HIV-1 mucosal infection through sexual transmission plays a critical role in viral pathogenesis [1,2,3•]. Defining the mechanisms of HIV-1 mucosal transmission can potentially help our combat against HIV-1/AIDS. Current antiretroviral therapies cannot eradicate HIV-1, and no effective vaccine is achievable soon; therefore, topical microbicides hold promise for HIV-1 prevention . Recent studies of HIV-1 interactions with target cells provide new insights into understanding HIV-1 mucosal transmission. Host factors and immune responses are multifaceted contributors to HIV-1 infection and transmission (Fig. 1). This review highlights the latest research advances in HIV-1 mucosal transmission, focusing on the mechanisms of cell–cell transmission of HIV-1.
Initial events of HIV-1 mucosal infection and transmission
CD4+ T cells, macrophages, and dendritic cells including Langerhans cells are considered as early targets of HIV-1 infection and transmission in the vaginal mucosa [1,2,3•]. The initial events in establishing vaginal HIV-1 infections, however, are poorly characterized owing to the lack of a suitable model. Hladik et al. [4••] developed a culture model of epithelial sheets separated from human vaginal stroma to study HIV-1 entry and infection. HIV-1 enters intraepithelial CD4+ T cells by viral receptor-mediated fusion, leading to productive infection. By contrast, HIV-1 enters vaginal Langerhans cells via endocytosis mediated by multiple receptors. Intact HIV-1 particles were retained within Langerhans cells for 3 days without detectable viral replication. The Langerhans cell–T-cell conjugates with concentrated HIV-1 were observed at 60 h, but not at 2 h after infection [4••]. These results suggest that initial HIV-1 infection of T cells is independent of Langerhans cells, while Langerhans cell-mediated HIV-1 transmission to T cells may occur at the later stage of infection. Although HIV-1 replication may not be readily detected in Langerhans cells at the initial infection, it is possible that dendritic cells hold infectious HIV-1 and augment viral replication upon interaction with CD4+ T cells [1,5,6,7••,8,9••,10,11].
Langerhans cells have been speculated to support HIV-1 trans-infection through langerin, a Langerhans cell-specific C-type lectin. Unexpectedly, a recent study [12•] suggested that langerin can be a natural barrier to HIV-1 infection. Langerin mediates HIV-1 internalization and intracellular degradation in skin-derived Langerhans cells, thereby inhibiting HIV-1 replication and transmission [12•]. It remains possible, however, that a proportion of endocytosed HIV-1 escapes from the degradation, and initiates trans-infection of CD4+ T cells upon cell-cell contact. A recent report [13•] indicates that epithelial Langerhans cells in human skin explants account for over 95% of HIV-1 dissemination. HIV-1 infection was detected only in Langerhans cells, but not dermal dendritic cells and macrophages in the skin emigrants, suggesting that productive HIV-1 infection of Langerhans cells plays a critical role in occupational HIV-1 transmission [13•]. Moreover, CD34+ progenitor cell-derived Langerhans cells mediate HIV-1 trans-infection to CD4+ T cells [10,14].
Epithelial cells in the vaginal mucosa are also involved in HIV-1 mucosal transmission, although controversial results have been reported regarding whether HIV-1 can productively infect epithelial cells [3•]. HIV-1 can penetrate the epithelial layer by transcytosis, although the efficiency of transcytosis appears to be very low (less than 0.02% of the initial HIV-1 inoculum) as indicated in a study using cultured primary genital epithelial cells . HIV-1 may also be endocytosed by epithelial cells to initiate viral spread to target leukocytes [3•]. Additional studies are required to confirm this potential mechanism of HIV-1 mucosal transmission.
Mechanisms of dendritic cell-mediated HIV-1 trans-infection
Numerous studies have indicated an important role for dendritic cells in HIV-1 mucosal transmission and viral pathogenesis [1,16]. Dendritic cells transfer captured HIV-1 to cocultured CD4+ T cells by trans and cis-infection pathways . Efficient HIV-1 trans-infection mediated by dendritic cells requires contact between dendritic cells and CD4+ target cells [7••]. The cell–cell junctions with concentrated HIV-1 are referred to as infectious/virological synapses [17,18], which facilitate HIV-1 transmission from dendritic cells to CD4+ T cells.
HIV-1 attachment factors expressed on dendritic cells contribute to viral capture and transmission. The best studied factor is the C-type lectin DC-SIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin), which partially accounts for HIV-1 transmission by certain dendritic cell subsets . Dendritic cell-mediated HIV-1 trans-infection, however, occurs independently of DC-SIGN [1,7••,19]. A recent study  indicated that syndecan-3, a dendritic cell-specific heparan sulfate proteoglycan, binds HIV-1 through viral envelope glycoprotein (Env) and enhances HIV-1 trans-infection. Accordingly, microbicides that block HIV-1 interactions with DC-SIGN and syndecan-3 might prevent dendritic cell-mediated viral transmission.
