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

Nowroozalizadeh, Salma; Gudmundsdotter, Lindvi; Hejdeman, Bo; Andersson, Lena; Esbjörnsson, Joakim LU ; Medstrand, Patrik LU ; Sandström, Eric; Gaines, Hans; Wahren, Britta and Jansson, Marianne LU (2013) In Human Vaccines & Immunotherapeutics 9(10). p.2103-2110
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA: immunology, DNA: administration & dosage, Vaccines, Toll-Like Receptors: immunology, HIV-1: immunology, HIV Infections: immunology, HIV Infections: drug therapy, Dendritic Cells: immunology, Anti-HIV Agents: therapeutic use, AIDS Vaccines: administration & dosage, AIDS Vaccines: immunology, Viremia: immunology, Viremia: virology
in
Human Vaccines & Immunotherapeutics
volume
9
issue
10
pages
2103 - 2110
publisher
Taylor & Francis
external identifiers
  • pmid:23912942
  • scopus:84885168407
  • wos:000330381600017
ISSN
2164-5515
DOI
10.4161/hv.25154
language
English
LU publication?
yes
id
12d60b1a-7474-4bac-ae5a-2fb70a7bb2c7 (old id 4935405)
alternative location
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906394/
date added to LUP
2015-01-15 07:26:20
date last changed
2019-02-20 01:10:56
@article{12d60b1a-7474-4bac-ae5a-2fb70a7bb2c7,
  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.},
  author       = {Nowroozalizadeh, Salma and Gudmundsdotter, Lindvi and Hejdeman, Bo and Andersson, Lena and Esbjörnsson, Joakim and Medstrand, Patrik and Sandström, Eric and Gaines, Hans and Wahren, Britta and Jansson, Marianne},
  issn         = {2164-5515},
  keyword      = {DNA: immunology,DNA: administration & dosage,Vaccines,Toll-Like Receptors: immunology,HIV-1: immunology,HIV Infections: immunology,HIV Infections: drug therapy,Dendritic Cells: immunology,Anti-HIV Agents: therapeutic use,AIDS Vaccines: administration & dosage,AIDS Vaccines: immunology,Viremia: immunology,Viremia: virology},
  language     = {eng},
  number       = {10},
  pages        = {2103--2110},
  publisher    = {Taylor & Francis},
  series       = {Human Vaccines & Immunotherapeutics},
  title        = {Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness.},
  url          = {http://dx.doi.org/10.4161/hv.25154},
  volume       = {9},
  year         = {2013},
}