Skip Navigation LinksHome > September 2011 - Volume 6 - Issue 5 > Innate signaling in HIV-1 infection of dendritic cells
Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e328349a2d1
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Innate signaling in HIV-1 infection of dendritic cells

van der Vlist, Michiel; van der Aar, Angelic M.G.; Gringhuis, Sonja I.; Geijtenbeek, Teunis B.H.

Free Access
Article Outline
Collapse Box

Author Information

Center for Experimental and Molecular Medicine and Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Correspondence to Teunis B.H. Geijtenbeek, Center for Experimental and Molecular Medicine and Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsTel: +31 205 666 309; fax: +31 206 977 192; e-mail: T.B.Geijtenbeek@amc.uva.nl

Collapse Box

Abstract

Purpose of review: This review summarizes the current knowledge of innate signaling events that are involved in HIV-1 infection. We here focus on dendritic cells, which are among the first cells that encounter HIV-1 after exposure.

Recent findings: HIV-1 triggers multiple pattern recognition receptors on dendritic cells that facilitate infection and transmission to T cells. Triggering of the C-type lectin DC-SIGN induces signals that promote HIV-1 replication in dendritic cells and transmission to T cells. Similarly, dendritic cell immunoreceptor has been shown to bind HIV-1 and facilitate transmission to T cells. The cytosolic sensors TRIM5 and cyclophilin A recognize capsid proteins and activate antiviral responses to prevent HIV-1 infection. Moreover, activation of mammalian target of rapamycin (mTOR) by HIV downregulates autophagy preventing adaptive immune responses.

Summary: Dendritic cells express an array of pattern recognition receptors that are involved in HIV-1 infection. However, HIV-1 dampens signaling by these receptors leading to suppressed responses or takes advantage of their signaling for its own benefit.

Back to Top | Article Outline

Introduction

HIV-1 is a sexually transmitted disease that primarily infects CD4+ T cells, dendritic cells and macrophages. Mucosal dendritic cells are among the first cells to encounter invading pathogens and it is becoming clear that different dendritic cells subsets have distinct functions in HIV-1 transmission. In the upper mucosal layers, Langerhans cells form a dense network that protects against HIV-1 infection [1]. In mucosa and dermis, mucosal and dermal dendritic cells, respectively, can become infected by HIV-1 and are hijacked by HIV-1 to facilitate transmission to T cells [2,3]. Dendritic cells can activate HIV-1 specific immune responses, resulting in production of neutralizing antibodies and activation of cytotoxic T cells. Together, these immune reactions suppress viral replication after the primary viremia. However, HIV-1 has also been reported to suppress the immunogenicity of dendritic cells by preventing activation [4,5] and blocking autophagy [6•]. These studies show that dendritic cells are involved in different aspects of HIV-1 infection and the initiation of immune responses against HIV-1. Further studies on this subject will lead to better understanding of immune (dis)regulation during HIV-1 infection. This information is crucial to the development of better antiviral drugs and efficient vaccine strategies to stop the HIV-1 pandemic.

Back to Top | Article Outline

Dendritic cells bridge innate and adaptive immunity

Dendritic cells need to be able to discriminate between different classes of pathogens to induce proper adaptive immune responses. Dendritic cells recognize pathogens via pattern recognition receptors (PRR) that bind to pathogen-associated molecular patterns (PAMP). Dendritic cells express several classes of PRR, including toll-like receptors (TLR), nucleotide-binding oligomerization domain (NOD)-like receptors, retinoic acid inducible gene I (RIG-I)-like receptors and C-type lectin receptors (CLR) [7]. These PRR induce signaling events that activate immune responses and tailor them to induce pathogen-specific responses. Therefore, the array of PRR that recognize a pathogen determines the type of adaptive immune response that is induced by dendritic cells. TLR and CLR recognize PAMP at the cell surface or after uptake in endosomes/lysosomes, and are therefore able to sense HIV-1 prior to infection of the cell. Cytosolic PAMP are recognized by sensors such as NOD- and RIG-I-like receptors or TRIM5, of which the latter has been recently shown to signal upon HIV-1 recognition [8••]. New insights have shown that these innate signaling pathways are not necessarily beneficial to the host. HIV-1 abuses their signaling pathways to decrease immune activation and dampen antiviral responses, enhance transmission to T cells, and increase HIV-1 replication.

