Pathogen entry at mucosal sites is, most of the time, well controlled and contained in local areas due to the initiation of inflammation and recruitment of immune cells prone to engage in efficient innate immune responses. However, in the case of some pathogens such as HIV, it appears that, once reached, infection establishment and viral spread in the genital subepithelial region benefits from the subversion of mucosa resident cells and from a delayed initiation of an adaptive immune response. During the very early events of HIV infection, the rapid contamination of a founder cell population and the hijacking of immune cells functions leads to viral spread toward lymphoid and nonlymphoid tissues. Among the resident immune cells, whose functions could be diverted, dendritic cell subtypes were suggested to participate in HIV transmission and viral spread , as indeed evidenced in vivo with a model of simian immunodeficiency virus (SIV) infection in rhesus macaques .
Different dendritic cell subtypes found at mucosal surfaces have been proposed to be involved in HIV transmission to target cells (reviewed in [3,4]). In fact, depending on the cell subtype, the functional presence of innate restriction factors and on the inflammatory or anti-inflammatory state of the environment, viral transfer from dendritic cells to target CD4+ T cells could be significantly altered or enhanced. All recent and past research on the involvement and mechanism of dendritic cell-mediated viral transfer may well be of critical importance to design new topical microbicides and further improve therapeutic strategies.
Early events of viral transmission from mucosal sites
The precise steps of events and cells involved in viral transfer across genital mucosal tissues are now intensively studied and slowly being uncovered (reviewed in [4,5]). Although there is still a lack of information concerning the potential founder population, which could account for infection spread and latency establishment , it is well accepted that some of specific cell types present at or directly under mucosal surfaces, such as Langerhans cells, dendritic cells, macrophages, and especially perhaps CD4+ T cells, are known to be very early targets for the virus (Fig. 1). Early events of HIV transmission in humans are quite difficult to look at for obvious reasons, such as timelines from infection to patient sampling or even ethical concerns to get access to human infected samples. For now, simian models of lentiviral infection are still one of the closest means to mimic and extrapolate sequential steps of HIV transmission at the genital mucosa. Such models clearly defined that, although CD4+ cells were among the majority of infected population, dendritic cells might also be infected but more importantly could act as early carriers of virus for local and distal viral transmission (reviewed in ). Intriguingly, a subset of dendritic cells, plasmacytoid dendritic cell (pDC), was shown to be highly and rapidly recruited in the challenged tissues and seemingly secreting chemoattractant factors CCL3 and CCL4, involved in the influx of CD4 lymphocytes to the endocervix . Interestingly, pDC enrichment beneath the endocervical epithelium in SIV-infected animals correlated with an increased level of CCL20, the CCR6 ligand, known to induce migration of pDC and T cells into peripheral issues . The local enrichment of CCL20 could stem from vaginal epithelial cells known to secrete this chemokine under pro-inflammatory conditions . Another important contribution of the epithelial/dendritic cell cross-talk could rely on the dramatic increase of thymic stromal lymphopoietin (TSLP) observed in the vaginal tissues within the first 2 weeks after vaginal SIV exposure and paralleling an increase in viral replication . In a human in-vitro model, the increase of TSLP, shown to be directly released following HIV binding on human cervical epithelial cells, was responsible for myeloid dendritic cell (myDC) activation and subsequent increased dendritic cell-mediated HIV-infection of activated CD4+ T cells . Another recent report showed that uterine epithelial cell secretions can decrease DC-SIGN expression on dendritic cell, thus leading to inhibition of dendritic cell-mediated trans-infection of HIV-1 . These data overall highlight the important contribution of structural cells of mucosal surfaces in secreting chemoattractant or soluble factors upon HIV challenge and modulating dendritic cell-mediated viral transmission. Hence, viral transmission in specialized lymphoid tissues could also be modulated by chemokines acting on dendritic cell-mediated HIV trans-infection. As an example, the SDF-1/CXCL12 chemokine, produced from mature dendritic cells (mDCs), was recently shown to inhibit viral propagation to T cells, thus maybe explaining the delayed appearance of X4-tropic viruses .
