Researchers from the Westmead Institute for Medical Research, the University of Sydney have made significant strides in understanding how newly identified immune cells participate in sexual transmission of HIV. The study, led by Dr. Najla Nasr, focuses on a specialized type of dendritic cells known as AXL+ SIGLEC6+ dendritic cells (ASDCs). Of key importance, Dr Nasr’s team demonstrated for the first time that these cells are found within inflamed human genital tissues which are the actual sites of HIV entry into the human body and that they play a crucial role in the first stages of HIV transmission. Given that HIV transmission is now known to be highly associated with inflammation, this represents a key missing piece of the puzzle regarding our understanding of how this virus is transmitted.
This groundbreaking work, published in the peer-reviewed journal PLOS Pathogens, sheds light on the intricate interactions between these immune cells and HIV, potentially opening new avenues for HIV prevention and vaccine delivery.
The research team, including Dr Orion Tong, Dr Thomas O’Neil, Dr Kirstie Bertram, Professor Andrew Harman, and Professor Anthony Cunningham discovered that ASDCs are present in a range of inflamed human tissues such as the skin, anogenital regions, and lymph nodes, all of which are associated with HIV transmission. Unlike other dendritic cells, ASDCs were found to express unique markers that allow them to migrate from blood into inflamed tissues. Once there, these cells interact with HIV using unique pathogen binding receptors. Critically ASDCs then go on to interact with another immune cells called CD4 T cells and transmit the virus to them. CD4 T cells are needed to combat HIV but sarcastically it is these cells that are the primary targets of HIV and are destroyed by the virus, and their depletion below critical levels leads to the onset of AIDS.
Interestingly, the study also revealed two specific subsets of ASDCs, identified by the markers CD11c and CD123 which behave differently when exposed to HIV. CD11c+ ASDCs were observed to transfer more HIV during the initial early phase of exposure, whereas CD123+ ASDCs transmitted the virus more efficiently at later stages and via an entirely separate mechanism.
Dr. Nasr emphasized the significance of these findings in a statement, saying, “Our research highlights the role of ASDCs in the early stages of HIV transmission in the inflamed tissues where transmission occurs. Inflammation is a prerequisite for HIV transmission, but key inflammatory HIV target cells have not yet been identified. Moreover, pre-exposure prophylaxis (PrEP) is ineffective in an inflammatory context so understanding how inflammatory ASDCs contribute to HIV’s spread opens new possibilities for developing targeted interventions that could prevent the virus from taking hold in the body.”
Another key revelation of this study is the functional differences between plasmacytoid DCs and ASDCs, said Freja Warner Van Dijk, the first author and a PhD student in Dr Nasr’s Laboratory. In HIV infection, pDCs were the main producers of interferons that fight infections, proinflammatory cytokines and chemokines (CCL3-5) that attract CD4 T cells to the inflamed tissues to mount an immune response while the two ASDC subsets, specifically the CD11c+ ASDCs, activated, polarised and induced the proliferation of CD4 T cells.
The study also explored the presence of ASDCs in different inflammatory disease settings and identified them in diverticulitis, colitis, psoriasis, and colon cancer. “As knowledge progresses into their role in the pathogenesis of other viruses and diseases, specific interventions may be become apparent”, said Dr Nasr.
In summary, the study conducted by Dr. Nasr and colleagues showed that ASDCs are a new HIV transmitting cell present in inflamed anogenital tissues. This research opens potential new strategies for preventing the spread of HIV, particularly in high-risk populations, and may have important implications in improved PrEP design. For example, current PrEP drugs that block the HIV replication cycle (e.g. Tenofovir) will likely be effective at blocking the ability of CD123+ ASDCs from becoming infected and transmitting HIV to T cells. However, drugs that block HIV interactions with its binding receptors will likely be required to block the initial early HIV transfer from CD11c+ ASDCs.
“Future research should focus on developing therapies that target ASDCs’ migration and their ability to transfer HIV,” said Dr. Nasr. “This could be a crucial step toward reducing the incidence of new HIV infections worldwide.”
Journal Reference
Warner van Dijk, Freja A., et al. “Characterising plasmacytoid and myeloid AXL+ SIGLEC-6+ dendritic cell functions and their interactions with HIV.” PLOS Pathogens (2024). DOI: https://doi.org/10.1371/journal.ppat.1012351
About the Authors
Najla Nasr completed her PhD at the University of Sydney focusing on HIV pathogenesis. She is currently a Senior Lecturer in the School of Medical Sciences at the University of Sydney and a Group Leader at the Westmead Institute for Medical Research. Her research focuses on HIV prevention and cure strategies. Her seminal highly cited work has focussed on how HIV manipulates innate immunity to evade detection and facilitate transmission by inhibiting the Type I interferon system- the body’s early warning system against invading viral pathogens.
Dr Nasr is funded by both the Australian National Health and Medical Research Council (Ideas Grant as CIA) and philanthropic funds from the Neil and Norma Hill Foundation. Her group currently has two lines of research. Firstly, they are investigating the use of CAR-T cell immunotherapy and the interferon system to find ways to eradicate dormant HIV from latently infected CD4 T cells. Secondly, they are investigating the dynamics of HIV transmission using inflamed human anogenital tissues where transmission occurs, and the clinically relevant HIV transmission strains derived from sub-Sharan Africa where the HIV pandemic continue to rage. This work aims to define the key myeloid and lymphoid HIV target cells to block HIV transmission via a vaccine, and in the meantime via more effective blocking strategies.
Freja Warner van Dijk is a PhD candidate at the University of Sydney working at the Westmead Institute for Medical Research as part of the Centre for Virus Research. Her PhD project is focused on elucidating the inflammatory mononuclear phagocytes that reside in human anogenital tissues and characterising their interactions with HIV utilising high parameter flow cytometry and single cell RNA sequencing technologies. Freja recently received the opportunity to present this publication at the International Congress of Mucosal Immunology (ICMI) 2024 in Copenhagen, Denmark and was awarded a travel award in support of her attendance. Freja is under the supervision of Dr Najla Nasr, Prof. Andrew Harman and Dr Kirstie Bertram.
