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Abstract
Human immunodeficiency virus type 1 (HIV-1)-infected cells respond to the infection with different outcomes depending on their cell type. The interplay of cellular and viral proteins is a key player of differences in virus replication and disease progression. Myeloid cells, including monocytes, macrophages, and myeloid dendritic cells (mDCs) play a crucial role in the transmission and pathogenesis of HIV. The viral protein Tat, which is the viral transcriptional activator, modulates the expression of both HIV and cellular genes in these myeloid cells. This review will focus on recent advances on the interplay between HIV and myeloid cells and will discuss how this interaction may contribute to HIV pathogenesis. A better understanding of the pathogenesis of HIV disease will provide us with the scientific rationale for novel approaches to prevention.
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Figure 1.
Overview of myeloid cell functions. Monocytes, macrophages, and myeloid dendritic cells (mDCs) express multiple receptors to recognize microbes, including toll-like receptors (TLRs), and c-type lectin receptors such as DC-SIGN (1). Chemokine receptors such as CCR2 and CX3CR1 direct the migration of blood monocytes to sites of inflammation (2), where they contribute to the pro-inflammatory cytokine milieu through the production of TNF-α, IL-6, IL-8, and IL-1β (3). Once present in tissues, monocytes are influenced by local signals to differentiate into either macrophages or mDCs. In vitro, M-CSF directs monocyte differentiation into macrophages while GM-CSF + IL-4 results in differentiation into mDCs(4). Tissue resident macrophages are also capable of producing pro-inflammatory cytokines as well as ample amounts of IL-10, an anti-inflammatory cytokine important for resolving local inflammation (3). Both monocytes and macrophages are capable of phagocytosis and intracellular killing of microbes through the production of reactive oxygen species (ROS) and reactive nitrogen species (5). Activated macrophages and mDCs secrete IL-12, a cytokine involved in the activation and differentiation of T cells (6). Activated mDCs also stimulate NK cell activation via the production of IL-15 and IL-18 (7). Adapted from “The myeloid cytokine network in AIDS pathogenesis”, by Mr et al., 2012, Cytokine Growth Factor Rev, 23, 224 as a reference 6 in the text.
Figure 2.
Host restriction factors and their action during HIV-1 replication. Schematic representation of (A) HIV-1-infected producer cell, and (B) HIV-1 target cell. Cellular restriction factors are represented by red ovals, and viral counterpartners are represented by gray hexagons. Black arrows represent the course of viral replication and actions. Broken arrows represent inhibition. Question marks (?) represent unresolved questions. Adapted from “Host factors and HIV-1 replication”, by Goncalves et al., 2013, Front Immunol, 4, 343 as a reference 35 in the text.
Figure 3.
Schematic of the pathway triggered by Tat and leading to activation of ISGs by Tat in APCs infected by HIV. (A) Tat triggers signaling pathways that activate ISGs by associating with MAPK kinases MAP2K3 (MKK3) and MAP2K6 (MKK6), which in turn activate p38 MAPK and STAT1, and with IRF7 in APCs infected by HIV. (B) Activation of MKK3, MKK6, and IRF7 leads to expression of many ISGs (shown here in connection with MKK3, MKK6, and IRF7), whose product can positively impact T-cell immunoactivation and negatively impact virus production. Bold labeling indicates genes found upregulated by HIV and Tat in APC. Adapted from “Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells”, by Kim et al., 2013, Blood, 121, 4090 as a reference 53 in the text.
Figure 4.
Schematic of the pathway triggered by Tat and leading to activation of ISGs by Tat in APCs infected by HIV. (A) Tat triggers signaling pathways that activate ISGs by associating with MAPK kinases MAP2K3 (MKK3) and MAP2K6 (MKK6), which in turn activate p38 MAPK and STAT1, and with IRF7 in APCs infected by HIV. (B) Activation of MKK3, MKK6, and IRF7 leads to expression of many ISGs (shown here in connection with MKK3, MKK6, and IRF7), whose product can positively impact T-cell immunoactivation and negatively impact virus production. Bold labeling indicates genes found upregulated by HIV and Tat in APC. Adapted from “Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells”, by Kim et al., 2013, Blood, 121, 4090 as a reference 53 in the text.
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