The C-type lectin DC-SIGN is highly expressed by dendritic cells and interacts with the envelope protein of HIV-1, gp120, which leads to HIV-1 capture and viral transmission. Notably, it has become clear that DC-SIGN binding by pathogens such as HIV-1 also induces signals that shape adaptive immunity and/or promote HIV-1 infection and transmission. DC-SIGN recognizes both mannose- and fucose-expressing pathogens, which include bacteria, viruses and helminths. Recent data show that DC-SIGN is crucial in shaping adaptive immune responses to specific pathogens [9,10]. Notably, DC-SIGN triggering alone does neither result in dendritic cells maturation nor in transcription of inflammatory genes. However, signaling induced by DC-SIGN shapes immune responses by modifying signaling cascades activated by other PRR, which can enhance or suppress specific proinflammatory cytokines [9]. Notably, signaling induced by DC-SIGN discriminates between mannose- and fucose-containing pathogens [10]. Mannose-expressing pathogens such as HIV-1 require a signalosome that is preassembled at the cytosolic domain of DC-SIGN. This signalosome contains KSR1, CNK and Raf-1, that link to the cytoplasmic domain of DC-SIGN through the adaptor protein LSP-1. This signalosome is required for the constitutive recruitment of Raf-1 to DC-SIGN. Upon binding of DC-SIGN by HIV-1 and other mannose-expressing pathogens, Raf-1 becomes activated by recruitment of the upstream effectors LARG and RhoA to the DC-SIGN signalosome. Signaling downstream of Raf-1 induces phosphorylation of the NF-κB subunit p65 at serine 276, which allows subsequent acetylation of p65 at different lysine residues [9,10]. Acetylation of p65 prolongs its activity and also enhances its transcription rate of genes such as il12a, il12b and il6[9]. Thus, p65 acetylation enhances expression of proinflammatory cytokines that are required for T helper cell type 1 differentiation [11]. Noteworthy, Raf-1 activation alone does not induce NF-κB activation and prior triggering of another PRR such as TLR is required to activate NF-κB subunit p65. In contrast, fucose-expressing ligands actively disassociate KSR1, CNK and Raf-1 from DC-SIGN, which results in activation of a signaling cascade that suppresses proinflammatory cytokines [10]. HIV-1 triggering of DC-SIGN activates Raf-1, which enhances TLR-induced proinflammatory cytokines IL-12p70 and IL-6 as well as the suppressive cytokine IL-10 [9]. These data suggest that HIV-1 can use this modulatory signaling pathway to affect adaptive immune responses in HIV-1-infected individuals. Currently, it is unclear whether the modulation is beneficial to the host or virus.

