title: 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 TI 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 TI cycles. TLR7/8-triggered secretion of IL-12 and IFN-α, as well as TLR9-triggered secretion of IL-12, was hyperactivated. In contrast, expression of IFN-α after TLR9 stimulation decreased during the initial cycle of TI. Reduced frequencies of pDCs and mDCs, compared with baseline, were noted before and during the second TI, respectively. Furthermore, spontaneous ex vivo release of IL-12 from PBMC was noted during cycles of TI. In conclusion, these results suggest that consequences of short-term TI 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.
authors.affiliation: The Swedish Institute for Communicable Disease Control; Stockholm, Sweden; Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Salma
authors.initials: S
authors.lastname: Nowroozalizadeh
authors.affiliation: The Swedish Institute for Communicable Disease Control; Stockholm, Sweden; Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Lindvi
authors.initials: L
authors.lastname: Gudmundsdotter
authors.affiliation: Department of Infectious Diseases/Venhälsan; Stockholm South General Hospital; Stockholm, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Hejdeman
authors.affiliation: The Swedish Institute for Communicable Disease Control; Stockholm, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Andersson
authors.affiliation: Department of Laboratory Medicine Malmö; Lund University; Lund, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Esbjörnsson
authors.affiliation: Department of Laboratory Medicine Malmö; Lund University; Lund, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Medstrand
authors.affiliation: Department of Infectious Diseases/Venhälsan; Stockholm South General Hospital; Stockholm, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Sandström
authors.affiliation: The Swedish Institute for Communicable Disease Control; Stockholm, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Gaines
authors.affiliation: The Swedish Institute for Communicable Disease Control; Stockholm, Sweden; Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.affiliation: Department of Microbiology; Tumor and Cell Biology; Karolinska Institutet; Stockholm, Sweden; Department of Laboratory Medicine Lund; Lund University; Lund, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Jansson
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051193:Toll-Like Receptors / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D014766:Viremia / Q000276:immunology / Q000821:virology; D028761:Withholding Treatment
chemical_list: D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D051193:Toll-Like Receptors; D019444:Vaccines, DNA
keywords: HIV; TLR responsiveness; dendritic cells; treatment interruption
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