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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283499e11
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Innate immune factors associated with HIV-1 transmission

Pollakis, Georgios; Stax, Martijn J.; Paxton, William A.

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Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity Amsterdam (CINIMA), Academic Medical Centre of the University of Amsterdam, The Netherlands

Correspondence to William A. Paxton, K3–106 Laboratory of Experimental Virology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ, Amsterdam, The NetherlandsTel: +31 20 566 4739; fax: +31 20 691 6531; e-mail:

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Purpose of review: Relatively little is known with regards to the mechanisms of HIV-1 transmission across a mucosal surface and more specifically what effects host factors have on influencing infection and early viral dissemination. The purpose of this review is to summarize which factors of the innate immune response can influence mucosal transmission of HIV-1.

Recent findings: A large array of cell types reside at the mucosal surface ranging from Langerhans cells, dendritic cells, macrophages as well as CD4+ lymphocytes, all of which interact with the virus in a unique and different way and which can contribute to risk of HIV-1 transmission. Numerous factors present in bodily secretions as well as the carrier fluids of HIV-1 (breast milk, vaginal secretions, semen and intestinal mucus) can influence transmission and early virus replication. These range from cytokines, chemokines, small peptides, glycoproteins as well as an array of host intracellular molecules which can influence viral uncoating, reverse transcription as well as egress from the infected cell.

Summary: Better understanding the cellular mechanisms of HIV-1 transmission and how different host factor can influence infection will aide in the future development of vaccines, microbicides, and therapies.

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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.

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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 [7], whereas dendritic cells underlie the tonsil tissue [8]. 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) [9] 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 [21].

Langerhans cells do not have classical mannose receptors, however, they express Langerin, which leads to the formation of Birbeck granules [22], organelles specializing in heightened antigenic capture and presentation [23]. 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 [32]. 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 [36]. Another study, however, has shown that 18 hours after vaginal inoculation, intraepithelial Langerhans cells were found to be infected [37], 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.

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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 [38]. 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 [39]. 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 [42]. 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 [46]. Additionally, a manuscript discusses how these innate factors can be targeted as a therapeutic approach to controlling HIV-1 transmission and/or infection [47].

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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 [48].

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 [49]. 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 [55]. 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 [56]. Small molecule inhibitors have been identified that have the potential to bind SEVI and neutralize the enhancing effect [57]. 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 [58]. 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 [61]. 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 [62]. 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 [65]. 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 [66]. 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 [67]. 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 [68]. 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 [69] 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 [70]. 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 [77]. 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.

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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 [47]. 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 [81]. 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].

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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 [85]. The review by Bosinger et al. [85] 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 [86]. 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 [88]. 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 [89].

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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.

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This article was supported by The Netherlands AIDS Foundation (MJS 2005024).

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Conflicts of interest

There are no conflicts of interest.

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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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1. Lim SG, Condez A, Lee CA, et al. Loss of mucosal CD4 lymphocytes is an early feature of HIV infection. Clin Exp Immunol 1993; 92:448–454.

2. Brenchley JM, Douek DC. HIV infection and the gastrointestinal immune system. Mucosal Immunol 2008; 1:23–30.

3•. Venkatesh KK, van der Straten A, Cheng H, et al. The relative contribution of viral and bacterial sexually transmitted infections on HIV acquisition in southern African women in the Methods for Improving Reproductive Health in Africa study. Int J STD AIDS 2011; 22:218–224.

This article puts in perspective the importance of other infectious agents in the acquisition of HIV-1, particularly in areas of limited resources.

4. Cunningham AL, Carbone F, Geijtenbeek TB. Langerhans cells and viral immunity. Eur J Immunol 2008; 38:2377–2385.

5. Kawamura T, Kurtz SE, Blauvelt A, et al. The role of Langerhans cells in the sexual transmission of HIV. J Dermatological Science 2005; 40:147–155.

6. de Witte L, Nabatov A, Geijtenbeek TB. Distinct roles for DC-SIGN+-dendritic cells and Langerhans cells in HIV-1 transmission. Trends Mol Med 2008; 14:12–19.

7. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18:767–811.

8. Plzák J, Holíková Z, Smetana K Jr, et al. The role of dendritic cells in the pharynx. Eur Arch Otorhinolaryngol 2003; 260:266–272.

9. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5:953–964.

10. Hume DA. The mononuclear phagocyte system. Curr Opin Immunol 2006; 18:49–53.

11. Lassmann H, Schmied M, Vass K, et al. Bone marrow derived elements and resident microglia in brain inflammation. Glia 1993; 7:19–24.

12•. Cassol E, Cassetta L, Alfano M, et al. Macrophage polarization and HIV-1 infection. J Leukoc Biol 2010; 87:599–608.

This article describes the role of monocytes and macrophages in HIV-1 transmission and indicates that soon after acute infection with HIV-1 these cells can be infected to high levels.

13•. Centlivre M, Legrand N, Steingrover R, et al. Altered dynamics and differential infection profiles of lymphoid and myeloid cell subsets during acute and chronic HIV-1 infection. J Leukoc Biol 2011; 89:785–795.

This article describes the role of monocytes and macrophages in HIV-1 transmission and indicates that soon after acute infection with HIV-1 these cells can be infected to high levels.

14. Yao H, Yang Y, Kim KJ, et al. Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood 2010; 115:4951–4962.

15. Madsen J, Mollenhauer J, Holmskov U. Review: Gp-340/DMBT1 in mucosal innate immunity. Innate Immun 2010; 16:160–167.

16. Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and Langerhans’ cells. Nature Rev Immunol 2002; 2:77–84.

17. Holíková Z, Hercogová J, Plzák J, et al. Dendritic cells and their role in skin-induced immune responses. JEADV 2001; 15:116–120.

18. Jiang W, Swiggard WJ, Heuffer M, et al. The receptor DEC-205 expressed by dendritic cells and thymic epithelial cells is involved in antigen processing. Nature 1995; 375:151–155.

19. Valladeau J, Duvert-Frances V, Pin JJ, et al. Immature human dendritic cells express asialoglycoprotein receptor isoforms for efficient receptor-mediated endocytosis. J Immunol 2001; 167:5767–5774.

20. Plzák J, Holíková Z, Smetana K Jr, et al. The role of dendritic cells in the pharynx. Eur Arch Otorhinolaryngol 2003; 260:266–272.

21. van der Vlist M, van der Aar AMG, Gringhuis SI, Geijtenbeek TBH. Innate signalling in HIV-1 infection of dendritic cells. Curr Opin HIV AIDS. 2011; 6.

22. Valladeau J, Ravel O, Dezutter-Dambuyant C. Langerin: a novel C-type lectin specific to Langerhans’ cell, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 2000; 12:71–81.

23. Plzák J, Smetana K Jr, Hrdličková E, et al. Expression of galectin-3-reactive ligands in squamous cancer and normal epithelial cells as a marker of differentiation. Int J Oncol 2001; 19:59–64.

24. Smetana K, Holíková Z, Klubal R, et al. Coexpression of binding sites for A(B) histo-blood group trisaccharides with galectin-3 and Lag antigen in human Langerhans cells. J Leukoc Biol 1999; 66:644–649.

25. Kaplan DH, Kissenpfenning A, Clausen BE. Insights into Langerhans cell function from Langerhans cell ablation models. Eur J Immunol 2008; 38:2369–2376.

26. He Y, Zhang J, Donahue C, et al. Skin-derived dendritic cells induce potent CD8(1) T cell immunity in recombinant lentivector-mediated genetic immunization. Immunity 2006; 24:643–656.

27. Mayerova D, Parke EA, Bursch LS, et al. Langerhans cells activate naive self-antigen-specific CD8 T cells in the steady state. Immunity 2004; 21:391–400.

28. Trumpfheller C, Park CG, Finke J, et al. Cell type-dependent retention and transmission of HIV-1 by DC-SIGN. Int Immunol 2003; 15:289–298.