Back to Top | Article Outline

DC-SIGN and Toll-like receptor-8 license HIV-1 transcription in dendritic cells

Box 1
Box 1
Image Tools

Dendritic cells capture HIV-1 through DC-SIGN, which facilitates transmission of HIV-1 to T cells [2]. Internalization of HIV-1 by DC-SIGN leads to routing into endosomes, in which HIV-1 is protected from degradation. Therefore, dendritic cells have been postulated to play a pivotal role in HIV-1 transmission to T cells. Furthermore, recently it has been shown that DC-SIGN signaling is required for infection of dendritic cells. Uptake of HIV-1 by dendritic cells results in activation of p65 through triggering of TLR-8 by HIV-1 ssRNA [12••]. Induction of p65 results in recruitment of cyclin-dependent kinase (CDK)-7 toward the long terminal repeat (LTR), the promoter/enhancer of HIV-1. Notably, RNA polymerase II (RNAPII) is already present on the LTR without need for any signaling, demonstrating that LTR is a poised promoter. CDK-7 mediates phosphorylation of RNAPII at serine 2 of the C-terminal domain (CTD). This phosphorylation is required for initiation of transcription by RNAPII. However, transcription initiation does not lead to full-length HIV-1 transcripts and transcription will abort after about 65 bases without additional signals. Hence, TLR-8 triggering alone results in abortive HIV-1 transcription [12••]. The second signal, that leads to transcriptional elongation, is provided by binding of gp120 to DC-SIGN. The interaction of HIV-1 gp120 with DC-SIGN results in activation of Raf-1 and subsequently phosphorylation of p65 at serine 276. This modification recruits positive transcription elongation factor b (p-TEFb) to the LTR. p-TEFb phosphorylates the CTD of RNAPII at a serine 5 [12••], a hallmark for transcriptional elongation. Together, HIV-1-induced innate signaling by DC-SIGN and TLR-8 results in full-length transcription of the HIV-1 genome and production of HIV-1 proteins. The early gene product HIV-1 Tat is able to recruit p-TEFb to the LTR, which provides a positive feedback loop to sustain transcription of HIV-1 genome. Thus, HIV-1-induced innate signaling via TLR-8 and DC-SIGN controls transcription initiation and elongation from the integrated provirus and enables HIV-1 replication in dendritic cells. Coinfections, such as with fungi, also induce Raf-1 activation and thereby can further increase HIV-1 transcription [10,12••]. These studies show that HIV-1 subverts innate signaling mechanisms for infection of dendritic cells and subsequent transmission.

Back to Top | Article Outline

DC-SIGN ruffles the cell membrane to enhance HIV-1 transmission

Dendritic cells have been postulated to play a pivotal role in HIV-1 dissemination. HIV-1 transmission from dendritic cells to T cells is an efficient process that makes use of cell-to-cell transfer of the virus. At the dendritic cells–T-cell interface, actin-dependent membrane deformations form the infectious synapse (also called the virological synapse) [13], in analogy to what is observed for the immunological synapse. Binding of HIV-1 to dendritic cell-SIGN enhances infectious synapse formation [13,14], and it was recently shown that DC-SIGN signaling is involved in this process [15•]. Within an hour after HIV-1 exposure, the membrane starts to form extensions at the entire border of the cell. Exposure of dendritic cells to HIV-1 or DC-SIGN agonistic antibody H200, but not to HIV-1Δenv, leads to activation of Src kinases and downstream activation of Pak1, WASP and Cdc42. Activation of Cdc42 is required for formation of membrane extensions and transport of HIV-1 virions to these extensions. Cdc42 silencing reduces the amount of membrane extensions, and hence reduces the contact area with T cells and transmission of HIV-1. Moreover, a similar reduction of HIV-1 transmission was observed in LARG-silenced cells, indicating that LARG is also involved in membrane extension formation [15•]. LARG was previously shown to activate Rho-GTPases after binding of HIV-1 to DC-SIGN [16], suggesting that LARG activation is upstream of Cdc42 activation. Thus, HIV-1 subverts DC-SIGN signaling not only to induce transcription, but also to enhance the formation of the infectious synapse between dendritic cells and T cells and thereby facilitates its transmission to T cells. These signaling events by DC-SIGN might be important during HIV-1 transmission. However, in later stages of disease DC-SIGN might provide signals that reactivate HIV-1 replication and thereby keeps fueling transmission to T cells. Furthermore, shedding of viral gp120 during chronic infection might affect adaptive immunity induced by dendritic cells through triggering of specific signaling processes.

