Arc of a vicious circle: pathways activated by Mycobacterium tuberculosis that target the HIV-1 long terminal repeat

Abstract

In this review, we examine how a subset of signal transduction cascades initiated by Mycobacterium tuberculosis (Mtb) infection modulates transcription mediated by the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR). We describe two distinct phases of signaling that target transcription factors known to bind the HIV-1 LTR, and thus drive viral transcription and replication, in cells of the Mtb-infected host. First, Mtb-derived molecules, including cell wall components and DNA, interact with a number of host pattern recognition receptors. Second, cytokines and chemokines secreted in response to Mtb infection initiate signal transduction cascades through their cognate receptors. Given the variation in cell wall components among distinct clinical Mtb strains, the initial pattern recognition receptor interaction leading to direct LTR activation and differential cytokine and chemokine production is likely to be an important aspect of Mtb strain-specific regulation of HIV-1 transcription and replication. Improved understanding of these molecular mechanisms in the context of bacterial and host genetics should provide key insights into the accelerated viral replication and disease progression characteristic of HIV/TB coinfection.

Figure 1.

Transcription factor binding motifs in the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). Top: Approximate positions of κB (red), Sp1 (blue), AP-1 (purple), and C/EBP (green) binding sites in the context of the HIV-1 subtype B LTR are indicated. Bottom: Representative sequences from the LTR core enhancer region (between the RBE III and Sp1-III sites (14, 16, 106) from isolates of the indicated subtypes of HIV-1 between the upstream U3 modulatory region and the conserved Sp1 binding sites of the core promoter region. The highlighted sequences are κB motifs (red), most of which bind NF-κB and NFATp (half-sites bound by NFATp [30] indicated by arrows) and some of which are also highly conserved NFAT5 binding motifs (red, with 3′ adenine in yellow).

Figure 2.

Signal transduction pathways activated by Mycobacterium tuberculosis (Mtb)-derived components. Generalized macrophage/dendritic cell showing intracellular cascades after engagement of Toll-like receptors (TLRs) (top left), C-type lectins (top right), and NOD2 by the indicated ligands derived from Mtb (green text). Receptors are in green; adapter proteins and upstream kinases are in blue; downstream kinases are in orange; and transcription factors are in red. HIV-1 LTR and activated cytokines are indicated at the bottom. Translocation of TLR4 into the endosome after ligand engagement is indicated by the green arrow.

Figure 3.

Signal transduction pathways activated by Mtb-induced cytokines. Intracellular cascades after association of TNF, IL-1, transforming growth factor (TGF)-β, monocyte chemoattractant protein (MCP)-1, IFN-γ, and IL-6 with their cognate receptors at the cell surface are shown in green and gray. The color scheme for upstream kinases and adaptor proteins, downstream kinases, and transcription factors is as in Figure 2.