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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jake W. Rhodes ◽  
Rachel A. Botting ◽  
Kirstie M. Bertram ◽  
Erica E. Vine ◽  
Hafsa Rana ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Pathogen Detection ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Mononuclear Phagocytes ◽  
Target Cells ◽  
Epithelial Surface ◽  
Transmission Studies

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

scholarly journals Identification of HIV-Transmitting Sub-Epithelial Mononuclear Phagocytes in Human Anogenital and Colorectal Tissues

2020 ◽  
Author(s):  
Jake W Rhodes ◽  
Rachel A Botting ◽  
Kirstie M Bertram ◽  
Hafsa Rana ◽  
Heeva Baharlou ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Target Cell ◽  
Cd4 T Cells ◽  
Pathogen Detection ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Mononuclear Phagocytes ◽  
Microbicide Development

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. They are the first cells of the immune system to encounter HIV and play a key role in transmission as they deliver the virus to CD4 T cells, which are the primary HIV target cell in which the virus undergoes replication. Most studies have investigated the role that epithelial MNPs play in HIV transmission but, as mucosal trauma and inflammation are strongly associated with HIV transmission, it is also important to examine the role that sub-epithelial MNPs play. Sub-epithelial MNPs are present in a diverse array of subsets which differ in their function and the pathogens they detect. Understanding how specific subsets interact with HIV and deliver the virus to CD4 T cells is therefore of key importance to vaccine and microbicide development. In this study we have shown that, after topical application, HIV can penetrate to interact with sub-epithelial resident myeloid cells in anogenital explants and defined the full array of MNP subsets that are present in all the human anogenital and colorectal sub-epithelial tissues that HIV may encounter during sexual transmission. In doing so we have identified two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+CD11c+ monocyte-derived dendritic cells and langerin-expressing dendritic cells 2 (DC2).

scholarly journals Hyaluronic acid is a negative regulator of mucosal fibroblast-mediated enhancement of HIV infection

2021 ◽  
Author(s):  
Johanne H. Egedal ◽  
Guorui Xie ◽  
Thomas A. Packard ◽  
Anders Laustsen ◽  
Jason Neidleman ◽  
...  
Keyword(s):  
T Cells ◽  
Hyaluronic Acid ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Hiv Transmission ◽  
Cell Metabolism ◽  
Sexual Transmission ◽  
Rectal Mucosa ◽  
Hiv Infections ◽  
Negative Regulator

AbstractThe majority of HIV infections are established through the genital or rectal mucosa. Fibroblasts are abundant in these tissues, and although not susceptible to infection, can potently enhance HIV infection of CD4+ T cells. Hyaluronic acid (HA) is a major component of the extracellular matrix of fibroblasts, and its levels are influenced by the inflammatory state of the tissue. Since inflammation is known to facilitate HIV sexual transmission, we investigated the role of HA in genital mucosal fibroblast-mediated enhancement of HIV infection. Depletion of HA by CRISPR-Cas9 in primary foreskin fibroblasts augmented the ability of the fibroblasts to increase HIV infection of CD4+ T cells. This amplified enhancement required direct contact between the fibroblasts and CD4+ T cells, and could be attributed to both increased rates of trans-infection and the increased ability of HA-deficient fibroblasts to push CD4+ T cells into a state of higher permissivity to infection. This HIV-permissive state was characterized by differential expression of genes associated with regulation of cell metabolism and death. Our results suggest that conditions resulting in diminished cell-surface HA on fibroblasts, such as genital inflammation, can promote HIV transmission by conditioning CD4+ T cells toward a state more vulnerable to infection by HIV.

scholarly journals Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype

2021 ◽  
Vol 17 (4) ◽  
pp. e1009522
Author(s):  
Orion Tong ◽  
Gabriel Duette ◽  
Thomas Ray O’Neil ◽  
Caroline M. Royle ◽  
Hafsa Rana ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Target Cells ◽  
Ccr5 Expression ◽  
Memory Cd4 T Cells

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, PDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

scholarly journals Antimicrobial Peptides from Amphibian Skin Potently Inhibit Human Immunodeficiency Virus Infection and Transfer of Virus from Dendritic Cells to T Cells

2005 ◽  
Vol 79 (18) ◽  
pp. 11598-11606 ◽  
Author(s):  
Scott E. VanCompernolle ◽  
R. Jeffery Taylor ◽  
Kyra Oswald-Richter ◽  
Jiyang Jiang ◽  
Bryan E. Youree ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Antimicrobial Peptides ◽  
Hiv Infection ◽  
Hiv Transmission ◽  
Great Promise ◽  
Target Cells ◽  
Amphibian Skin ◽  
Immunodeficiency Virus