Back to Top | Article Outline

Dendritic cell immunoreceptor increases HIV-1 susceptibility

Another C-type lectin that is expressed by dendritic cells and is involved in recognition of HIV-1 is dendritic cell immunoreceptor (DCIR) [17]. Similar to DC-SIGN, DCIR facilitates transmission of HIV-1 from dendritic cells to T cells and enhances infection of DCIR expressing cells [18]. Recently, it was shown that DCIR-induced signaling results in increased HIV-1 entry/binding [19•]. The DCIR signaling pathway involves the ITIM motive present in its cytosolic domain. Competitive peptides containing the ITIM-domain reduced HIV-1 capture and infection of dendritic cells. Ligation of DCIR results in recruitment of Src homology 2-containing tyrosine phosphatase (SHP)-1 and SHP-2. Enhancement of HIV-1 binding/entry is dependent on Src family members Src, Fyn and Hck; the Syk family; and PKC-α [19•]. It has to be established whether signaling of DCIR leads to enhance capture or that it enhances internalization. DCIR signaling could also be involved in recruitment of CD4 and/or the HIV-1 coreceptors to HIV-1 because its signaling is required for the enhanced infection seen in cells transfected with DCIR. Thus, DCIR is a novel receptor that HIV-1 abuses to promote its transmission and infection.

Back to Top | Article Outline

HIV-1 capsid recognition increases antiviral responses

Cytosolic recognition of HIV-1 also plays an important role in HIV-1 infection. TRIM proteins are cytosolic innate immune sensors that are known to restrict virus infections. TRIM5 can recognize the lattice formed by HIV-1 capsid protein upon infection [8••]. TRIM5 accelerates the uncoating of the core, which negatively influences HIV-1 infectivity [20]. Besides this direct effect on HIV-1, TRIM5 promotes innate signaling, which is enhanced after HIV-1 infection [8••]. Upon capsid recognition, TRIM5 induces transcriptional activation of NF-κB and AP1, and enhances IRF3-mediated interferon (IFN)-β transcription. TRIM5 acts with CBC13 and UEV1A to form free lysine-63-linked polyubiquitin chains that activate TAK-1. Subsequently, downstream of TAK-1 the transcription factors AP1 and NF-κB are activated. Hence, TRIM5 is a PRR that recognizes HIV-1 infection before integration of HIV-1 into the host genome. This results in a two-pronged response, leading to degradation of the viral core and activation of the immune system.

HIV-1 capsid protein is also recognized at another stage of the HIV-1 live cycle. De novo synthesized capsid can be recognized by the cytosolic receptor cyclophilin A [21••]. Upon recognition of capsid by cyclophilin A, dendritic cells mature, produce type-1 IFN and induce HIV-1-specific CD4+ and CD8+ T cells [21••]. Type-1 IFNs are well known for their antiviral properties and this results in an antiviral state that suppresses transmission to, or infection of T cells. However, in these experiments dendritic cells were coinfected with a simian immunodeficiency virus (SIV)-like particle expressing SIV vpx to overcome limited infection of dendritic cells by HIV-1. The latter is debated in literature, as other groups have reported infection of dendritic cells with HIV-1 [2,12••,19•]. Thus, further research is needed to address the differences between the efficiency of HIV-1 infection of dendritic cells in different laboratories, and to the effect of SIV coinfections on dendritic cells.

Back to Top | Article Outline

HIV-1 exhausts autophagy and thereby limits dendritic cell activation and induction of T cell responses

Dendritic cells can degrade cytosolic antigens by a specialized lysosomal degradation pathway called autophagy [22,23]. This pathway is mainly used for self-digestion. However, it has also been shown to be involved in the induction of immune responses against cytosolic pathogens [24,25] by targeting them to stimulate TLR [26]. Therefore, autophagy is a powerful tool for dendritic cells to induce anti-HIV-1 immune responses. Indeed, HIV-1 ends up in lysosomes after autophagocytosis [6•]. However, HIV-1 shuts autophagy down by activation of mTOR signaling [6•]. Down-regulation of autophagy by HIV-1 leads to increased HIV-1 levels in dendritic cells and increased transmission to T cells. Similarly, enhancing autophagy by silencing negative regulators or stimulation with rapamycin boosts HIV-1 degradation and HIV-1-antigen presentation to specific T cells. Besides protecting HIV-1 from autophagocytosis, this pathway probably prevents immune activation because HIV-1-induced downregulation of autophagy reduces the sensitivity of dendritic cells to TLR ligands. This shows that HIV-1 interferes with innate signaling pathways that are in place to promote antigen presentation and immune activation.

