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HIV-1 INFECTION LEADS TO INCREASED TOLL-LIKE RECEPTOR EXPRESSION AND RESPONSIVENESS CONTRIBUTING TO PATHOGENESIS
RT Lester1, X Yao2, TB Ball1, LR McKinnon1, R Kaul3, C Wachihi4, W Jaoko4, FA Plummer1, KL Rosenthal2
1Winnipeg, MB; 2Hamilton, ON; 3Toronto, ON; 4Nairobi, Kenya
Objectives: The role of innate immunity in HIV infection is poorly understood. Toll-like receptors (TLRs) are important in rapidly recognizing and responding to infection by triggering innate immune responses. The objective of this study was to evaluate the effect of chronic untreated and treated HIV-1 infection on TLR expression and signaling and its association with disease progression.
Methods: Two hundred high risk HIV-infected and uninfected women from a Kenyan cohort participated in these studies. Analysis of mRNA expression of all human TLRs was determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). TLR ligand responsiveness was assessed ex vivo by cytokine production in culture supernatants.
Results: Chronic, untreated HIV-1 infection was significantly associated with increased expression of TLR6, 7 and 8. TLR2, TLR3 and TLR4 were additionally increased in individuals with advanced disease. Elevation of select TLR expression correlated with plasma HIV RNA load, suggesting that increased viral replication and/or higher levels of circulating virus may drive increased TLR expression in vivo. Indeed, single-stranded RNA from HIV alone increased TLR expression in vitro. PBMC from HIV-infected subjects also demonstrated profoundly increased proinflammatory responsiveness to TLR ligands, suggesting sensitization of TLR signaling in HIV. Lastly, TLR expression was normalized in subjects taking antiretroviral therapy, independent of CD4+ T-cell recovery.
Conclusions: Together these data indicate that chronic viremic HIV-1 is associated with increased TLR expression and responsiveness which may exacerbate immune activation and pathogenesis.