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Background: Toll-like receptors (TLRs) may be important in the ability of host innate immunity to control HIV infection. To investigate TLR activity in association with HIV disease, we examined the compared the ex vivo stimulatory capacity of TLRs in patients with chronic, asymptomatic HIV infection (long term non-progressors, LTNPs) and those exhibiting accelerated disease (rapid progressors, RPs). Methods: Therapy-naïve patients asymptomatically infected with HIV for over 10 years (LTNPs) matching in immunological status with those experiencing CD4+ cell decline below 350 cells/microlitre within 3 years of infection (RPs) were recruited to the study. Cytometric bead array was used to measure levels of secreted proinflammatory cytokines in peripheral blood from HIV-infected patients and uninfected controls after ex vivo treatment with agonists specific for TLRs 2-9. Flow cytometry was used to assess frequencies of cells bearing TLR4 in peripheral blood. Results: In comparison to RPs and uninfected controls, significantly increased (P < 0.05) levels of secreted TNFalpha IL-6, and IL-8 were observed in LTNP samples in response to treatment with the TLR4 ligand lipopolysaccharide and the TLR3 ligand polyinosinic:polycytidylic acid. In contrast, RPs exhibited a decreased (P < 0.05) pro-inflammatory response to TLR4 and TLR3 activation. Frequencies of TLR4-positive CD14+ monocytes, CD4+ or CD8+ lymphocytes were equivalent between patient groups. Conclusions: Rapid disease progression after HIV infection is characterized by reduced pro-inflammatory capacity of TLR3 and TLR4, whereas asymptomatic status correlated with enhanced activity of these receptors. Differential TLR4 activity between patient groups is independent of the frequency of TLR4-bearing cells.