Cellular proteins and signaling pathways modulate dendritic cell-mediated HIV-1 transmission by interacting with DC-SIGN. Leukocyte-specific protein 1 (LSP1), an F-actin binding protein involved in leukocyte motility, binds to DC-SIGN and directs internalized HIV-1 to the proteasome in dendritic cells for viral degradation . Silencing LSP1 expression in dendritic cells enhances HIV-1 transmission to CD4+ T cells, suggesting that HIV-1 trafficking through the cytoskeleton is important for viral transmission . HIV-1 or DC-SIGN-specific antibodies activate DC-SIGN signaling through the leukemia-associated Rho guanine nucleotide-exchange factor (LARG), which increases Rho-GTPase activity . Activation of LARG in dendritic cells facilitates HIV-1 transmission to CD4+ T cells by enhancing virological synapse formation between dendritic cells and T cells . Moreover, interactions of DC-SIGN with different human pathogens including HIV-1 activate the Raf-1 kinase-dependent acetylation to modulate Toll-like receptor (TLR) signaling . Given the importance of TLRs in dendritic cell-initiated adaptive immunity, this DC-SIGN-mediated signaling pathway may regulate the immune responses to various pathogens.
HIV-1 trafficking in dendritic cells contributes to viral transmission and the formation of virological synapses between dendritic cells and T cells [7••,8,10,19,21,24–26]. We found that intracellular trafficking inhibitors partially block viral transmission [7••]. Our results indicate that both cell surface-bound and internalized HIV-1 contribute to dendritic cell-mediated trans-infection [7••]. Compared with immature dendritic cell-mediated HIV-1 transmission, viral trafficking in mature dendritic cells appears to play a more important role in trans-infection [5,7••,8,10,24,26]. Cavrois et al. , however, reported that dendritic cell-mediated HIV-1 trans-infection mainly derives from dendritic cell surface-bound viruses. Although it is difficult directly to compare these results owing to the different experimental approaches, the dynamic trafficking and recycling of internalized HIV-1 to dendritic cell surfaces could also mediate viral transmission. This factor should be an important consideration in studying dendritic cell–HIV-1 interactions and in developing effective microbicides.
HIV-1-bearing dendritic cells probably interact with different T cell subsets in vivo and mediate viral transfer. Dendritic cells may play a decisive role in differential susceptibility of HIV-1 infection in naïve and memory CD4+ T cells . R5 HIV-1 is most efficiently transmitted to effector memory T cells, which are the major targets for HIV-1 replication and abundantly present in mucosal tissues, while X4 HIV-1 is preferentially transmitted to naïve T cells by dendritic cells. Thus, dendritic cells may contribute to the initial burst of HIV-1 replication in effector memory T cells, and to the replication of X4 HIV-1 in naïve T cells at the late stage of infection .
HIV-1 cis-infection of dendritic cells and viral transmission
Similar to mucosal HIV-1 transmission, the selection for R5 HIV-1 strains occurs during parenteral transmission. The cell types responsible for this selection, however, have not been defined. Using sorted blood mononuclear cells to model HIV-1 parenteral infection, Cameron et al. [28•] reported preferential HIV-1 infection of myeloid dendritic cells and plasmacytoid dendritic cells (pDCs) relative to monocytes and resting CD4+ T cells. The selective infection of blood dendritic cells by R5 HIV-1 and enhanced viral transmission to CD4+ T cells suggest a potential mechanism of R5 HIV-1 selection during parenteral transmission.
HIV-1 infection of dendritic cells can lead to virus production and long-term viral transmission, implying that HIV-1-infected dendritic cells are viral reservoirs in vivo [1,9••,16,29•]. To understand HIV-1 cis-infection of dendritic cells more, it is important to define viral entry pathway that leads to productive infection in dendritic cells. Previous studies [30–33] and our recent data [9••,34] indicate that productive infection of HIV-1 in dendritic cells requires fusion-mediated viral entry. HIV-1 enters dendritic cells predominately through endocytosis; however, endocytosed HIV-1 cannot initiate productive HIV-1 infection [4••,9••,34]. The majority of endocytosed HIV-1 in intracellular compartments in dendritic cells will eventually be degraded [5,7••,30,35]; however, when HIV-1-bearing dendritic cells encounter CD4+ T cells prior to viral degradation, efficient HIV-1 trans-infection of CD4+ T cells can occur in vitro [5,6,7••,8,9••,10,11]. Furthermore, we compared cis- and trans-infections of HIV-1 mediated by immature dendritic cells and various stimulus-induced mature dendritic cells, and found that these two infection pathways are dissociable [9••]. Various dendritic cell subsets in vivo may differentially contribute to HIV-1 dissemination, therefore, via dissociable cis and trans-infection.