HIV trafficking and transmission from dendritic cell subtypes
Viruses, such as HIV, can subvert dendritic cell functions to evade immune responses. Interestingly, HIV benefits from specialized endocytic and trafficking cellular pathways in dendritic cells to reach replication-competent CD4+ T cells [3,4]. Efficient HIV transmission to target cells largely depends on the subtype and maturation state of dendritic cell. Whereas immature dendritic cells (imDCs) can capture HIV and support covert infection, mDCs are quite refractory to HIV infection but behave with greater capacity to transfer HIV infectious virions to CD4+ T cells [3,4,13]. Several reports have shown that Lipopolysaccharide-mediated dendritic cell and myDC maturation leads to the clustering of tetraspanin-enriched microdomains (TEMs) wherein HIV virions can localize [14–16]. This tetraspanin-rich compartment, also described in infected macrophages , seems dynamic and appears to be connected to the cell surface in both types of cells [16–19]. Even if the TEM is likely to contribute to HIV polarization and transfer toward target cells, the mechanisms underlying formation of this viral docking compartment are still unknown. Another potential important trafficking pathway used by HIV in mDC intersects with the exosome-dissemination pathway for efficient viral transfer . Even if such processes were exacerbated in mDCs, the involvement of the TEMs and the exosome-pathway was also demonstrated for HIV trans-infection stemming from imDCs [14,21]. Maturation of dendritic cells can readily occur upon most microbial invasion and thus could be a means of increased HIV dissemination in lymphoid tissues during pathogenic co-infection. Recent reports showed that the malarial pigment hemozoin can partially mature DC  and activate CD4+ T cells, leading to a significant enhancement of dendritic cell-mediated transfer of HIV-1 infection . With previous reports, this is another cumulative evidence of the nefarious effect of pathogen co-infection on dendritic cell subversion and HIV spread.
The virological synapse: a bridge for viral transfer
Efficient viral transfer from dendritic cells to target CD4+ T cells was shown to rely on the formation of a virological synapse (also called infectious synapse) originally reported to concentrate HIV and cognate receptors at the dendritic cell–T-cell contact zone . Virological synapses are cytoskeleton-dependent polarized structures allowing recruitment of virions or viral components at the contact zone between an infected effector cell and a bystander target cell (reviewed in ). This type of organized structure could be a means for pathogens to discreetly infect target cells, while hiding from immune system recognition and avoiding efficient antibody neutralization, although, in a context of T cell–T cell virological synapse, it has been recently shown that viral transfer was sensitive to viral entry inhibitors . In comparison with cell-free infection, cell-to-cell pathogen transmission via the virological synapse could potently contribute to infection spread, as recently exemplified by a 1000-fold enhancement of human T lymphotropic virus type-I infection upon cell-to-cell contact . The virological synapse formed between HIV-infected dendritic cells and CD4+ T cells was also demonstrated to be an efficient means for viral spread and it was recently shown that Langerhans cells can rapidly acquire viral particles from apical foreskin keratinocytes and transfer HIV to target T cells at the epidermis–dermis interface of the inner foreskin [28•]. It was shown that HIV acquisition was largely decreased upon circumcision, thus suggesting an important role of the foreskin in HIV transmission. This could consequently imply epithelial Langerhans cell as the main first barrier defense upon HIV challenge. Interestingly, a recent study demonstrated that under pro-inflammatory conditions, Langerhans cells from foreskin inner explants became activated, thus initiating an influx of CD4+ T cells into the epithelial layer and were also more prone to sample environmental factors . As these properties were only apparent with Langerhans cells from the inner but not the outer foreskin, it could be a potential explanation of why and how circumcision decreases HIV transmission . A better characterization