| 1. |
- Aravantinou, Meropi, et al.
(författare)
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PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo
- 2016
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239 Delta Nef (SIV Delta Nef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of alpha(4)beta(7) and CD169, and induced type IIFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro-and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIV Delta Nef-infected animals, SIV Delta Nef viremia was higher, in line with the importance of DC and T cell activation in SIV Delta Nef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity.
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| 2. |
- Barrenäs, Fredrik, et al.
(författare)
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Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy
- 2021
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:7
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Tidskriftsartikel (refereegranskat)abstract
- Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68-1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in similar to 55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8(+) T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68-1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68-1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8(+) T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8(+) T cells to mediate protection against SIV challenge.
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| 3. |
- Beignon, Anne-Sophie, et al.
(författare)
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Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions
- 2005
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 115:11, s. 3265-3275
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 directly activates human plasmacytoid DCs (pDCs) by upregulating the expression of costimulatory and MHC molecules and maturation markers, increasing T cell stimulatory activity, and inducing the production of type I interferons and TNF-α. A consequence of this activation is the bystander maturation of myeloid DCs and overall enhancement of antigen-presenting function. However, little is known about the mechanism(s) of pDC activation by HIV-1. Here we demonstrate by in vitro studies that IFN-α production by pDC in response to HIV-1 requires at least 2 interactions between the cell and virus. Initially, envelope-CD4 interactions mediate endocytosis of HIV-1, as demonstrated through the use of inhibitors of binding, fusion, endocytosis, and endosomal acidification. Subsequently, endosomally delivered viral nucleic acids, particularly RNA, stimulate pDCs through TLRs, as activation is reproduced with purified genomic RNA but not viral RNA packaging-deficient HIV-1 and blocked with different inhibitory TLR ligands. Finally, by using genetic complementation, we show that TLR7 is the likely primary target. Viral RNA rather than DNA in early retrotranscripts appears to be the active factor in HIV-1 that induces IFN-α secretion by pDCs. Since the decline in pDCs in chronic HIV-1 infection is associated with high viral loads and opportunistic infections, exploiting this natural adjuvant activity of HIV-1 RNA might be useful in the development of vaccines for the prevention of AIDS.
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| 4. |
- Che, Karlhans Fru, et al.
(författare)
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Cross Talk between P38MAPK and STAT3 Regulates Expression of Negative Costimulatory Molecules and Transcriptional Repressors in HIV-1 Primed T cells
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 infection enhances the expression of negative costimulatory molecules on T cellsleading to T cell impairment. The signaling pathway underlying the regulation ofinhibitory molecules and the subsequent onset of T cell impairment remains to beinvestigated. Herein, we showed that the T cells activated by HIV-pulsed dendritic cells(DCs) upregulated CTLA-4, TRAIL, LAG-3, TIM-3, and CD160 and suppressionassociated transcription factors BLIMP-1, DTX1, and FOXP3, leading to T cellsuppression. The induction of suppressor T cells was regulated by the signal transducerand activator of transcription 3 (STAT3) molecules as blockade of this pathwaysignificantly down regulates the expression of inhibitory molecules. The cytokines IL-6and IL-10 were not responsible for STAT3 activation as their neutralization could neitherrecover T cell proliferation nor decrease the expression of negative costimulatorymolecules. Contrarily, we demonstrated that the intracytoplasmic cross-talk of P38Mitogen-Activated Protein Kinase (MAPK) with STAT3 was responsible as blockade ofthe P38MAPK significantly impaired negative costimulatory molecular expression andthe subsequent recovery of T cell proliferation. Notably, the blockade of viral access toDC cytosol, via CD4 binding and fusion, significantly reduced the negative effects DCsimposed on the primed T cells. In conclusion, viral access to cytosol modulated theDCs- T cell priming to induce T cells with upreguled expression of negativecostimulatory molecules in a P38MAPK/STAT3 pathway dependent fashion
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| 5. |
- Ellegård, Rada, et al.
