After crossing the mucosal barrier, the main target cells for HIV-1 replication are the CD4+ lymphocytes, which are rapidly depleted, both in the periphery and in the mucosa tissues [1,2]. However, many variant cell-types of the lymphocyte and monocyte lineages can be found in the subepithelia of mucosal tissues and which are potential targets for the incoming virus (Fig. 1). Which cells first interact with HIV-1 depend on the morphology and integrity of the mucosa or the concurrence of other infections [3•]. There are numerous host factors to be found in bodily secretions of HIV-1 exposed individuals as well as within the carrier fluid of the HIV-1-positive donors, which can influence HIV-1 transmission. Here we discuss the recent observations of which cellular as well as extracellular components of the innate response can contribute to HIV-infection.
Innate cells associated with HIV-1 transmission
Tissue morphology as well as distribution of relevant cell-types within the mucosa can greatly influence viral transmission. Langerhans cells are dispersed in the interstitial area of the vagina, ectocervix, penis glands and outer foreskin that are composed of stratified squamous epithelial cells overlying the lamina propria in which dendritic cells reside [4–6]. By contrast, a single layer of columnar epithelial cells composing the endocervical, rectal, inner foreskin and glands corona mucosas, lack Langerhans cells but are underlined with interstitial dendritic cells [4,5] (Fig. 1). Langerhans cells cluster in the subepithelial papillae of the buccal mucosa , whereas dendritic cells underlie the tonsil tissue . However, Langerhans cells and dendritic cells are not the only cell types of the mucosal tissues targeted by HIV-1. Terminally differentiated macrophages are also located at sites of pathogen entry [9,10]. These cells are constantly replenished by circulating monocytes as well as through local proliferation [9,11] and are long lived cell populations surviving from a few weeks (gastrointestinal)  to months (lung alveolar) or even decades (microglia). Plasmacytoid dendritic cells (pDCs), best known for their ability to produce large quantities of IFN-α in response to stimulation with DNA or RNA viruses are found to be HIV-1 infected both in the periphery and the mucosal tissues [12•,13•].
HIV-1 can find its target cell via lesions/tears at the mucosal surface or through being captured by interdigitating dendrites of Langerhans cells/dendritic cells or crossing the epithelia via complex mechanisms of transmigration and transcytosis [14,15]. Several receptors are involved in capturing pathogens and pathogen antigen, including Toll-like receptors (TLRs), C-type lectin receptors such as dendritic cell-specific intrecellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), macrophage mannose receptor, blood dendritic cell antigen-2, dendritic cell inhibitory receptor, dendritic cell lectin, C-type lectin receptor-1 as well as the asialoglycoprotein receptor that recognizes the polysaccharide patterns on the pathogens (often characterized by their terminal mannose molecules, which are uncommon on the surface of mammalian cells) [16–20]. The binding of numerous pathogen antigens (or host factors) to this array of receptors on different cell types at mucosal surfaces can establish a complex signalling cascade, which modulates HIV-1 replication as well as induction of immune responses and has been reviewed in this issue .
Langerhans cells do not have classical mannose receptors, however, they express Langerin, which leads to the formation of Birbeck granules , organelles specializing in heightened antigenic capture and presentation . In addition, the galectin-3, β-galactoside-binding lectin is also expressed in the granules potentially playing a role in the capture of glycosylated antigens [23,24]. The primary role of Langerhans cells and dendritic cells is to capture and process antigens at sites of infection before migrating to lymph nodes in which it is presented to various lymphocyte populations [25–27]. However, both Langerin and DC-SIGN have a high affinity for the HIV-1 gp120 surface protein, and thus virus can be captured and transferred to CD4+ lymphocytes as infectious particles [28–30], referred to as transinfection. It has more recently been shown that langerin inhibits rather than enhances HIV-1 infection through viral degradation in Birbeck granules [31••]. Another study has shown that mature CD34+-derived Langerhans cell-like cells are able to transmit HIV-1 without being infected and that lipopolysaccharide along with TNF-α stimulation is required . Additionally, HIV-1 infects both dendritic cells and Langerhans cells through the classic CD4/coreceptor interaction (cisinfection) leading to de-novo virus production either at site of entry or in the lymph nodes. Langerhans cells have a restricted susceptibility to infection with C-chemokine receptor (CCR)-5 using viruses only due to the lack of CX-chemokine receptor (CXCR)-4 expression on the cell surface [33–35], one explanation for the preferential transmission of R5 viruses.