and understanding of the mechanisms underlying HIV acquisition and transmission from specific subtypes of Langerhans cell could thus help to develop new strategies to counteract HIV infection in the very early events of viral challenge. For this purpose, the use of cell lines like the Mutz-3 cell lines, shown to phenotypically and functionally behave like human primary Langerhans cells, was proposed to be a suitable model to study the role of Langerhans cells in HIV transmission and to screen potential viral inhibitors . A recent analysis of the spatial architecture of the virological synapse formed between virus-bearing mDCs and T cells proposed that HIV virions sequestered deep within a three-dimensional network of surface-accessible compartments in the dendritic cells are not released passively at the cell–cell contact zone. Indeed, using state-of-the-art imaging technologies (IA-SEM and electron tomography), the authors showed that viral transfer was initiated upon contact of virions localized within surface-accessible membrane invaginations in the dendritic cells with microvillar/filopodial extensions from the T cell [31••]. The transfer of viral particles could also rely on induced actin-based structures stemming from the dendritic cells upon contact with T cells [31••]. In fact, it was shown that HIV was able to induce Cdc42-mediated membrane protrusions rapidly after DC-SIGN engagement by the viral envelope . In this report, the authors clearly demonstrated the presence of HIV-1 on membrane protrusions at the dendritic cell–T-cell interface, thus facilitating infection of contacting CD4+ T cells . These recent findings also contribute to explain the role of DC-SIGN in the formation of the virological synapse. The emergence of new imaging technologies in parallel with the use of adapted genetically modified or fluorescently labeled virions  will undoubtedly contribute to a better characterization of virological synapse formation and structure .
Dendritic cell-mediated HIV transmission and antiviral innate defenses
Dendritic cells, as one of the very first immune cells to encounter pathogens, behave with broad panoply of antiviral innate effectors and machineries. However, most pathogens have developed potent strategies to facilitate their dissemination while dampening and avoiding antiviral innate immune defenses. HIV has already been shown to subvert and even benefit from activities of cellular factors and machineries mostly involved in cytoskeleton organization, vesicle trafficking, and transcription. Now, it is also becoming evident that HIV has evolved different means to counteract or exploit innate functions in dendritic cells to facilitate viral transmission. Indeed, HIV was shown to benefit from Toll-like receptor 8 (TLR8) and DC-SIGN signaling to replicate in dendritic cells and facilitate dendritic cell-mediated viral transfer to T cells [35••]. Whereas TLR8-mediated NF-κB activation was required for RNA polymerase II (RNAPII)-dependent transcription initiation of integrated provirus, DC-SIGN-mediated Raf-1 signaling was demonstrated to be essential for transcription elongation upon recruitment of pTEF-b to nascent transcripts [35••]. Importantly, pharmacological inhibition of Raf-1 kinase activity prevented dendritic cell-mediated viral transfer [35••]. During the very first events of viral capture, HIV envelop is likely to initiate signaling aimed at altering dendritic cell functions in order for the virus to establish a favorable niche and facilitate dendritic cell-mediated viral transmission. This situation was exemplified recently by the profound dampening of autophagy in dendritic cells upon HIV-1 capture [36•]. This autophagy exhaustion was mediated upon binding of the viral envelope, thus initiating a signaling cascade leading to mammalian Target Of Rapamycin activation, known to antagonize autophagy flux initiation. It was demonstrated that autophagy reduction in dendritic cells correlated with an increase in cell-associated virus and enhanced transfer of HIV infection in-trans from dendritic cells to CD4+ T cells across virological synapse [36•]. Given the multiple roles of the autophagosomal machinery in innate and adaptive responses, this viral-mediated effect was shown to impair dendritic cell-mediated innate and adaptive immune responses.
