and recognition by NKT cells in anti-viral immune responses is not yet well defined, as virally derived antigens presented by CD1d have yet to be identified. Taken together, the studies reviewed here show that HIV-1 affects dendritic cells in multiple ways, which may impact the overall adaptive immune response to the virus and thus merits further investigation.
The functionality of dendritic cells in HIV-1-infected individuals remains controversial. As reviewed here, detailed ex-vivo analyses as well as in-vitro experiments suggest that, overall, dendritic cells are functional in HIV-1 infection. In vivo, a minority of dendritic cells are infected and could have reduced expression of co-stimulatory molecules and impaired cytokine production. However, the majority of dendritic cells in HIV-1-infected patients can most likely respond to stimulation and present antigen to T cells, although the quality of the response generated may be altered. To this end, there may be unrivaled opportunities to improve anti-HIV-1 immunity by therapeutic strategies based on providing dendritic cells with appropriate immune adjuvants and antigen . In conclusion, the field has made significant progress in recent years but many important questions regarding the role of dendritic cells in HIV-1 infection remain to be elucidated.
The authors are grateful to Jessica Ma for critical reading of the review.
The work was supported by grants from the Swedish International Development Agency (SIDA)/Department of Research Cooperation (SAREC) to A.S.-S. (Dnr SWE-2009-086) and K.L. (Dnr SWE-2009-063), the Swedish Governmental Agency for Innovation Systems (Vinnova) to A.S.-S. (Dnr 2009-04074) and K.L. (Dnr 2010-00999), the Swedish Research Council to K.L. (Dnr 521-2009-4809), and the Swedish Physicians against AIDS Foundation to A.S.-S. (Dnr FO2009-0017) and K.L. (Dnr FOb 2010-0013).
Conflicts of interest
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
* • of special interest
* •• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 447).
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