(författare)
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Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
- 2014
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 193:9, s. 4590-4601
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Tidskriftsartikel (refereegranskat)abstract
- Immature dendritic cells (iDCs) in genital and rectal mucosa may be one of the first cells to come into contact with HIV-1 during sexual transmission of virus. HIV-1 activates the host complement system, which results in opsonization of virus by inactivated complement fragments, for example, iC3b. We investigated antiviral and inflammatory responses induced in human iDCs after exposure to free HIV-1 (F-HIV), complement-opsonized HIV-1 (C-HIV), and complement and Ab-opsonized HIV-1 (CI-HIV). F-HIV gave rise to a significantly higher expression of antiviral factors such as IFN-beta, myxovirus resistance protein A, and IFN-stimulated genes, compared with C-HIV and CI-HIV. Additionally, F-HIV induced inflammatory factors such as IL-1 beta, IL-6, and TNF-alpha, whereas these responses were weakened or absent after C-HIV or CI-HIV exposure. The responses induced by F-HIV were TLR8-dependent with subsequent activation of IFN regulatory factor 1, p38, ERK, PI3K, and NF-kappa B pathways, whereas these responses were not induced by C-HIV, which instead induced activation of IFN regulatory factor 3 and Lyn. This modulation of TLR8 signaling was mediated by complement receptor 3 and led to enhanced infection. The impact that viral hijacking of the complement system has on iDC function could be an important immune evasion mechanism used by HIV-1 to establish infection in the host.
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| 6. |
- Lubong Sabado, Rachel, et al.
(författare)
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Evidence of dysregulation of dendritic cells in primary HIV infection
- 2010
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Ingår i: BLOOD. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:19, s. 3839-3852
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.
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| 7. |
- Sabado, Rachel L., et al.
(författare)
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Pathways utilized by dendritic cells for binding, uptake, processing and presentation of antigens derived from HIV-1
- 2007
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 37:7, s. 1752-1763
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Tidskriftsartikel (refereegranskat)abstract
- The outcome following HIV infection depends on the nature and durability of the HIV-specific T cell response induced initially. The activation of protective T cell responses depends upon dendritic cells (DC), antigen-presenting cells which have the capacity to process and present viral antigens. DC pulsed with aldrithiol-2-inactivated HIV and delivered in vivo were reported to induce immune responses and promote virologic control in chronically HIV-1-infected subjects. To gain an understanding of this phenomenon, we characterized the steps involved in the presentation of antigens derived from aldrithiol-2-treated vs. infectious HIV-1 by DC. Antigen presentation, on both MHC class I and II, was independent of DC-specific ICAM-3-grabbing integrin, DEC-205 and macrophage mannose receptor, C-type lectins expressed by the DC. Inhibitor studies showed that presentation on MHC class I was dependent on viral fusion in a CD4/coreceptor-dependent manner, both at the cell surface and within endosomes, and access to the classical endosomal processing pathway. MHC class II presentation of HIV-associated antigens was dependent on active endocytosis, probably receptor-mediated, and subsequent degradation of virions in acidified endosomes in the DC. Our study brings forth new facts regarding the binding, uptake, and processing of chemically inactivated virions leading to efficient antigen presentation and should aid in the design of more effective HIV vaccines. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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| 8. |
- Shankar, Esakimuthu, et al.
(författare)
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Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T Cells following Priming by HIV-1 Pulsed Dendritic Cells
- 2011
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Ingår i: MOLECULAR MEDICINE. - : Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 17:3-4, s. 229-240
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence indicates that immune impairment in persistent viral infections could lead to T-cell exhaustion. To evaluate the potential contribution of induction of negative costimulatory molecules to impaired T-cell responses, we primed naive T cells with mature monocyte-derived dendritic cells (MDDCs) pulsed with HIV-1 in vitro. We used quantitative real-time polymerase chain reaction and flow cytometry, respectively, to compare the gene and surface-protein expression profiles of naive T cells primed with HIV-pulsed or mock-pulsed DCs. We detected elevated expressions of negative costimulatory molecules, including lymphocyte activation gene-3 (LAG-3). CD160, cytolytic T-lymphocyte antigen-4 (CTLA-4). T-cell immunoglobulin mucin-containing domain-3 (TIM-3), programmed death-1 (PD-1) and TRAIL (tumor necrosis-factor-related apoptosis-inducing ligand) in T cells primed by HIV-pulsed DCs. The PD-1(+) T-cell population also coexpressed TIM-3, LAG-3, and CTLA-4. Interestingly, we also found an increase in gene expression of the transcriptional repressors Blimp-1 (B-lymphocyte-induced maturation protein-1) and Foxp3 (forkhead transcription factor) in T-cells primed by HIV-pulsed DCs; Blimp-1 expression was directly proportional to the expression of the negative costimulatory molecules. Furthermore, levels of the effector cytokines interleukin-2, tumor necrosis factor-alpha and interferon-gamma, and perforin and granzyme B were decreased in T-cell populations primed by HIV-pulsed DCs. In conclusion, in vitro priming of halve T-cells with HIV-pulsed DC leads to expansion of T cells with coexpression of a broad array of negative costimulatory mclecules and Blimp-1, with potential deleterious consequences for T-cell responses.