Although dendritic cells are known to be much less susceptible to productive infection in comparison to CD4+ T cells, an interesting recent report showed that when dendritic cell resistance to infection was circumvented by the presence of Vpx-expressing lentivectors, HIV-1 induced dendritic cell maturation and efficient dendritic cell-mediated innate and adaptive immune responses [37••]. The innate response induced by HIV infection was shown to rely on the activation of the transcription factor Interferon Regulatory Factor 3 upon recognition of newly synthesized HIV-1 capsid by the cellular peptidylprolyl isomerase cyclophilin A (CYPA), and was linked to the restriction of dendritic cell-mediated trans-infection of CD4+ T cells [37••]. These promising data, showing that dendritic cells own a functional intrinsic antiviral machinery, could be of importance for future research areas aimed at elucidating mechanisms of HIV immune escape and transmission.
Among innate antiviral restriction factors, tetherin/BST-2 was shown to antagonize HIV release from infected cells in the absence of Vpu . Its antiviral activity relies on structural determinants and subcellular localization at the viral budding sites rather than sequence specificity or enzymatic activity. This confers a particular interest on the potential involvement of this restriction factor during viral transmission, as already shown in T cell–T cell models of HIV transfer [39–41], and it will, thus, be of importance to decipher any role of tetherin during dendritic cell-mediated transfer of infection to CD4+ T cells.
Maturation of dendritic cells, while restricting HIV replication and subsequently impeding transfer of de-novo produced virions, is known to enhance viral capture and infection of CD4+ T cells in-trans. A recent report demonstrated that the nuclear receptors peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor (LXR) once activated, induced a decrease in dendritic cell-associated cholesterol, thus preventing viral capture by dendritic cells and subsequently inhibiting dendritic cell-mediated HIV-1 trans-infection .
Potential strategies to block HIV transmission
Several strategies have been developed to try generating efficient vaccines against HIV-1, but, despite recent encouraging results obtained with the RV144 HIV vaccine trial, for now there is a clear lack of efficient prophylactic vaccines. Alternative strategies have emerged, with the use of microbicides, aimed at targeting and preventing specific steps of viral transmission upon mucosal surfaces challenge by HIV-1 (reviewed in ). Targeting steps involving dendritic cell-mediated HIV transmission are gaining recognition, as this would occur during the very first event of viral challenge. Recent candidate microbicides, like PRO2000, were shown to potently block dendritic cell-mediated HIV transfer and infection in the highly permissive dendritic cell-T-cell environment . Microbicidal agents can be designed to target viral or cellular components and, recently, entry inhibitors targeting the viral envelope (BMS-C and T-1249) or CCR5 (CMPD167) at the surface of dendritic cell were proven to efficiently block HIV infection in dendritic cell–T-cell co-cultures . However, a clear proof of concept was still required to demonstrate the efficiency of microbicide to abrogate HIV transmission in humans. For the first time, the potential use of a microbicide-based prophylactic strategy was convincingly demonstrated in a recent report, from the CAPRISA 004 trial, showing that a 1% tenofovir-based gel could prevent HIV acquisition in women by almost 40% [46••]. This preventive effect was even shown to reach 54% when gel adherence was optimal (>80%) [46••]. Even if the cell type(s) targeted by the microbicide were not characterized, this study offers a clear breakthrough in the field of antiviral gel-based microbicides in humans to block the early events of HIV transmission. Another compound based on a hybrid Syndecan–Fc molecule, hypothesized to target a highly conserved Arg298 in the V3 region of gp120, was shown to exert a potent antiviral activity against a broad range of viral isolates and to profoundly block dendritic cell-mediated HIV transfer to CD4+ T cells .