There is still much controversy as to which cell-types are the first cells infected with HIV-1. Many studies have been performed using the rhesus monkey/simian immunodeficiency virus (SIV) model system in which 48–72 hours postinoculation the main cell populations found infected reside in the lamina propria of the cervicovaginal mucosa, with CD4+ lymphocytes, macrophages, submucosal dendritic cells but not Langerhans cells being infected . Another study, however, has shown that 18 hours after vaginal inoculation, intraepithelial Langerhans cells were found to be infected , with 90% infected 1 hour after inoculation, suggesting that in the first study infected Langerhans cells may have already migrated toward the draining lymph nodes or reflect differences in the infection process.
Macrophages derived from the genital mucosa support HIV-1 infection and peripheral monocytes have been shown to carry HIV-1 during the early acute phase [13•]. The role of macrophages in HIV-1 has been reviewed here . During acute infection, they may possess local effector functions, however, upon inflammation they can migrate to adjacent lymph nodes (like Langerhans cells and dendritic cells) in which they can be involved with viral dissemination. It still remains to be determined from which infected cell population the virus likely propagates and establishes infection. HIV-1 infected pDCs have been found both in the periphery and lymphoid tissues early in acute infection [13•]. Soon after inoculation of the vaginal mucosa in rhesus macaques, the pDCs were found to create loci of virus production, whereas recruiting CD4+ lymphocyte targets through secretion of chemoattractants . Albeit that many studies have unveiled strong restrictions to virus replication in these cell populations we cannot disregard that they are key players in transmission and disease progression, especially when relating to potential reservoirs of infection. The role of pDCs in HIV-1 infection and specifically acute infection has been extensively reviewed in this edition [40••,41].
In short, the various cell types defining the innate immune system can play a role in influencing HIV-1 transmission as well as disease progression . They protect against incoming pathogens, including HIV-1, through modulating immune responses at mucosal sites and through cytokine production. Each of the different cell types involved with HIV-1 transmission or the subsequent disease course have been separately reviewed in this issue. This includes macrophages, natural killer (NK) cells and pDCs [41–45]. The innate immune response also provides the activation for the adaptive response and this has also been reviewed in this edition . Additionally, a manuscript discusses how these innate factors can be targeted as a therapeutic approach to controlling HIV-1 transmission and/or infection .
Innate extracellular factors associated with HIV-1 transmission
A large number of extracellular innate factors are present at mucosal surfaces in which HIV-1 transmission occurs. The virus will be exposed to an array of bodily secretions (saliva, human milk, vaginal secretions, sperm as well as intestinal mucus). These fluids contain a multitude of cytokines, CC–CXC chemokines, antibodies of variant subclasses [immunoglobulin (Ig)A and IgG] as well as an array of (glyco)proteins that have been shown to modulate HIV-1 infectivity and can inhibit transmission. Here we summarize selected factors found in secretions, which have the potential to modulate HIV-1 infectivity. Although beyond the scope of this article, it should be noted that cytokines in bodily fluids possess the potential to modulate immune activation and/or skew mucosal responses. A recent study has shown that HIV-1 positive commercial sex workers (CSWs) possessed higher levels of monocyte chemotactic protein-3 and monokine induced by gamma interferon in their genital mucosa and serum along with lower levels macrophage inflammatory protein (MIP)-1α and MIP-1β in serum when compared with noninfected or nonexposed control groups, thereby linking chemokine responses at mucosal sites with risk of infection .