HIV-1 proteins and host factors influence viral replication in dendritic cells, and regulate viral transmission efficiency. We recently reported that HIV-1 Nef promotes HIV-1 transfer from dendritic cells to CD4+ T cells [29•]. Nef-induced CD4 downregulation in HIV-1-infected-dendritic cells correlates with enhanced viral transmission. Interestingly, blocking CD4 on dendritic cells with specific antibodies enhances dendritic cell-mediated HIV-1 trans-infection [29•]. These results suggest that CD4 and Nef can modulate HIV-1 transmission by dendritic cells. Moreover, HIV-1 replication in dendritic cells occurs through a tetraspanin-containing compartment enriched in adaptor protein 3 (AP-3), and viral production is dependent on AP-3 .
Host immune responses contribute to the attenuated disease progression of HIV-2 infection . The lack of productive HIV-2 infection in dendritic cells may help to explain the less pathogenic HIV-2 infection relative to HIV-1 infection. Duvall et al.  showed that various HIV-2 isolates could not efficiently infect myeloid dendritic cells or pDCs, and myeloid dendritic cells failed to transfer HIV-2 to autologous CD4+ T cells. HIV-2-specific CD4+ T cells, however, contain more viral DNA than those of other specificities in vivo , suggesting that dendritic cells are not an important contributor to infection of HIV-2-specific CD4+ T cells in vivo.
HIV-1 cell-cell transmission by CD4+ T cells and macrophages
HIV-1-infected CD4+ T cells can initiate efficient cell–cell transmission to uninfected T cells through Env and cytoskeleton-dependent virological synapses [38•,39]. Cell-associated transfer of HIV-1 is estimated to be 92 to 18 600-fold more efficient than that of cell-free virus, and virological synapses-mediated HIV-1 transfer is resistant to patient-derived neutralizing antisera [38•]. Cellular proteins that enhance immunological synapse formation, such as intercellular adhesion molecules and ZAP-70 kinase, also facilitate virological synapse formation and HIV-1 transmission between CD4+ T cells [40,41]. Interestingly, HIV-1-infected CD4+ T cells can transfer viruses to uninfected T cells through intercellular membrane nanotubes [42•], suggesting that HIV-1 usurps intercellular connections between immune cells to enhance viral spread. Further studies are required to examine if these newly identified mechanisms also occur in dendritic cell- and macrophage-mediated HIV-1 transmission to CD4+ T cells.
HIV-1-infected macrophages act as viral reservoirs, and play an important role in HIV-1 pathogenesis. HIV-1-infected macrophages transmit viruses to CD4+ T cells through virological synapses [43,44••]. Studying HIV-1 assembly in macrophages may aid in development of novel antivirals or microbicides. HIV-1 assembles mainly at the plasma membrane [45,46] or into an intracellular plasma membrane domain in macrophages . HIV-1 can also bud and accumulate in nonacidic endosomes of macrophages [48•], suggesting that HIV-1 survives within a nonacidic assembly compartment by preventing intracellular degradation. HIV-1 may use the same strategy to survive in infected-dendritic cells. In fact, dendritic cells have mechanisms to control phagosomal acidification to preserve antigen cross-presentation .
Inhibitors that block HIV-1 infection in macrophages might be potential candidates for microbicides or antivirals. Carbohydrate-binding agents have been shown to inhibit HIV-1 infection in macrophages and prevent viral transmission to CD4+ T cells . Moreover, HIV-1 protects infected macrophages from apoptosis by viral Env-induced signaling; therefore, pharmacological restoration of apoptotic sensitivity for HIV-1-infected macrophages could be a potential therapeutic strategy . As HIV-1 infection elevates Akt kinase activity in macrophages, PI3K/Akt inhibitors might be used as novel antivirals to block HIV-1 infection in macrophages .
Host factors influencing HIV-1 mucosal transmission
Host factors can promote or inhibit HIV-1 infection and transmission, thereby influencing viral infection and AIDS progression [53•]. In the screen of host factors that affect the efficiency of sexual viral transmission, Münch et al. [54••] identified that human semen-derived amyloid fibrils dramatically enhance HIV-1 in-vitro infection. The semen-derived amyloid fibrils might play an important role in sexual transmission of HIV-1, and could represent a new target of microbicide development. By contrast, Sabatté et al.  reported that human seminal plasma markedly inhibits HIV-1 transmission to CD4+ T cells mediated by dendritic cells and DC-SIGN-expressing cells. These discrepant results might derive from the different experimental approaches and procedures, which require further investigation.
