Researchers at the University of Sydney's Westmead Institute for Medical Research have made significant progress in understanding how newly identified immune cells are involved in the sexual transmission of HIV. The study, led by Dr Najla Nasr, focuses on a specialized type of dendritic cell known as AXL.+ SIGLEC6+ Autoimmune dendritic cells (ASDC). Dr. Nasr’s team demonstrated for the first time that these cells are found in inflamed human genital tissues, which are the actual sites of entry of HIV into the human body, and that they play a crucial role in the early stages of HIV transmission. Since 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 up 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 variety of inflamed human tissues, including 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 the blood into inflamed tissues. Once there, these cells interact with HIV using unique pathogen-binding receptors. ASDCs then interact with other immune cells called CD4 T cells and transmit the virus to them. CD4 T cells are needed to fight HIV, but, sarcastically, it is these cells that are the main 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 ASDC, identified by the markers CD11c and CD123, that behave differently when exposed to HIV. CD11c+ ASDCs were found to transfer more HIV during the early initial phase of exposure, whereas CD123+ ASDCs transmitted the virus more efficiently at later stages and through a completely separate mechanism.
Dr. Nasr highlighted the importance of these findings in a statement, saying, “Our research highlights the role of antiviral dendritic cells in the early stages of HIV transmission in inflamed tissues where transmission occurs. Inflammation is a prerequisite for HIV transmission, but key HIV inflammatory target cells have not yet been identified. Furthermore, pre-exposure prophylaxis (PrEP) is ineffective in an inflammatory setting, so understanding how inflammatory antiviral dendritic cells contribute to HIV spread opens up new possibilities for developing targeted interventions that could prevent the virus from taking hold in the body.”
Another key revelation from 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 lab. In HIV infection, pDCs were the main producers of infection-fighting interferons, pro-inflammatory cytokines and chemokines (CCL3-5) that attract CD4 T cells to inflamed tissues to mount an immune response, while the two ASDC subsets, specifically CD11c+ ASDC activated, polarized and induced proliferation of CD4 T cells.
The study also explored the presence of activated T cells in different contexts of inflammatory diseases and identified them in cases of diverticulitis, colitis, psoriasis and colon cancer. “As knowledge about their role in the pathogenesis of other viruses and diseases advances, targeted interventions may emerge,” said Dr. Nasr.
In summary, the study by Dr. Nasr and colleagues demonstrated that autoimmune dendritic cells (ASDCs) are a novel HIV-transmitting cell present in inflamed anogenital tissues. This research opens the door to potential new strategies to prevent the spread of HIV, particularly in high-risk populations, and may have important implications for 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 to transmit HIV to the target organ.+ ASDCs become infected and transmit HIV to T cells. However, drugs that block HIV interactions with their binding receptors will likely be required to block the early initial transfer of HIV from CD11c.+ ASDC.
“Future research should focus on developing therapies targeting ASDC migration and its ability to transmit 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. “Characterization of the functions of AXL+ SIGLEC-6+ plasmacytoid and myeloid dendritic cells and their interactions with HIV.” PLOS Pathogens (2024). DOI: https://doi.org/10.1371/journal.ppat.1012351
About the authors
Najla Nasr She completed her PhD at the University of Sydney, focusing on HIV pathogenesis. She is currently a Senior Lecturer in the Faculty 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 focused 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 National Health and Medical Research Council of Australia (Ideas Grant as CIA) and philanthropic funding 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 latent 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 clinically relevant HIV transmission strains derived from sub-Saharan Africa where the HIV pandemic continues to rage. This work aims to define key HIV myeloid and lymphoid target cells to block HIV transmission through a vaccine and in the meantime through more effective blocking strategies.
Freja Warner van Dijk Freja 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 focuses on elucidating inflammatory mononuclear phagocytes residing in human anogenital tissues and characterising their interactions with HIV using high-parameter flow cytometry and single cell RNA sequencing technologies. Freja was recently given the opportunity to present this publication at the International Congress of Mucosal Immunology (ICMI) 2024 in Copenhagen, Denmark and was awarded a travel grant to support her attendance. Freja is under the supervision of Dr Najla Nasr, Prof Andrew Harman and Dr Kirstie Bertram.
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