Many components of the various bodily secretions are similar. Lactoferrin and lysozyme are factors common to most secretions, which can restrict infectivity through disrupting direct infection of CD4+ cells . Similarly, there are a large number of small peptides present in secretions, which have been shown to possess anti-HIV-1 activity, which include the α- and β-defensin group of peptides, which exert their effects through either disrupting viral particles or altering target cells for infection [50–53]. Another peptide, LL-37 cathelicidin, has been shown to possess anti-HIV-1 activity as well as induce expression of α-defensins from neutrophils [53,54]. Levels of expression of both α-defensin and LL-37 in cervicovaginal lavage, although possessing anti-HIV-1 activity, have been associated with heightened HIV-1 acquisition amongst a group of CSWs with bacterial coinfections . This example highlights the complexity of the situation with the effects of coinfections and potential skewing of immune responses negating any antiviral effects present in bodily fluids. A small molecule peptide, semen-derived enhancer of virus infection (SEVI), has been identified in seminal plasma, which has the capacity to enhance direct infection of CD4+ lymphocytes or transfer of virus by cells expressing DC-SIGN to CD4+ cells . Small molecule inhibitors have been identified that have the potential to bind SEVI and neutralize the enhancing effect . Not only can SEVI influence HIV-1 transmission but also spermatozoa can capture HIV-1 through heparin sulphate and efficiently pass the virus to iDCs . The same interaction was also shown to induce dendritic cells to express immunomodulatory cytokines, namely as IL-10. We have also shown that Ab-coated viruses can be more efficiently captured and transferred by dendritic cells to CD4+ lymphocytes than noncoated viruses and that the mechanism is Fc-mediated [59,60].
Secretory leukocyte protease inhibitor (SLPI) is an extracellular innate factor with anti-HIV-1 activity, which can be found in a variety of mucosal fluids . The molecule prevents HIV-1 from infecting macrophages through binding to the phospholipid-binding protein, annexin II, on the cell surface, which is a cofactor required for infection . This would indicate that SLPI expression at mucosal surfaces may protect against HIV-1 infection of macrophages when such cells are exposed, such as within lesions generated from coinfections. A more recent report has also indicated that SLPI-treated monocytes have the potential to down-modulate human CD4+ lymphocyte proliferation with obvious implications for reducing immune activation and inflammation at sites of exposure [63••]. The DMBT1 gene encodes for a number of factors at mucosal surfaces, which can play a role in directing innate immunity [64••]. A recombinant fragment of DMBT1 has been shown to bind gp120 and agglutinate the virus, either of which can result in the clearance of HIV-1 . Alternatively, the interaction of DMBT1/gp340 has been associated with a transcytosis of HIV-1 from the apical to the basolateral side of epithelial cells, which may enhance HIV-1 transmission across a mucosal barrier . Additionally, the DMBT1 proteins have been shown to bind an array of endogenous ligands involved with innate immunity (including IgA, MUC5B, complement factor C1q and lactoferrin to name a few) [64••]. We have identified a factor in human milk, bile salt-stimulated lipase (BSSL), which can potently bind to DC-SIGN and prevent HIV-1 capture and transfer to CD4+ lymphocytes . This molecule is composed of multiple 11 amino acid repeats at its C-terminus, which carry Lewis X sugar modifications and thereby determine binding to DC-SIGN but not molecules such as Langerin. We have additionally shown that individuals carrying specific combinations of BSSL repeat alleles can correlate with the binding capacity of breast milk to DC-SIGN . Whether this genetic variation in repeat number can correlate with protection against mother to child transmission of HIV-1 through breastfeeding needs to be addressed through screening of at risk cohorts. Interestingly, BSSL is also found in plasma and has been shown to bind to CXCR4  and from screening a cohort of HIV-1 infected individuals we have associated specific BSSL genotypes with rates of disease progression and timing of the CCR5 to CXCR4 coreceptor switch (Stax, Pollakis and Paxton, unpublished observations).
