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

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

doi:10.1038/s41467-021-22375-x

Abstract

Tissue 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).

Highlights

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation
In abdominal skin we found that dermal conventional dendritic cells 2 (cDC2) were the overwhelmingly predominant cell population in contrast anogenital and colorectal tissues where these cells were present in much smaller proportions
In this study we have investigated the role that sub-epithelial MNPs play in HIV transmission

Summary

Introduction

Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. The effects of long-term administration of PrEP to healthy individuals are unknown and can be associated with decreased condom use[1], increased sexually transmitted infections and concomitant genital tract inflammation[2], enhancing HIV transmission[3,4,5,6], especially in sub-Saharan Africa. In order to develop a vaccine (or more effective PrEP regimens) the precise definition of the initial HIV target cells in the anogenital mucosa is necessary, especially mononuclear phagocytes (MNP). These consist of Langerhans cells (LC), dendritic cells (DC) and macrophages which express the HIV entry receptors CD4 and CCR5 allowing them to be directly infected. The second phase occurs from 72 h onwards and increases with time as newly formed virions bud off from the surface of cells that have become productively infected via CD4/CCR5 mediated entry into viral synapses[17]

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Conclusion