29. McDonald D, Wu L, Bohks SM, et al. Recruitment of HIV and its receptors to dendritic cell-T cell junctions. Science 2003; 300:1295–1297.

30. Arrighi JF, Pion M, Garcia E, et al. DC-SIGN-mediated infectious synapse formation enhances X4 HIV-1 transmission from dendritic cells to T cells. J Exp Med 2004; 200:1279–1288.

31••. van der Vlist M, Geijtenbeek TB. Langerin functions as an antiviral receptor on Langerhans cells. Immunol Cell Biol 2010; 88:410–415.

This article demonstrates the protective role of Langerin, which provides a mechanism that can potentially restrict HIV-1 transmission.

32. Fahrbach KM, Barry SM, Ayehunie S, et al. Activated CD34-derived Langerhans cells mediate transinfection with human immunodeficiency virus. J Virol 2007; 81:6858–6868.

33. Kawamura T, Cohen SS, Borris DL, et al. Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 2000; 192:1491–1500.

34. Zaitseva M, Blauvelt A, Lee S, et al. Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nat Med 1997; 3:1369–1375.

35. Reece JC, Handley AJ, Anstee EJ, et al. HIV-1 selection by epidermal dendritic cells during transmission across human skin. J Exp Med 1998; 187:1623–1631.

36. Spira AI, Marx PA, Patterson BK, et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 1996; 183:215–225.

37. Hu J, Gardner MB, Miller CJ. Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 2000; 74:6087–6095.

38. Cobos-Jiménez V, Booiman T, Hamann J, Kootstra NA. V Macrophages and HIV-1 Curr Opin HIV AIDS. 2011; 6.

39. Li Q, Estes JD, Schlievert PM, et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 2009; 458:1034–1038.

40••. Benlahrech A, Patterson S. HIV-1 infection and induction of interferon alpha in plasmacytoid dendritic cells. Curr Opin HIV AIDS. 2011; 6.

Direct evidence that pDCs can be infected at the site of virus entry and play a role in the enhancement of the CD4+ cell infection.

41. Borrow P. Innate immunity in acute HIV-1 infection. Curr Opin HIV AIDS. 2011; 6.

42. Chang JJ, Altfeld M. Innate immune activation in primary HIV-1 infection. J Infect Dis 2010; 202 (Suppl 2):S297–S301.

43. Derby N, Martinelli E, Robbiani M. Myeloid DCs in HIV Infection Curr Opin HIV AIDS. 2011; 6.

44. Gougeon M-L, Bras M. Natural killer cells, dendritic cells and the alarmin HMGB1: a dangerous trio in HIV-1 infection? Curr Opin HIV AIDS. 2011; 6.

45. Smed-Sörensen A, Loré K. Dendritic cells in the interface of innate and adaptive immunity to HIV-1. Curr Opin HIV AIDS. 2011; 6.

46. Ellegård R, Shankar EM, Larsson M. Targetting HIV-1 innate immune responses therapeutically. Curr Opin HIV AIDS. 2011; 6.

47. Choi WT. Biology and clinical relevance of chemokines and chemokine receptors CXCR4 and CCR5 in human diseases. Exp Biol Med 2011; 236:637–647.

48. Lajoie J, Poudrier J, Loembe MM, et al. Chemokine expression patterns in the systemic and genital tract compartments are associated with HIV-1 infection in women from Benin. J Clin Immunol 2010; 30:90–98.

49. Berkhout B, van Wamel JL, Beljaars L, et al. Characterization of the anti-HIV effects of native lactoferrin and other milk proteins and protein-derived peptides. Antiviral Res 2002; 55:341–355.

50. Levinson P, Kaul R, Kimani J, et al. HIV Study Group. Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS 2009; 23:309–317.

51. Quinones-Mateu ME, Lederman MM, Feng Z, et al. Human epithelial beta-defensins 2 and 3 inhibit HIV-1 replication. AIDS 2003; 17:F39–F48.