Mucins (MUC glycoproteins) are a major component to all bodily secretions. Purified MUC5B and MUC7 isolated from human saliva have been shown to inhibit HIV-1 direct infection of CD4+ cells, with the mechanism of action speculated to be aggregation of viral particles through the carbohydrate moieties of the glycoproteins . It has been shown that MUC1 in human milk and MUC6 from seminal plasma can potently bind to DC-SIGN and prevent viral capture and transfer to CD4+ lymphocytes [71,72]. Because MUC6 carries fucose containing sugar modifications, one speculation is that alterations in genes directing such modifications may differ between individuals and hence alter their inhibitory capacity. In particular, the FUT2 and FUT 3 gene, encoding fucosyltransferases 2 and 3 involved in the synthesis of DC-SIGN-binding Lewis type sugars have been associated to other pathogen infection [73–76]. Modifications in the number of repeat sequences within the MUC6 gene have been associated with risk of helicobacter pylori infections within the gut . Individuals can be characterized into secretors and nonsecretors on the basis of their blood group antigens and which correlates to risk of infection with other pathogens [78,79]. It has recently been described that cellular or soluble P-k/Gb [3•] histoblood group antigen provides protection against HIV-1 infection, through inhibiting viral fusion [80••]. Further research is needed to identify whether such blood antigens can influence HIV-1 replication once infection has occurred.
Genetic association with risk of HIV-1 infection
Genetic associations are powerful ways to determine which mechanisms are important for influencing HIV-1 transmission and a large number have now been identified for the CC-chemokine and chemokine receptor axis . Many genetic mutations are now being discovered in genes encoding for proteins involved in the innate immune response, including cytokines, cytokine receptors, TLRs, killer immunoglobulin-like receptors and C-type lectins (such as DC-SIGN) and all which have been linked with either risk of HIV-1 infection or disease progression . A large list of intracellular innate factors have also been generated which encompass a large number of proteins which can be associated with transmission or subsequent viral replication following infection (with the APOBEC family, Trim5 and tetherin being amongst them) [82,83•,84].
What can be learnt from simian immunodeficiency virus and HIV-2
Much can be learnt from comparative science and this is true when comparing the pathogenic and nonpathogenic models for SIV infection in nonhuman primates. The hallmark for HIV-1 pathogenesis is chronic immune activation as driven by the innate immune response against the virus . The review by Bosinger et al.  highlights what mechanisms of action are associated with lack of disease in monkeys and which are primarily involved in down-regulation of interferon induced responses in SIV-infected sooty mangabeys and African green monkeys who are disease free in comparison to macaques infected with SIV. Similar comparisons have been made between HIV-1 and HIV-2, a less pathogenic form of HIV characterized by lower rates of transmission and disease . Two interesting studies have shown that lower levels of HIV-2 are present in the female genital tract or semen of HIV-2-positive females and males, respectively [86,87]. Better understanding the factors associated with lower HIV-2 loads would advance our understanding of HIV-1 pathogenesis. A number of recent interesting findings have indicated that numerous differences in a number of innate factors or responses may contribute to lower viral loads. The Vpx protein of HIV-2 (not present in HIV-1) has been shown to modulate infection of various cell types of the innate immune response, namely monocytes, and one proposed mechanism is through the interaction of Vpx with APOBEC3A, thereby circumventing its inhibitory effect . The result would indicate a disruption to the innate response that favors a down-modulation of immune activation. Such a mechanism has also been suggested by the recent finding that pDCs are preferentially depleted in HIV-2 infection, again supporting down-modulation of over immune activation .
An array of factors of the extracellular innate immune response present in bodily secretions and carrier fluids have been shown to interfere with HIV-1 infection or interaction with various cell types of the innate immune system. Factors present in sperm have been shown to enhance infection of CD4+ T lymphocytes, whereas MUC6 in seminal plasma can prevent viral capture and transfer by dendritic cells through binding DC-SIGN. Additional glycoproteins found in breast-milk, including MUC1 and BSSL, have also been shown to provide similar effects. These factors add to the already large array of molecules in bodily fluids, which can modulate HIV-1 transmission, including cytokines, chemokines, small molecule inhibitors, as well as larger proteins and glycoproteins. These cellular and body fluid factors are likely to interfere not only with transmission but also with virus dissemination as well as with disease progression.
This article was supported by The Netherlands AIDS Foundation (MJS 2005024).
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. 444).
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