HIV-1 Selection by Epidermal Dendritic Cells during Transmission across Human Skin

Reece, Jeanette C.; Handley, Amanda; Anstee, E. John; Morrison, Wayne A.; Crowe, Suzanne; Cameron, Paul

doi:10.1084/jem.187.10.1623

Cited by 152 publications

(140 citation statements)

References 50 publications

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“…Several studies have demonstrated that LC infection with R5-tropic HIV-1 is essential to its role in transmission [34][35][36][37]. However, recently it was shown that mature CD34 1 -derived LC-like cells can transmit HIV-1 without infection [38].…”

Section: Subsets In Hiv-1 Transmissionmentioning

confidence: 99%

Langerhans cells and viral immunity

2008

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Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

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Section: Subsets In Hiv-1 Transmissionmentioning

confidence: 99%

Langerhans cells and viral immunity

2008

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“…DC-SIGN interacts with the envelope glycoprotein gp120 of HIV-1, HIV-2, and SIV (3)(4)(5)(6)(7)(8), as well as other pathogens such as hepatitis C (9, 10), Ebola (11), cytomegalovirus (12), Dengue virus (13), Mycobacterium (14)(15)(16), Leishmania (17,18), Candida albicans (19), and Helicobacter pylori (20,21). DC-SIGN has been implicated as playing an important role in HIV-1 transmission and the establishment of infection (4,6,(22)(23)(24)(25). The interaction of HIV-1 with DC-SIGN can lead to infection of the DCs, or alternatively the virus can be internalized into a trypsin-resistant compartment prior to undergoing transfer to its main target cells, and this mechanism has been shown to greatly enhance infection of T cells in vitro (26,27).…”

Section: Introductionmentioning

confidence: 99%

Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4+ T lymphocytes

Naarding

Ludwig²,

Groot³

et al. 2005

Journal of Clinical Investigation

169

135

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DC-specific ICAM3-grabbing non-integrin (DC-SIGN), which is expressed on DCs, can interact with a variety of pathogens such as HIV-1, hepatitis C, Ebola, cytomegalovirus, Dengue virus, Mycobacterium, Leishmania, and Candida albicans. We demonstrate that human milk can inhibit the DC-SIGN-mediated transfer of HIV-1 to CD4 + T lymphocytes as well as viral transfer by both immature and mature DCs. The inhibitory factor directly interacted with DC-SIGN and prevented the HIV-1 gp120 envelope protein from binding to the receptor. The human milk proteins lactoferrin, α-lactalbumin, lysozyme, β-casein, and secretory leukocyte protease inhibitor did not bind DC-SIGN or demonstrate inhibition of viral transfer. The inhibitory effect could be fully alleviated with an Ab recognizing the Lewis X (Le X ) sugar epitope, commonly found in human milk. Le X in polymeric form or conjugated to protein could mimic the inhibitory activity, whereas free Le X sugar epitopes could not. We reveal that a Le X motif present in human milk can bind to DC-SIGN and thereby prevent the capture and subsequent transfer of HIV-1 to CD4 + T lymphocytes. The presence of such a DC-SIGN-binding molecule in human milk may both influence antigenic presentation and interfere with pathogen transfer in breastfed infants.

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“…Although they do not express DC-SIGN, LCs express CD4 and HIV chemokine coreceptors, and these molecules have been shown to mediate infection of LCs (11)(12)(13)(14). Immature LCs express surface CCR5, but not surface CXCR4, immediately after isolation from skin; CCR5 on LCs also mediates fusion with cells expressing the HIV envelope protein gp120 (11).…”

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confidence: 99%

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

Kawamura

Gulden

Sugaya

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

177

165

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Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4 ؉ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4 ؉ T cells were mediated by CCR5-dependent as well as DCspecific ICAM-3-grabbing nonintegrin-dependent pathways. Furthermore, in 62 healthy individuals, R5 HIV infection levels in LCs ex vivo were associated with CCR5 genotype. Specifically, genotyping for ORF⌬32 revealed that LCs isolated from ORF⌬32͞wt individuals were significantly less susceptible to HIV when compared with LCs isolated from ORFwt͞wt individuals (P ‫؍‬ 0.016). Strikingly, further genetic analyses of the A-2459G CCR5 promoter polymorphism in ORF⌬32͞wt heterozygous individuals revealed that LCs isolated from ؊2459A͞G ϩ ORF⌬32͞wt individuals were markedly less susceptible to HIV than were LCs from ؊2459A͞A ϩ ORF⌬32͞wt individuals (P ‫؍‬ 0.012). Interestingly, these genetic susceptibility data in LCs parallel those of genetic susceptibility studies performed in cohorts of HIV-infected individuals. Thus, we suggest that CCR5-mediated infection of LCs, and not capture of virus by LCs, provides a biologic basis for understanding certain aspects of host genetic susceptibility to initial HIV infection.

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HIV-1 Selection by Epidermal Dendritic Cells during Transmission across Human Skin

Cited by 152 publications

References 50 publications

Langerhans cells and viral immunity

Langerhans cells and viral immunity

Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4+ T lymphocytes

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compoundCCR5polymorphisms

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