Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2

Abstract

Mycobacterial infection has been implicated as a possible factor in AIDS progression in populations where HIV-1 and Mycobacterium tuberculosis are coendemic. In support of this concept, we have previously shown that HIV-1-transgenic (Tg) mice infected with mycobacteria display enhanced viral gene and protein expression. In this study, we demonstrate that the induction of HIV-1 observed in this model is dependent on Toll-like receptor 2 (TLR2), a pattern recognition receptor known to be involved in mycobacteria-host interaction. Spleen cells from HIV-1-Tg mice deficient in TLR2 (Tg/TLR2−/−) were found to be completely defective in p24 production induced in response to live M. tuberculosis or Mycobacterium avium as well as certain mycobacterial products. Importantly, following in vivo mycobacterial infection, Tg/TLR2−/− mice failed to display the enhanced HIV-1 gag/env mRNA and p24 protein synthesis exhibited by wild-type Tg animals. Together, these results argue that TLR2 plays a crucial role in the activation of HIV-1 expression by mycobacterial coinfections.

Nuclear Receptor Signaling Inhibits HIV-1 Replication in Macrophages through Multipletrans-Repression Mechanisms

“…This indicates that NR signaling, in addition to directly repressing virus expression in infected cells, is capable of dampening the proinflammatory cytokine response that activates HIV-1 expression in an autocrine or paracrine fashion. , it is not surprising that a number of TLR ligands activate HIV-1 expression in immune cells (3,11,34,36,114,145,161). In agreement with other reports (3,11,36,98,114,145,161), we show that signaling through TLR2 activates HIV-1 expression in macrophages and DCs ( Fig.…”

Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system

“…Similarly, A. fumigatus also evades immune recognition during germination through TLR2-mediated IL-10 production, whereas proinflammatory TLR4-mediated signals are lost [47]. Another example of deleterious TLR2 activation is that of mycobacteria and human immunodeficiency virus type 1 (HIV-1) coinfection, in which HIV-1 expression is induced by mycobateria through TLR2 signaling [66]. All these data suggest that several microorganisms, among which the fungal pathogens C. albicans and A. fumigatus are prominent, use TLR2-mediated induction of anti-inflammatory cytokines to down-modulate the microbicidal functions of leukocytes and evade the host defense (Fig.…”

GeneChip Analyses of Global Transcriptional Responses of Murine Macrophages to the Lethal Toxin ofBacillus anthracis

“…Engagement of TLR2 has also been shown to result in activation of NF-B, cytokine production, and apoptosis (1). Alternatively, recent data have also suggested that several pathogens might utilize TLR2 as an immune escape mechanism via the production of anti-inflammatory cytokines (3,20,46,50,54).…”