52. Chang TL, Vargas J Jr, DelPortillo A, et al. Dual role of alpha-defensin-1 in anti-HIV-1 innate immunity. J Clin Invest 2005; 115:765–773.

53. Bergman P, Walter-Jallow L, Broliden K, et al. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr HIV Res 2007; 5:410–415.

54. Zheng Y, Niyonsaba F, Ushio H, et al. Cathelicidin LL-37 induces the generation of reactive oxygen species and release of human alpha-defensins from neutrophils. Br J Dermatol 2007; 157:1124–1131.

55. Levinson P, Kaul R, Kimani J, et al. Levels of innate immune factors in genital fluids: association of alpha defensins and LL-37 with genital infections and increased HIV acquisition. AIDS 2009; 23:309–317.

56. Kim KA, Yolamanova M, Zirafi O, et al. Semen-mediated enhancement of HIV infection is donor-dependent and correlates with the levels of SEVI. Retrovirology 2010; 7:55.

57. Olsen JS, Brown C, Capule CC, et al. Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection)- and semen-mediated enhancement of HIV-1 infection. J Biol Chem 2010; 285:35488–35496.

58. Ceballos A, Remes Lenicov F, Sabatté J, et al. Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells. J Exp Med 2009; 206:2717–2733.

59. van Montfort T, Nabatov A, Geijtenbeek TBH, et al. Efficient capture of antibody neutralized HIV-1 by cells expressing DC-SIGN and transfer to CD4+ T lymphocytes. J Immunol 2007; 177:3177–3185.

60. van Montfort T, Thomas AAAM, Pollakis G, et al. Dendritic cells preferentially transmit CXCR4-using HIV-1 variants to CD4+ T lymphocytes in trans. J Virol 2008; 82:7886–7896.

61. Thompson RC, Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci USA 1986; 83:6692–6696.

62. Ma G, Greenwell-Wild T, Lei K, et al. Secretory leukocyte protease inhibitor binds to annexin II, a cofactor for macrophage HIV-1 infection. J Exp Med 2004; 200:1337–1346.

63••. Guerrieri D, Tateosian NL, Maffía PC et al. Serine leucocyte proteinase inhibitor-treated monocyte inhibits human CD4+ lymphocyte proliferation. Immunology 2011. [Epub ahead of print]. DOI:1111/j.1365-2567.2011.03451.x

This article describes another mechanism whereby SLP1 can interfere with HIV-1 transmission through modulating CD4 activation and proliferation, but not CD8 cells.

64••. Madsen J, Mollenhauer J, Holmskov U. Review: Gp-340/DMBT1 in mucosal innate immunity. Innate Immun 2010; 16:160–167.

Provides a review of how gp-340 can interfere with many and varied aspects of the innate immune response, which would have the potential to interfere and modulate HIV-1 transmission.

65. Wu Z, Lee S, Abrams W, et al. The N-terminal SRCR-SID domain of gp-340 interacts with HIV type 1 gp120 sequences and inhibits viral infection. AIDS Res Hum Retroviruses 2006; 22:508–515.

66. Stoddard E, Ni H, Cannon G, et al. gp340 promotes transcytosis of human immunodeficiency virus type 1 in genital tract-derived cell lines and primary endocervical tissue. J Virol 2009; 83:8596–8603.

67. Naarding MA, Dirac AM, Ludwig IS, et al. Bile salt-stimulated lipase from human milk binds DC-SIGN and inhibits human immunodeficiency virus type 1 transfer to CD4+ T cells. Antimicrob Agents Chemother 2006; 50:3367–3374.

68. Stax MJ, Naarding MA, Tanck MWT, et al. Binding of human milk to pathogen receptor DC-SIGN varies with bile salt-stimulated lipase (BSSL) gene polymorphism. PLoS ONE 2011; 6:e17316.

69. Panicot-Dubois L, Thomas GM, Furie BC, et al. Bile salt-dependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans. J Clin Invest 2007; 117:3708–3719.