Dendritic cell restriction of HIV-1 infection reflects innate antiviral immunity. HIV-1 replication in CD4+ T cells is inhibited by pDCs through the secretion of interferon α (IFNα) and other unidentified antiviral factors [56,57•]. High levels of viral replication in vivo are associated with cell death of pDCs, and pDCs from HIV-1-infected individuals, who maintain low levels of viremia without antiretroviral therapy, suppress HIV-1 replication ex vivo [57•]. Moreover, HIV-1 infection in monocytes, monocyte-derived dendritic cells, and pDCs can be partially blocked by the antiretroviral factor APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) and its family molecules [58–60], suggesting that dendritic cells, particularly pDCs, could be important mediators of innate anti-HIV immunity. HIV-1 gp120, however, inhibits TLR9-mediated activation in pDCs, resulting in a decreased secretion of IFNα and inflammatory cytokines [61•]. Further studies of anti-HIV mechanisms in dendritic cells may help to develop new strategies against HIV/AIDS.
HIV-1 exploits the cytoskeletal network to facilitate viral infection and dissemination . We observed that an intact cytoskeleton network is required for efficient dendritic cell-mediated HIV-1 transmission (J.H. Wang and L. Wu, unpublished data). It might be worth exploring if cytoskeleton inhibitors can be developed as reversible or topical agents to block HIV-1 transmission in vivo. The actin cytoskeleton also contributes to T-cell activation by forming immunological synapses between antigen-presenting cells and T cells . The immunological synapses appear to share structural similarities with the virological synapses, and may play a role in HIV-1 pathogenesis . HIV-1 facilitates cell–cell transmission by promoting virological synapse formation, whereas HIV-1 infection impairs immunological synapse formation . Theoretically, blocking the formation of virological synapses may prevent dendritic cell-mediated HIV-1 transmission to CD4+ T cells; however, the structure and function of immunological synapses should be protected to maintain anti-HIV immunity.
Recently, over 250 cellular proteins required for HIV-1 replication have been identified through a functional genomic screen, and only 36 of them are previously associated with HIV-1 infection [66••]. A cell-membrane protein that inhibits HIV-1 release has been recently discovered and termed tetherin (also called CD317, BST-2 or HM1.24), whereas HIV-1 Vpu counteracts tetherin's antiviral function [67••,68]. These new findings shed light on the development of potential strategies for anti-HIV interventions.
Host immunity and HIV-1 mucosal transmission
Dendritic cells play a crucial role in the generation and the regulation of adaptive immunity . Dendritic cells efficiently present HIV-1 antigens to T cells via MHC-I- and MHC-II-restricted pathways [35,70,71]. HIV-1 and host proteins, however, can mediate viral immune evasion and affect AIDS pathogenesis. For example, gp120 mannoses induce immunosuppressive responses from dendritic cells , and dendritic cells capture and transfer antibody-neutralized HIV-1 to CD4+ T cells via DC-SIGN . A recent study [74••] identified that the HIV-1 coreceptor CCR5 and its chemokine agonist CCL3L1 (also called macrophage inflammatory protein 1alpha, or MIP1α) are major determinants of cell-mediated immunity to HIV-1, suggesting these host factors influence viral pathogenesis through cell-mediated immunity and viral entry-independent mechanisms.
Chronic activation of the immune system is a hallmark of progressive HIV-1 infection and AIDS. Microbial translocation can be a cause of systemic immune activation in chronic HIV-1 infection , suggesting chronic immune activation during HIV-1 infection is associated with a compromised gut mucosal surface. HIV-1 replication in gut-associated lymphoid tissue mediates massive depletion of gut CD4+ T cells, which contribute to HIV-1 immune pathogenesis. A recent study [76•] reported that HIV-1 Env binds to and signals through integrin α4β7, the gut mucosal homing receptor for peripheral T cells. Engagement of α4β7 on CD4+ T cells via HIV-1 gp120 activates leukocyte function-associated antigen-1 [76•], which can facilitate virological synapse formation and HIV-1 transmission.
A better understanding of the biology of HIV-1 mucosal transmission can facilitate the development of prophylactic and therapeutic approaches against HIV-1 infection. Recent research advances in HIV-1 mucosal transmission provide new insights into the design of effective microbicides, antiviral drugs, and vaccines. Although laboratory-adapted HIV-1 strains and monocyte-derived dendritic cells/macrophages are commonly used in studies, these in-vitro systems cannot fully recapitulate the physiological conditions in HIV-1 infection. Thus, clinical HIV-1 isolates, blood/mucosal dendritic cells, tissue macrophages, and animal models should be used for confirming studies.
The author thanks Dr Michael Dwinell and the members of the author's laboratory for critical reading of the manuscript and helpful discussions. The author's laboratory is supported by grants from the National Institutes of Health (AI068493) and the Campbell Foundation. The author apologizes to all those whose work has not been cited as a result of space limitations.
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. 599–600).
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