Abstract
The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention.
Highlights
human immunodeficiency virus (HIV)-1 infection, as well as the progression of HIV-1 disease, usually occurs in the presence of other microbes [1,2,3,4,5]
To investigate the mechanisms of modulation of HIV-1 replication by Toll-like receptors (TLRs) ligands, we further focused on two ligands that affect HIV in opposite ways: flagellin and ODN M362
Clinical and experimental evidence suggests that various microbes are able to affect the HIV-1 life cycle by changing the systemic and/or local environment [69,70,71,72,73,74,75] or by interacting with HIV-1 directly [76,77]
Summary
HIV-1 infection, as well as the progression of HIV-1 disease, usually occurs in the presence of other microbes [1,2,3,4,5]. Some infectious agents seem to have an opposite effect and can alleviate the course of HIV-1 disease [6,7,8,9,10] Evidence exists that these microbes interact locally with HIV-1 by up- or down-regulating HIV-1 coreceptors [11,12,13] and receptors [14] as well as by inducing changes in the production of various cytokines [11,13]. Since the pattern of expression of TLRs depends on a particular cell subtype and on the engagement of a ligand to a particular TLR receptor, the system responds to different pathogens differently [17,26] This response may include cell activation and differentiation [27,28], secretion of type I IFNs, and/or production of proinflamatory cytokines [17,29]. Because of the profound role of TLRs engagement in immune response, TLR agonists, antagonists, specific antibodies or shRNA are being tested as novel therapeutics and adjuvants for vaccines [26,30,31,32,33,34,35,36,37,38,39,40]
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