ABSTRACT Topical antimicrobicides hold great promise in reducing human immunodeficiency virus (HIV) transmission. Amphibian skin provides a rich source of broad-spectrum antimicrobial peptides including some that have antiviral activity. We tested 14 peptides derived from diverse amphibian species for the capacity to inhibit HIV infection. Three peptides (caerin 1.1, caerin 1.9, and maculatin 1.1) completely inhibited HIV infection of T cells within minutes of exposure to virus at concentrations that were not toxic to target cells. These peptides also suppressed infection by murine leukemia virus but not by reovirus, a structurally unrelated nonenveloped virus. Preincubation with peptides prevented viral fusion to target cells and disrupted the HIV envelope. Remarkably, these amphibian peptides also were highly effective in inhibiting the transfer of HIV by dendritic cells (DCs) to T cells, even when DCs were transiently exposed to peptides 8 h after virus capture. These data suggest that amphibian-derived peptides can access DC-sequestered HIV and destroy the virus before it can be transferred to T cells. Thus, amphibian-derived antimicrobial peptides show promise as topical inhibitors of mucosal HIV transmission and provide novel tools to understand the complex biology of HIV capture by DCs.

scholarly journals Syndecan-Fc Hybrid Molecule as a Potent In Vitro Microbicidal Anti-HIV-1 Agent

2010 ◽  
Vol 54 (7) ◽  
pp. 2753-2766 ◽  
Author(s):  
Michael D. Bobardt ◽  
Udayan Chatterji ◽  
Lana Schaffer ◽  
Lot de Witte ◽  
Philippe A. Gallay
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Sexual Transmission ◽  
Antiviral Agent ◽  
Target Cells ◽  
Hybrid Molecule ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT In the absence of a vaccine, there is an urgent need for the development of safe and effective topical microbicides to prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In this study, we proposed to develop a novel class of microbicides using syndecan as the antiviral agent. Specifically, we generated a soluble syndecan-Fc hybrid molecule by fusing the ectodomain of syndecan-1 to the Fc domain of a human IgG. We then tested the syndecan-Fc hybrid molecule for various in vitro microbicidal anti-HIV-1 properties. Remarkably, the syndecan-Fc hybrid molecule possesses multiple attractive microbicidal properties: (i) it blocks HIV-1 infection of primary targets including T cells, macrophages, and dendritic cells (DC); (ii) it exhibits a broad range of antiviral activity against primary HIV-1 isolates, multidrug resistant HIV-1 isolates, HIV-2, and simian immunodeficiency virus (SIV); (iii) it prevents transmigration of HIV-1 through human primary genital epithelial cells; (iv) it prevents HIV-1 transfer from dendritic cells to CD4+ T cells; (v) it is potent when added 2 h prior to addition of HIV-1 to target cells; (vi) it is potent at a low pH; (vii) it blocks HIV-1 infectivity when diluted in genital fluids; and (viii) it prevents herpes simplex virus infection. The heparan sulfate chains of the syndecan-Fc hybrid molecule are absolutely required for HIV-1 neutralization. Several lines of evidence suggest that the highly conserved Arg298 in the V3 region of gp120 serves as the locus for the syndecan-Fc hybrid molecule neutralization. In conclusion, this study suggests that the syndecan-Fc hybrid molecule represents the prototype of a new generation of microbicidal agents that may have promise for HIV-1 prevention.

HIV transmission from infected CD4+ T cells to allogenic T and dendritic cells is inhibited by broadly neutralizing antibodies

AIDS ◽  
2018 ◽  
Vol 32 (10) ◽  
pp. 1239-1245
Author(s):  
Camille Ducloy ◽  
Bin Su ◽  
Luzia Mayr ◽  
Jéromine Klingler ◽  
Thomas Decoville ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Neutralizing Antibodies ◽  
Hiv Transmission ◽  
Broadly Neutralizing Antibodies

scholarly journals Activated CD34-Derived Langerhans Cells Mediate Transinfection with Human Immunodeficiency Virus

2007 ◽  
Vol 81 (13) ◽  
pp. 6858-6868 ◽  
Author(s):  
Kelly M. Fahrbach ◽  
Sheila M. Barry ◽  
Seyoum Ayehunie ◽  
Sarah Lamore ◽  
Mitchell Klausner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Langerhans Cells ◽  
Potential Role ◽  
Hiv Transmission ◽  
Sexual Transmission ◽  
Target Cells ◽  
Mucosal Tissue ◽  
Sexually Transmitted ◽  
Immunodeficiency Virus

ABSTRACT Langerhans cells (LCs) are a subset of dendritic cells (DCs) that reside within epidermal and mucosal tissue. Because of their location, LCs are potentially the first cells to encounter human immunodeficiency virus (HIV) during sexual transmission. We report that LCs purified from CD34+-derived DCs can facilitate the transinfection of target cells but only after activation. Virions were observed in an intracellular compartment that contains several tetraspanins, in addition to the unique LC markers langerin and CD1a. This reveals that the trafficking of HIV within LCs is reminiscent of that which occurs in mature monocyte-derived DCs and that it varies with the activation state of the cell. The observation that activated LCs can mediate transinfection suggests a potential role for these cells in the known increase in HIV transmission associated with sexually transmitted infections that would cause inflammation of the genital lining.

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