70. Habte HH, Mall AS, de Beer C, et al. The role of crude human saliva and purified salivary MUC5B and MUC7 mucins in the inhibition of human immunodeficiency virus type 1 in an inhibition assay. Virol J 2006; 3:99.

71. Stax MJ, van Montfort T, Sprenger RR, et al. Mucin 6 in seminal plasma binds DC-SIGN and potently blocks dendritic cell mediated transfer of HIV-1 to CD4+ T-lymphocytes. Virology 2009; 391:203–211.

72. Saeland E, de Jong MA, Nabatov AA, et al. MUC1 in human milk blocks transmission of human immunodeficiency virus from dendritic cells to T cells. Mol Immunol 2009; 46:2309–2316.

73. Newburg DS. Neonatal protection by an innate immune system of human milk consisting of oligosaccharides and glycans. J Anim Sci 2009; 87 (13 Suppl):26–34.

74. Ruvoën-Clouet N, Mas E, Marionneau S, et al. Bile-salt-stimulated lipase and mucins from milk of ‘secretor’ mothers inhibit the binding of Norwalk virus capsids to their carbohydrate ligands. Biochem J 2006; 393:627–634.

75. Borén T, Falk P, Roth KA, et al. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 1993; 262:1892–1895.

76. Sheinfeld J, Schaeffer AJ, Cordon-Cardo C, et al. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women. N Engl J Med 1989; 320:773–777.

77. Nguyen TV, Janssen M Jr, Gritters P, et al. Short mucin 6 alleles are associated with H pylori infection. World J Gastroenterol 2006; 12:6021–6025.

78. Moulds JM, Nowicki S, Moulds JJ, et al. Human blood groups: incidental receptors for viruses and bacteria. Transfusion 1996; 36:362–374.

79. Fumagalli M, Cagliani R, Pozzoli U, et al. Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res 2009; 19:199–212.

80••. Branch DR. Blood groups and susceptibility to virus infection: new developments. Curr Opin Hematol 2010; 17:558–564.

Review describing how blood group antigens can modulate viral infectivity, a relatively unknown and underappreciated mechanism of how viruses interact with the host to enable transmission.

81. Sobieszczyk ME, Lingappa J, McElrath JM. Host genetic polymorphisms associated with innate immune factors and HIV-1. Curr Opin HIV AIDS. 2011; 6.

82. Malim MH, Emerman M. HIV-1 accessory proteins-ensuring viral survival in a hostile environment. Cell Host Microbe 2008; 3:388–398.

83•. Berger A, Münk C, Schweizer M, et al. Interaction of Vpx and apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A) correlates with efficient lentivirus infection of monocytes. J Biol Chem 2010; 285:12248–12254.

This article provides evidence of how vpx of HIV-2 can modulate infection of macrophages.

84. Evans DT, Serra-Moreno R, Singh RK, et al. BST-2/tetherin: a new component of the innate immune response to enveloped viruses. Trends Microbiol 2010; 18:388–396.

85. Bosinger SE, Sodora DL, Silvestri G. Generalized immune activation and innate immune responses in SIV infection. Curr Opin HIV AIDS. 2011; 6.

86. Hawes SE, Sow PS, Stern JE, et al. Lower levels of HIV-2 than HIV-1 in the female genital tract: correlates and longitudinal assessment of viral shedding. AIDS 2008; 22:2517–2525.

87. Gottlieb GS, Hawes SE, Agne HD, et al. Lower levels of HIV RNA in semen in HIV-2 compared with HIV-1 infection: implications for differences in transmission. AIDS 2006; 20:895–900.

88. Berger A, Münk C, Schweizer M, et al. Interaction of Vpx and apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A) correlates with efficient lentivirus infection of monocytes. J Biol Chem 2010; 16:12248–12254.

89. Cavaleiro R, Baptista AP, Soares RS, et al. Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease. PLoS Pathog 2009; 5:e1000667.


HIV-1 transmission; innate extracellular factors; innate immune cells

© 2011 Lippincott Williams & Wilkins, Inc.


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