Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness

Abstract

Viremia during human immunodeficiency virus type-1 (HIV-1) infection results in progressive impairment of several components of the immune system. Here a unique model of repeated treatment interruptions (TIs) was used with the aim to reveal the effect of controlled short-term viremia on innate stimuli responsiveness and circulating dendritic cells (DCs). Sequential peripheral blood samples from HIV-1-infected patients on combination antiretroviral therapy, subjected to repeated Tl cycles as part of a therapeutic DNA vaccination study, were analyzed. In vitro responsiveness of peripheral blood mononuclear cells to toll-like receptor (TLR) stimuli was analyzed by cytokine secretion, and frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were monitored by flow cytometry. These parameters were found not to be significantly different between the vaccinated and placebo groups. Instead, independent of vaccination altered in vitro TLR responsiveness was observed in parallel with Tl cycles. TLR7/8-triggered secretion of IL-12 and IFN-a, as well as TLR9-triggered secretion of IL-12, was hyperactivated. In contrast, expression of IFN-a after TLR9 stimulation decreased during the initial cycle of Tl. Reduced frequencies of pDCs and mDCs, compared with baseline, were noted before and during the second Tl, respectively. Furthermore, spontaneous ex vivo release of IL-12 from PBMC was noted during cycles of Tl. In conclusion, these results suggest that consequences of short-term Tl include dysregulated TLR responses and fluctuations in the frequencies of circulating DCs. Knowledge of these immunological factors may influence the continuation of stringent treatment schedules during HIV infections. © 2013 Landes Bioscience.