Back to Top | Article Outline

Tipping the balance of innate signaling

Type-I IFN production is associated with an antiviral state that suppresses viral replication and in-vitro, type-I IFN is able to reduce HIV-1 replication. Plasmacytoid dendritic cells have an innate capacity to produce large amounts of type-I IFN. Cell-free HIV-1 [27] and HIV-1-infected cells [28] induce IFN production by plasmacytoid dendritic cells, which can suppress HIV-1 replication. The induction of IFN was linked to innate signaling events of TLR-7 and -9 and subsequent IRF3 transcription [27]. However, excesses of IFN can induce chronic hyper activation of the immune system, which is one of the pathogenic effects in HIV [27]. This suggests that although innate immune responses are highly potent in suppressing HIV-1 replication, repetitive induction of these signaling pathways can do more harm than good.

Not only HIV-1 itself induces innate signals that influence HIV-1 infection, but also coinfections induce innate responses that can interfere with HIV-1 infection. Langerhans cells are a subset of dendritic cells that protect against HIV-1 infection by degrading virions and prevent further spreading of the virus [1,29]. However, also Langerhans cells can be infected by HIV-1 during inflammation [30–32]. The precise mechanisms still have to be deciphered, but it is evident that activation of Langerhans cells breaches their innate tolerance to HIV-1 infection and transmission. Moreover, also nonmucosal coinfection with Mycobacterium tuberculosis and Candida albicans has been shown to increase HIV-1 replication [33–35]. This suggests that HIV-1 benefits from immune activation, which might negatively influence disease progression. Therefore, the innate signals triggered by coinfections can make way for HIV-1 dissemination.

Back to Top | Article Outline

Conclusion

The innate immune system is highly potent in preventing spreading of pathogens, and innate signaling is key in this response. Several studies indicate that HIV-1 circumvents the same innate mechanisms by shutting them down. Strikingly, HIV-1 is able to use the receptors and/or their signaling pathways to enhance its infectivity. Therefore, detailed knowledge of these innate events that allows us to interfere where needed is essential in limiting HIV-1 replication. Most anti-HIV-1 drugs target viral proteins, but these new insights might provide targets that affect host processes to increase the immune response, whereas decreasing the susceptibility to HIV-1.

Back to Top | Article Outline

Acknowledgements

The authors are supported by the Netherlands Organisation for Scientific Research (NWO Vici 91810619, T.B.H.G.) and the AIDS Foundation (M.v.d.V: 2007036; A.M.G.v.d.A: 2009024).

Back to Top | Article Outline
Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

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).

Back to Top | Article Outline

References

1. de Witte L, Nabatov A, Pion M, et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 2007; 13:367–371.

2. Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000; 100:587–597.

3. Cameron PU, Freudenthal PS, Barker JM, et al. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells [3;3]. Science 1992; 257:383–387.

4. Granelli-Piperno A, Golebiowska A, Trumpfheller C, et al. HIV-1-infected monocyte-derived dendritic cells do not undergo maturation but can elicit IL-10 production and T cell regulation. Proc Natl Acad Sci U S A 2004; 101:7669–7674.

5. Kawamura T, Gatanaga H, Borris DL, et al. Decreased stimulation of CD4+ T cell proliferation and IL-2 production by highly enriched populations of HIV-infected dendritic cells. J Immunol 2003; 170:4260–4266.

6•. Blanchet FP, Moris A, Nikolic DS, et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 2010; 32:654–669.

This article shows that HIV-1 activates mTOR to limit autophagy in dendritic cells. This leads to decreased activation of dendritic cells.

7. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783–801.

8••. Pertel T, Hausmann S, Morger D, et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 2011; 472:361–365.

This article shows that TRIM5 is an PRR that recognizes HIV-1 capsid and activates NF-κB and AP1. Moreover, they show that TRIM5 is involved in TLR4 signaling.

9. Gringhuis SI, den Dunnen J, Litjens M, et al. C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB. Immunity 2007; 26:605–616.