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| 9. |
- Tjomsland, Veronica, et al.
(författare)
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Blocking of integrins inhibits HIV-1 infection of human cervical mucosa immune cells with free and complement-opsonized virions
- 2013
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 43:9, s. 2361-2372
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Tidskriftsartikel (refereegranskat)abstract
- The initial interaction between HIV-1 and the host occurs at the mucosa during sexual intercourse. In cervical mucosa, HIV-1 exists both as free and opsonized virions and this might influence initial infection. We used cervical explants to study HIV-1 transmission, the effects of opsonization on infectivity, and how infection can be prevented. Complement opsonization enhanced HIV-1 infection of dendritic cells (DCs) compared with that by free HIV-1, but this increased infection was not observed with CD4+ T cells. Blockage of the α4-, β7-, and β1-integrins significantly inhibited HIV-1 infection of both DCs and CD4+ T cells. We found a greater impairment of HIV-1 infection in DCs for complement-opsonized virions compared with that of free virions when αM/β2- and α4-integrins were blocked. Blocking the C-type lectin receptor macrophage mannose receptor (MMR) inhibited infection of emigrating DCs but had no effect on CD4+ T-cell infection. We show that blocking of integrins decreases the HIV-1 infection of both mucosal DCs and CD4+ T cells emigrating from the cervical tissues. These findings may provide the basis of novel microbicidal strategies that may help limit or prevent initial infection of the cervical mucosa, thereby reducing or averting systemic HIV-1 infection.
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| 10. |
- Tjomsland, Veronica, et al.
(författare)
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Blocking of integrins significantly inhibits HIV-1 infection of human cervical mucosa immune cells and development of founder populations
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Slightly more than half of the HIV-1 infected individuals in the world are women and almost all acquire the infection through sexual intercourse. The initial interaction between HIV-1 and the host occurs at the mucosa site and the most common mode to access the submucosa is through dendritic cells (DCs). In the cervical mucosa, HIV-1 exist both as free and opsonized virions and this might influence initial infection. We used a cervical tissue explant model and both free and opsonized virions to study HIV-1 transmission and how it can be prevented. We found that complement opsonization significantly enhanced HIV-1 infection of DCs compared to free HIV-1, but this increased infection was not seen for CD4+ T cells. Blocking of α4, β7, and β1 integrins demonstrated significant inhibition of infection of both DCs and CD4+ T cells emigrating from mucosa, independent of the use of free or complement opsonized HIV-1. We found a higher impairment of HIV-1 infection in emigrating DCs for complement opsonized virions compared to free virions when the use of αM/β2 and α4 integrins was blocked. This study showed that block of integrins decreased the HIV-1 infection of both DCs and CD4+ T cells emigrating from the cervical explant tissues and, remarkably, the establishment of founder populations in these tissues. This indicates that preventing or severely lowering initial infection of the cervical mucosa could avert systemic HIV-1 infection and should be considered for development of microbicides to prevent HIV infection and transmission.
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| 11. |
- Tjomsland, Veronica, et al.
(författare)
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Complement Opsonization of HIV-1 Enhances the Uptake by Dendritic Cells and Involves the Endocytic Lectin and Integrin Receptor Families
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Interaction with the complement system is an underappreciated aspect of HIV-1 infection; even in primary infection, complement fragments are found on virions with potential to affect the interplay between the virus and dendritic cells (DC). Since opsonization may affect the efficiency of uptake and the type of receptors utilized, we compared the interactions of DC with free HIV-1 (F-HIV) and complement opsonized HIV-1 (C-HIV). We demonstrate that C-HIV significantly enhanced the uptake by immature DC (IDC) and mature DC (MDC) and that the internalization rate was dependent on both opsonization of the virus and DC maturation state. Increased DC uptake of C-HIV was not due to opsonization related increased binding of virus to the surface of DC but rather increased internalization of C-HIV despite utilizing a similar repertoire of receptors as F-HIV. Both F-HIV and C-HIV interacted with C-type lectins, integrins, and CD4 and blocking these receptor families prevented HIV-1 from binding to DC at 4 degrees C. Blocking integrins significantly reduced the binding and uptake of F-HIV and C-HIV implicating the involvement of several integrins such as beta 1-integrin, CR3, LFA-1, and alpha 4 beta 7. Distinctive for C-HIV was usage of beta 1-integrin and for F-HIV, usage of beta 7-integrin, whereas both F-HIV and C-HIV utilized both integrin chains of CR3. We have in this study identified the receptor types used by both F-HIV and C-HIV to bind to DC. Noteworthy, C-HIV was internalized more efficiently by DC than F-HIV, probably via receptor mediated endocytosis, which may entail different intracellular processing of the virus leading to both elevated infection and altered activation of HIV specific immune responses.
