Dendritic-cell interactions with HIV: infection and viral dissemination

Abstract

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.

Figure 1

The role of dendritic cells in HIV infection and viral dissemination. At mucosal surfaces during the sexual transmission of HIV, dendritic cells (DCs) are proposed to be among the first targets to encounter the virus. These DCs include non-migratory Langerhans cells in epithelial and mucosal tissues, as well as immature myeloid DCs in the submucosa. C-type lectins and/or other viral attachment factors expressed by immature DCs capture HIV and migrate to CD4⁺ T-cell-enriched lymphoid tissues, where HIV trans-infection of active CD4⁺ T cells occurs and facilitates viral dissemination. HIV-bearing immature DCs can differentiate into mature DCs by viral infection or by cytokines in the microenvironment during the migration. Mature DCs present HIV antigens to T cells in the lymphoid tissues and initiate viral immune responses. DC-associated HIV may be protected intracellularly from degradation during the migration or retention in the lymphoid tissues. Some DC subsets are susceptible to HIV infection, and subsequently infect neighbouring CD4⁺ T cells. Follicular DCs (FDCs) in germinal centres can trap large amounts of HIV on their cell surfaces, which provide a stable virus hideaway and also facilitate viral dissemination.

Figure 2

Dendritic-cell maturation affects HIV transmission. Monocyte-derived immature dendritic cells (DCs) develop into T helper 1 (T_H1)-cell-promoting or T_H2-cell-promoting effector subsets, depending on the activation signal they receive. CD14⁺ monocytes are cultured in the presence of interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to develop into immature DCs, which can be further cultured with diverse stimuli to obtain different mature DC subtypes. Polarization of T_H-cell function by mature DC subsets is depicted. Compared with immature DCs, HIV transmission to CD4⁺ T cells significantly varies in different mature DC subsets. CD40L: CD40 ligand; IFNγ: interferon-γ; poly I-C, polyinosinic–polycytidylic acid; MF: maturation factors such as interleukin-1β (IL-1β) and tumour-necrosis factor (TNF); LPS: lipopolysaccharide; PGE₂: prostaglandin E₂; T_H0: naïve T helper cells.

Figure 3

Mechanisms of dendritic-cell-mediated HIV transmission. Two types of dendritic cell (DC)-mediated HIV transmission have been proposed, namely, trans- and cis-infection of DCs. Trans-infection of DCs includes two pathways: (a). HIV transmission across the infectious synapse. DCs transfer captured HIV to target CD4⁺ T cells through the cell-cell junctions known as infectious synapses. DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) participates in formation of the infectious synapse. (b). Exocytotic pathway of HIV-bearing exosomes. Endocytosed HIV can gain access to endosomal multivesicular bodies (MVBs), enabling release as exosome-associated viruses. Exosome-associated HIV particles are likely to be transmitted to CD4⁺ T cells through membrane binding and fusion. Cis-infection: (c). After the initial viral exposure, HIV infection and replication in DCs results in de novo viral production and long-term transmission. It is conceivable that these three mechanisms coexist in vitro, however, the relative importance of these pathways in vivo remains to be investigated. CCR5, CC chemokine receptor 5; CXCR4, CXC chemokine receptor 4.