10. Gringhuis SI, den Dunnen J, Litjens M, et al. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol 2009; 10:1081–1088.

11. de Jong EC, Smits HH, Kapsenberg ML. Dendritic cell-mediated T cell polarization. Springer Semin Immunopathol 2005; 26:289–307.

12••. Gringhuis SI, van der Vlist M, van den Berg LM, et al. HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol 2010; 11:419–426.

This article shows that HIV-1 abuses TLR-8 to initiate, and DC-SIGN to elongate transcription of the integrated HIV-1 genome.

13. 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.

14. 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.

15•. Nikolic DS, Lehmann M, Felts R, et al. HIV-1 activates Cdc42 and induces membrane extensions in immature dendritic cells to facilitate cell-to-cell virus propagation. Blood 2011 [Epub ahead of print].

This article shows that HIV-1 signals via DC-SIGN to form membrane extrusions that enhance transmission of HIV-1 to T cells.

16. Hodges A, Sharrocks K, Edelmann M, et al. Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat Immunol 2007; 8:569–577.

17. Bates EE, Fournier N, Garcia E, et al. APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based inhibitory motif. J Immunol 1999; 163:1973–1983.

18. Lambert AA, Gilbert C, Richard M, et al. The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways. Blood 2008; 112:1299–1307.

19•. Lambert AA, Barabe F, Gilbert C, Tremblay MJ. DCIR-mediated enhancement of HIV-1 infection requires the ITIM-associated signal transduction pathway. Blood 2011; 117:6589–6599.

This article shows that the ITIM domain of DCIR is involved in HIV-1-induced signaling that enhanced infection of dendritic cells.

20. Stremlau M, Perron M, Lee M, et al. Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor. Proc Natl Acad Sci U S A 2006; 103:5514–5519.

21••. Manel N, Hogstad B, Wang Y, et al. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 2010; 467:214–217.

This article shows that cyclophilin A is a cytosolic receptor that activates dendritic cells and stimulates induction of HIV-1 specific T cells.

22. Klionsky DJ. Autophagy. Curr Biol 2005; 15:R282–R283.

23. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature 2011; 469:323–335.

24. Gutierrez MG, Master SS, Singh SB, et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004; 119:753–766.

25. Orvedahl A, Alexander D, Talloczy Z, et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 2007; 1:23–35.

26. Lee HK, Lund JM, Ramanathan B, et al. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 2007; 315:1398–1401.

27. Mandl JN, Barry AP, Vanderford TH, et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 2008; 14:1077–1087.

28. Lepelley A, Louis S, Sourisseau M, et al. Innate sensing of HIV-infected cells. PLoS Pathog 2011; 7:e1001284.

29. de Jong MA, de Witte L, Santegoets SJ, et al. Mutz-3-derived Langerhans cells are a model to study HIV-1 transmission and potential inhibitors. J Leukoc Biol 2010; 87:637–643.

30. de Jong MA, de Witte L, Oudhoff MJ, et al. TNF-alpha and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo. J Clin Invest 2008; 118:3440–3452.

31. de Jong MA, de Witte L, Taylor ME, Geijtenbeek TB. Herpes simplex virus type 2 enhances HIV-1 susceptibility by affecting Langerhans cell function. J Immunol 2010; 185:1633–1641.

32. Ogawa Y, Kawamura T, Kimura T, et al. Gram-positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via Toll-like receptor activation. Blood 2009; 113:5157–5166.

33. Lawn SD. AIDS in Africa: the impact of coinfections on the pathogenesis of HIV-1 infection. J Infect 2004; 48:1–12.

34. Ranjbar S, Boshoff HI, Mulder A, et al. HIV-1 replication is differentially regulated by distinct clinical strains of Mycobacterium tuberculosis. PLoS One 2009; 4:e6116.

35. Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis 2003; 188:1146–1155.

Keywords:

DC-SIGN; dendritic cell; HIV-1; innate signaling

© 2011 Lippincott Williams & Wilkins, Inc.

Login

Article Tools

Images

Share

Article Level Metrics

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.