Dendritic cells (DCs) are located in the mucosae and the lymphoid tissues. They are proposed to be among the first cells to encounter HIV during sexual transmission.
The main populations of DCs include myeloid DCs and plasmacytoid DCs in the blood, and Langerhans cells in the tissues. Myeloid DCs, plasmacytoid DCs and Langerhans cells are all susceptible to infection with HIV; they can also transfer HIV to CD4+ T cells.
Follicular DCs can trap and maintain large quantities of HIV, thereby functioning as a persistent reservoir of virus.
Immunomodulation of DCs by HIV infection is a key aspect of viral pathogenesis, particularly through the modulation or interference of the antigen-presenting function of DCs.
DCs express high levels of C-type lectins, including DC-specific intercellular adhesion molecule 3 (ICAM3)-grabbing non-integrin (DC-SIGN; also known as CD209). C-type lectins are the main HIV attachment factors at the surface of dermal and mucosal DCs.
DCs have DC-SIGN-dependent and DC-SIGN-independent mechanisms of HIV trans-infection of CD4+ T cells. The efficiency of HIV transmission can be increased by maturation of DCs.
The transfer of virus from DCs to CD4+ T cells occurs in three discrete steps. First, DCs capture and bind HIV. Second, HIV traffics within these DCs. And third, HIV is transferred to CD4+ T cells by a process that is known as trans-infection.
DC-mediated HIV trans-infection might occur by several distinct processes that can take place concurrently, including rapid HIV trans-infection through infectious synapses and exosome-associated viruses. HIV transmission can also be mediated by de novo viral production in DCs, known as cis-infection.
Elucidating the interactions of HIV with DCs will be vital to uncover the contribution of DCs to viral pathogenesis.
Dendritic cells (DCs) are crucial for the generation and the regulation of adaptive immunity. Because DCs have a pivotal role in marshalling immune responses, HIV has evolved ways to exploit DCs, thereby facilitating viral dissemination and allowing evasion of antiviral immunity. Defining the mechanisms that underlie cell–cell transmission of HIV and understanding the role of DCs in this process should help us in the fight against HIV infection. This Review highlights the latest advances in our understanding of the interactions between DCs and HIV, focusing on the mechanisms of DC-mediated viral dissemination.
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We thank J. Barbieri for critical reading of the manuscript. L.W. is supported by grants from the National Institutes of Health (United States) and the Research Affairs Committee of the Medical College of Wisconsin (United States). V.N.K. is supported by intramural research funds from the National Institutes of Health. The authors apologize to all those whose work has not been cited as a result of space limitations.
The authors declare no competing financial interests.
- Infectious synapse
Also known as the virological synapse. The cell–cell contact zone between dendritic cells and CD4+ T cells that facilitates transmission of HIV by locally concentrating virus and viral receptors.
Monocyte-derived dendritic cells and certain types of cell that have been transfected with vectors that encode DC-SIGN (DC-specific intercellular adhesion molecule 3 (ICAM3)-grabbing non-integrin) can capture and transfer HIV to target cells without themselves becoming infected.
Small lipid-bilayer vesicles that are released from dendritic cells and other cells. They are composed of plasma membranes or are derived from the membranes of intracellular vesicles. They might contain antigen–MHC complexes and interact with antigen-specific lymphocytes directly, or they might be taken up by antigen-presenting cells.
- C-type lectins
A family of transmembrane proteins (with calcium-dependent activities) that function as cell-adhesion molecules. C-type lectins are involved in the regulation of signalling pathways and recognize specific carbohydrate structures of pathogens and self antigens.
- R5 HIV
An HIV strain that uses CC-chemokine receptor 5 (CCR5) as the co-receptor to gain entry to target cells.
- X4 HIV
An HIV strain that uses CXC-chemokine receptor 4 (CXCR4) as the co-receptor to gain entry to target cells.
- Simian immunodeficiency virus
(SIV). Collectively, different HIV-related lentiviruses isolated from non-human primates. SIV infection of rhesus macaques is an experimental model for HIV infection of humans.
HIV infection of permissive cells through viral-receptor-mediated entry, resulting in the production of progeny viruses. HIV transmission to target cells can be mediated after infection of dendritic cells.
An actin-dependent process by which cells engulf large volumes of fluid.
- Immunological synapse
A junctional structure that is formed between an antigen-presenting cell and a T cell. Important molecules involved in T-cell activation — including the T-cell receptor, signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Mobilization of the actin cytoskeleton is required for formation of the immunological synapse.
- Multivesicular body
An endocytic organelle that contains small vesicles generated from budding of an endosomal membrane into the lumen of the compartment.
A family of transmembrane proteins that have transmembrane and extracellular domains of different sizes. The function of tetraspanins has not been properly established, but they seem to interact with many other transmembrane proteins and seem to form large multimeric protein networks, which might be involved in intracellular signalling.
- Single-cycle reporter HIV
An infectious HIV vector that can establish an integrated provirus but cannot undergo additional cycles of replication, owing to an inactivated viral envelope gene. The viral genome encodes a reporter gene (such as firefly luciferase or green fluorescent protein), and this gene is expressed on integration of viral DNA in permissive target cells, enabling measurement of infectivity.
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Wu, L., KewalRamani, V. Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol 6, 859–868 (2006). https://doi.org/10.1038/nri1960
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