Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells

Rhodes, Jake W.; Botting, Rachel A.; Bertram, Kirstie M.; Vine, Erica E.; Rana, Hafsa; Baharlou, Heeva; Végh, Péter; O’Neil, Thomas R.; Ashhurst, Anneliese S.; Fletcher, James; Parnell, Grant P; Graham, J. Dinny; Nasr, Najla; Lim, Jake; Barnouti, Laith; Haertsch, Peter; Gosselink, M.; Re, Angelina Di; Reza, Faizur; Ctercteko, Grahame; Jenkins, Gregory J.; Brooks, Andrew J.; Patrick, Ellis; Byrne, Scott N.; Hunter, Eric; Haniffa, Muzlifah; Cunningham, Anthony L.; Harman, Andrew N.

doi:10.1038/s41467-021-22375-x

Cited by 32 publications

(53 citation statements)

References 68 publications

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“…It has been demonstrated that CHO cells engineered to express human nectin-1 are susceptible to infection via a pH-dependent route whereas CHO cells expressing human paired immunoglobulin-like type 2 receptor alpha (PILRα) are infected via a pH-independent route [ 56 ], possibly by associating with gB. As the receptor repertoire between LCs and cDC2s is vastly different [ 35 , 57 ], we hypothesise a receptor on cDC2s but not LCs may play the same role as PILRα does on CHO-PILRα cells. Additionally another recent study using CHO-HVEM cells has identified a nonconventional endocytic pathway of HSV-1 entry, independent of the involvement of Rab GTPases that are required in the canonical endosomal-lysosomal pathway [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

et al. 2021

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Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro, inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived MNPs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal MNPs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting.

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Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

et al. 2021

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“…This important early role of DCs and CD14+ myeloid cells in the capture the HIV and harboring of infectious virions and in the transmission of HIV to CD4+ T cells (29) might also play an important role in our system. Besides the role of DCs in capturing the virions in the upper epithelium, Rhodes et al showed that HIV-1 penetrated to the sub-epithelial layer where the myeloid cells, i.e., CD14+ CD1c+ monocyte derived DCs and cDC2s, became HIV-1 infected and transmitted the virus to CD4+ T cells (30). Integrated HIV DNA was found early in T cells but not myeloid cells indicating the initial replication occurred in the T cells not myeloid cells in the cervical mucosa (29).…”

Section: Discussionmentioning

confidence: 99%

“…HIV-BaL SUPT1-CCR5 CL. 30 (39) and aliquots were frozen down. All virus preparations were assayed for infectivity.…”

Section: Virus Production and Opsonizationmentioning

confidence: 99%

“…DC subsets are found both at the basal membrane as well as in the outer layers of the epithelium, and represent one of the first cell types to encounter HIV in the cervical mucosa ( 28 ). DCs and myeloid DCs in cervical mucosa play an important early role in the capture the HIV and harboring of infectious virions and in the transmission of HIV to CD4+ T cells ( 29 , 30 ). For instant, the epithelium also contains CD1a+ DCs that reportedly preserve HIV virions and support their replication ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

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Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study

et al. 2021

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Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.

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“…Langerin-expressing DC are found in human tissues and are distinct from LC [ 30 ]. These cells also present in mucosa are prone to HIV-1 and to transfer the virus to the CD4 + T cells populations [ 31 ]. Also, the cDC1 subset in mouse dermis express Langerin, and presents equivalent functions with dermic human dendritic cells subsets [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting human langerin promotes HIV-1 specific humoral immune responses

et al. 2021

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The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC and in vitro differentiated LC induce differentiation and expansion of naïve CD4+ T cells into T follicular helper (Tfh) cells. Second, when human LC are pre-treated with αLC.Env, differentiated Tfh cells significantly promote the production of specific IgG by B cells. Strikingly, HIV-Env-specific Ig are secreted by HIV-specific memory B cells. Consistently, we found that receptors and cytokines involved in Tfh differentiation and B cell functions are upregulated by LC during their maturation and after targeting Langerin. Finally, we show that subcutaneous immunization of mice by αLC.Env induces germinal center (GC) reaction in draining lymph nodes with higher numbers of Tfh cells, Env-specific B cells, as well as specific IgG serum levels compared to mice immunized with the non-targeting Env antigen. Altogether, we provide evidence that human LC properly targeted may be licensed to efficiently induce Tfh cell and B cell responses in GC.

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Human anogenital monocyte-derived dendritic cells and langerin+cDC2 are major HIV target cells

Cited by 32 publications

References 68 publications

Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

Herpes Simplex Virus type 1 infects Langerhans cells and the novel epidermal dendritic cell, Epi-cDC2s, via different entry pathways

Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study

Targeting human langerin promotes HIV-1 specific humoral immune responses

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