As HIV gets access to the host mainly through mucosal surfaces, inducing a strong and potent mucosal immunity to HIV might hopefully stop the establishment of early HIV infection, and transmission to CD4+ T cells. In nonhuman primates, Bomsel et al.[48••] recently reported that intranasal immunization with HIVgp41 induced mucosal antibodies providing protection against repeated low-dose intravaginal challenges. In vitro, the authors further demonstrated that mucosal antibodies could neutralize HIV and also block HIV transcytosis through epithelial cell monolayers [48••]. Several strategies are currently being developed to induce sterilizing humoral and/or T-cell immunity at mucosal sites. Vaccine carriers include DNA, antibodies, nanoparticles, virus-like particles, or viral vectors. Most of these strategies are designed to facilitate the uptake of HIV antigens by antigen presenting cells. Viral vectors, and to a lesser extent virus-like particles, trigger innate immunity that can potentially provide a natural adjuvant effect. For instance, modified vaccinia virus ankara (MVA), a nonpersisting vector with excellent safety records, triggers innate sensors such as TLRs and NALP3 inflammasome leading to chemokines, IFN-β and IL-1β secretions . MVA has a very large tropism including epithelial cells, lung fibroblasts, pulmonary, and bronchial cells [50•]. Hence, dendritic cells can capture MVA-infected cells that express HIV antigens to activate HIV-specific CD8+ and CD4+ T cells [50•]. Recombinant antibodies directed to dendritic cell surface receptors such as lectins (Dendritic and Epithelial Cell-205, DC-SIGN...) also offer a chance to supply HIV antigen to dendritic cells [51,52]. However, an increasing number of human dendritic cell subsets with distinct capacity to prime cellular or humoral immune responses are being recognized. Thereafter, a better understanding of the biology of the dendritic cell subsets will be necessary to design dendritic cell-based vaccines for HIV .
Mucosal intrinsic antiviral immunity might also confer some degree of protection upon viral encounter. Following mucosal immunization of nonhuman primates, two recent studies reported upregulation of the antiviral factor APOBEC-3G (A3G) in CCR5+CD4+ memory T cells  and mucosal dendritic cells or CD14+ cells [55••]. Upregulation of A3G mRNA was maintained for several weeks after immunization. Remarkably, upon SIV challenge, A3G mRNA upregulation correlated inversely with viral loads suggesting that A3G upregulation provided an antiviral effect. Although the correlation between A3G expression and antiviral effect was observed in different cell types in these studies, due probably to the use of different vaccine adjuvants, they provide the first evidence that mucosal immunization triggers an innate signature reminiscent of a memory response. Although the exact mechanism underlying A3G correlation with protection from SIV infection is not clear, it might be due to the action of A3G on HIV replication  or on the generation of Major Histocompatibility Complex-I-restricted HIV antigen and HIV-specific T-cell activation [57•].
Therapeutic vaccines might also be used to boost immune responses against HIV to eliminate residual viral replication and eradicate reservoirs or to reduce drug regimens on HAART. However, a major drawback would be to create a milieu facilitating HIV replication and spread. Illustrating this issue, a greater viral rebound and reduced time to resume antiretroviral therapy was observed after therapeutic immunization with an ALVAC-HIV vaccine . Indeed, it was shown recently that virus rebound upon vaccination was associated with an increased activation of HIV-specific CD4(+) T cells , known to be preferential targets of viral transmission and infection [60,61]. A thorough characterization of the interactions between vaccine candidates, HIV and cells of the immune system, especially dendritic cells, will be probably required. MVA, for instance, has been shown in vitro to abolish HIV transfer from dendritic cells to activated T cells probably due to IFN-α secretions [50•].
As dendritic cells and their subsets have altered cellular and immune functions following HIV infection, these cells are likely to be excellent targets for future vaccine and prophylactic strategies aimed at abrogating viral infection and spread to CD4+ T cells. However, a better characterization of the early events of HIV trafficking and impact on dendritic cell functions would enable us to refine future immunotherapeutic strategies aimed at improving immunogenicity and dendritic cell-mediated antiviral responses.
Hence, improvement of available in-vitro human mucosal or ex-vivo organ culture models and the use of new animal models to study the very early events of HIV transmission will undoubtedly contribute to better characterization of immune components sufficient in preventing HIV-1 transmission and to development of efficient therapeutic and prophylactic strategies.
The present work was supported by a Swiss National Science Foundation (SNF) grant and a Global Health Grant from the Gates foundation to V.P., as well as program and project grants from Agence Nationale de Recherche sur le SIDA (ANRS) and SIDACTION for A.M.
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 (pp. 446–447).
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