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Review
. 2010 Apr 9:7:34.
doi: 10.1186/1742-4690-7-34.

Macrophage signaling in HIV-1 infection

Georges Herbein  1 , Gabriel Gras, Kashif Aziz Khan, Wasim Abbas
Affiliations
Review

Macrophage signaling in HIV-1 infection

Georges Herbein et al. Retrovirology. .

Abstract

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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Figures

Figure 1
Figure 1
HIV-1 proteins modulate signaling in the macrophage. The HIV-1 proteins Nef, Tat, Vpr, and gp120 alter cell signaling pathways, both in infected and uninfected macrophages. The presence of exogenous Nef, Tat and Vpr has been reported in sera of AIDS patients, which have the ability to enter the cells. HIV-1 proteins activate multiple transcription factors in macrophages including NF-κB, Sp-1 and AP-1, which have binding sites in the long terminal repeat (LTR) of HIV-1. The induction of these factors results in increased viral production. Furthermore, the activation of these transcription factors enhances cytokine production by macrophages primarily involved in AIDS pathogenesis. TNF promoter is shown as a prototype containing binding sites of NF-κB, Sp-1, and AP-1. Exogenous Nef and Vpr may enhance Tat-mediated transcription in addition to their effect on transcription factors. Moreover, the viral glycoprotein gp120 activates MAPK in uninfected and infected cells, resulting in increased TNFα production through ATF-2 binding sites of its promoter. Tat also stimulates CXCR4/CCR5 surface co-receptor expression, thus enhancing viral entry in cells. Besides LTR activation through transcription factors, Vpr-induced cell cycle arrest facilitates LTR stimulation.
Figure 2
Figure 2
A model of HIV-1 pathogenesis based on interactions between macrophages and T cells which account for increased immune suppression and cellular virion reservoirs. a) Viral glycoprotein gp120 activates the production of pro-inflammatory cytokines and chemokines by macrophages, attracting T cells in the vicinity of macrophages, thereby increasing the number of infected cells and fueling the viral reservoirs. HIV-1 proteins Nef, Tat, and Vpr activate the long terminal repeat (LTR) of HIV-1, resulting in sustained viral growth while also activating anti-apoptotic pathways that favor viral persistence and formation of viral reservoir. b) Viral protein Tat participates in CD4+ T cell death through TRAIL secretion by HIV-1 infected macrophages. Viral gp120 glycoproteins increase the expression of TNF and TNFR on macrophages and T cells, leading to CD8+ T cell apoptosis. Thus, macrophage signaling using viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection.
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