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J Infect Dis. 2011 Jul 15;204(2):299-308. doi: 10.1093/infdis/jir260.

Endometrial epithelial cell responses to coinfecting viral and bacterial pathogens in the genital tract can activate the HIV-1 LTR in an NF{kappa}B-and AP-1-dependent manner.

Author information

1
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, Michael DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, ON L8N 3Z5, Canada.

Abstract

BACKGROUND:

Sexually transmitted infections (STIs) are associated with increased human immunodeficiency virus type 1 (HIV-1) susceptibility and viral shedding in the genital tract, but the mechanisms underlying this association are poorly understood.

METHODS:

Direct activation of HIV long terminal repeats (LTRs), a proxy measure for HIV-1 replication, was measured after treatment of 1G5 T cells with Toll-like receptor (TLR) ligands, herpes simplex virus type 1 or 2 (HSV-1/2), or Neisseria gonorrhoeae. For indirect activation, 1G5 T cells were incubated with supernatants from female primary genital epithelial cells (GECs) previously exposed to these agents. Proinflammatory cytokines and chemokines were measured in GEC supernatants. Proinflammatory pathways were blocked to determine the mechanisms of direct and indirect HIV-LTR activation.

RESULTS:

HSV-1/2, N. gonorrhoeae, and TLR ligands FimH (TLR-4), flagellin (TLR-5), and Poly (I:C) (TLR-3) directly induced HIV-LTR activation in 1G5 T cells. Supernatants collected from GECs incubated with these agents indirectly induced HIV-LTR activation. Production of tumor necrosis factor α, interleukin 6, interleukin 8, and monocyte chemoattractant protein-1 was elevated in GECs exposed to copathogens. Inhibition of nuclear factor κB and activator protein-1 (AP-1) signaling pathways in 1G5 T cells abrogated both direct and indirect HIV-LTR activation.

CONCLUSIONS:

STIs may increase HIV-1 replication in the female genital tract via proinflammatory signaling pathways directly and indirectly via their effects on GECs. This increased HIV-1 replication may enhance sexual and vertical HIV transmission.

PMID:
21673042
DOI:
10.1093/infdis/jir260
[Indexed for MEDLINE]

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