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| 12. |
- Tjomsland, Veronica, et al.
(författare)
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Complement opsonization of HIV-1 results in a different intracellular processing pattern and efficiency leading to an enhanced MHC I presentation by dendritic cells
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The antigen processing and presentation processes occurring in dendritic cells (DCs) required for induction of HIV-1 specific T cell responses, which are essential for controlling the viral infection in vivo. The initial interactions of DCs with free HIV-1 (FHIV), or complement opsonized HIV-1 (C-HIV) might influence the routing and nature of pathways used for MHC class I and II restricted presentation. We have examined FHIV, C-HIV, and complement and antibody opsonized HIV-1 (C-IgG-HIV) effects on immature DCs (IDCs) and mature DCs (MDCs) antigen proteolysis, MHC class I and II antigen presentation, and the role of endocytic receptors in presentation of antigens derived from HIV-1. We found that opsonized virions promoted MHC class I presentation by both IDCs and MDCs compared to F-HIV. Indicative of that complement opsonization routes more virions towards the MHC class I presentation pathway. We found that blocking macrophage mannose receptor (MMR) rerouted the HIV-1 to a path leading to higher levels of MHC class I and II presentation. Furthermore, the blocking of β7-integrin also gave an enhanced MHC class I and II presentation by both IDCs and MDCs, whereas the block of αMβ2 integrins, i.e. complement receptor 3 (CR3), decreased the MHC class I and II presentation. In addition, we found that IDCs and MDCs proteolytic activities were modulated by the HIV-1 exposure, for example C-HIV induced an increased proteasome activity in IDCs. Taken together, these findings indicated that endocytic receptors, such as MMR, CR3, and β7 integrin, can promote or disfavor antigen presentation by routing HIV-1 into different endosomal compartments with distinct properties and efficiencies for degradation of viral antigens and MHC class I and II presentation and that HIV-1 affects the antigen processing machineries.
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| 13. |
- Tjomsland, Veronica, et al.
(författare)
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Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells
- 2013
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Ingår i: European Journal of Immunology. - : Wiley-VCH Verlag. - 0014-2980 .- 1521-4141. ; 43:6, s. 1470-1483
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Tidskriftsartikel (refereegranskat)abstract
- Induction of optimal HIV-1-specific T-cell responses, which can contribute to controlling viral infection in vivo, depends on antigen processing and presentation processes occurring in DCs. Opsonization can influence the routing of antigen processing and pathways used for presentation. We studied antigen proteolysis and the role of endocytic receptors in MHC class I (MHCI) and II (MHCII) presentation of antigens derived from HIV-1 in human monocyte-derived immature DCs (IDCs) and mature DCs, comparing free and complement opsonized HIV-1 particles. Opsonization of virions promoted MHCI presentation by DCs, indicating that complement opsonization routes more virions toward the MHCI presentation pathway. Blockade of macrophage mannose receptor (MMR) and β7-integrin enhanced MHCI and MHCII presentation by IDCs and mature DCs, whereas the block of complement receptor 3 decreased MHCI and MHCII presentation. In addition, we found that IDC and MDC proteolytic activities were modulated by HIV-1 exposure; complement-opsonized HIV-1 induced an increased proteasome activity in IDCs. Taken together, these findings indicate that endocytic receptors such as MMR, complement receptor 3, and β7-integrin can promote or disfavor antigen presentation probably by routing HIV-1 into different endosomal compartments with distinct efficiencies for degradation of viral antigens and MHCI and MHCII presentation, and that HIV-1 affects the antigen-processing machinery.
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