Macrophage signaling in HIV-1 infection

Department of Virology, UPRES 4266 Pathogens and Inflammation, IFR 133 INSERM, University of Franche-Comté, CHU Besançon, F-25030 Besançon, France.
Retrovirology (Impact Factor: 4.19). 04/2010; 7(1):34. DOI: 10.1186/1742-4690-7-34
Source: PubMed


The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

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Available from: Gabriel Gras, Feb 20, 2014
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    • "Antigen-presenting cells (APCs) are critical for both innate and adaptive immunity. Professional APCs such as macrophages play an integral role in the immune pathogenesis of the human immunodeficiency virus type 1 (HIV-1) [1]. HIV-1 is a member of the lentivirus family and is the etiologic agent of acquired immunodeficiency syndrome (AIDS). "
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    ABSTRACT: Macrophages act as reservoirs of human immunodeficiency virus type 1 (HIV-1) and play an important role in its transmission to other cells. HIV-1 Vpr is a multi-functional protein involved in HIV-1 replication and pathogenesis; however, its exact role in HIV-1-infected human macrophages remains poorly understood. In this study, we used a microarray approach to explore the effects of HIV-1 Vpr on the transcriptional profile of human monocyte-derived macrophages (MDMs). More than 500 genes, mainly those involved in the innate immune response, the type I interferon pathway, cytokine production, and signal transduction, were differentially regulated (fold change >2.0) after infection with a recombinant adenovirus expressing HIV-1 Vpr protein. The differential expression profiles of select interferon-stimulated genes (ISGs) and genes involved in the innate immune response, including STAT1, IRF7, MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, APOBEC3A, DDX58 (RIG-I), TNFSF10 (TRAIL), and RSAD2 (viperin) were confirmed by real-time quantitative PCR and were consistent with the microarray data. In addition, at the post-translational level, HIV-1 Vpr induced the phosphorylation of STAT1 at tyrosine 701 in human MDMs. These results demonstrate that HIV-1 Vpr leads to the induction of ISGs and expand the current understanding of the function of Vpr and its role in HIV-1 immune pathogenesis.
    PLoS ONE 08/2014; 9(8):e106418. DOI:10.1371/journal.pone.0106418 · 3.23 Impact Factor
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    • "Of these, Nef, Tat, Vpr, and Vpu have been detected in soluble forms in sera of HIV-1-infected patients. These are likely to be released by infected/apoptotic cell, enter into macrophages, and then modulate both cellular machinery and viral transcription (Herbein et al. 2010). It is well established that Nef, a 27-kDa protein, downregulates cell surface expression of CD4, CD28, and MHC class I (Lundquist et al. 2002; Yang et al. 2002), thus exerting a key role in HIV pathogenesis. "

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    • "These immune cells play a duplicitous role during early HIV-1 infection. Macrophages in the vaginal mucosa have been shown to be productively infected [55], secreting cytokines to recruit CD4+ T cells at the sites of viral entry to fuel the infection [56]. Moreover, infected macrophages possess potent immune evasion mechanisms, are long-lived viral reservoirs and are particularly efficient at transmitting the virus to new CD4+ T cells [57]. "
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    ABSTRACT: Severe genetic bottleneck occurs during HIV-1 sexual transmission whereby most infections are initiated by a single transmitted/founder (T/F) virus. Similar observations had been made in nonhuman primates exposed mucosally to SIV/SHIV. We previously reported variable clinical outcome in rhesus macaques inoculated intravaginally (ivg) with a high dose of R5 SHIVSF162P3N. Given the potential contributions of viral diversity to HIV-1 persistence and AIDS pathogenesis and recombination between retroviral genomes increases the genetic diversity, we tested the hypothesis that transmission of multiple variants contributes to heightened levels of virus replication and faster disease progression in the SHIVSF162P3N ivg-infected monkeys. We found that the differences in viral replication and disease progression between the transiently viremic (TV; n = 2), chronically-infected (CP; n = 8) and rapid progressor (RP; n = 4) ivg-infected macaques cannot be explained by which variant in the inoculum was infecting the animal. Rather, transmission of a single variant was observed in both TV rhesus, with 1-2 T/F viruses found in the CPs and 2-4 in all four RP macaques. Moreover, the genetic relatedness of the T/F viruses in the CP monkeys with multivariant transmission was greater than that seen in the RPs. Biological characterization of a subset of T/F envelopes from chronic and rapid progressors revealed differences in their ability to mediate entry into monocyte-derived macrophages, with enhanced macrophage tropism observed in the former as compared to the latter. Our study supports the tenet that sequence diversity of the infecting virus contributes to higher steady-state levels of HIV-1 virus replication and faster disease progression and highlights the role of macrophage tropism in HIV-1 transmission and persistence.
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