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Complement Opsonization of HIV-1 Results in Decreased Antiviral and Inflammatory Responses in Immature Dendritic Cells via CR3
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
University of Manitoba, Winnipeg, Canada; Public Health Agency of Canada, Winnipeg, Canada.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Reumatologiska kliniken i Östergötland.
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2014 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 193, nr 9, s. 4590-4601Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
American Association of Immunologists , 2014. Vol. 193, nr 9, s. 4590-4601
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-112625DOI: 10.4049/jimmunol.1401781ISI: 000344079500033PubMedID: 25252956OAI: oai:DiVA.org:liu-112625DiVA, id: diva2:769449
Merknad

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; Swedish International Development Cooperation Agency; VINNMER for Vinnova; Linkoping University Hospital Research Fund Grant C-ALF; Swedish Society of Medicine; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Swedish Society for Medical Research

Tilgjengelig fra: 2014-12-08 Laget: 2014-12-05 Sist oppdatert: 2018-09-28bibliografisk kontrollert
Inngår i avhandling
1. Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
Åpne denne publikasjonen i ny fane eller vindu >>Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Dendritic cells are key players during HIV pathogenesis, and shape both the immediate immune response at the site of infection as well as directing the adaptive immune response against the virus. HIV has developed a plethora of immune evasion mechanisms that hijack dendritic cell functions, suppressing their ability to mount an accurate immune response and exploiting them for efficient viral transfer to target T cells.

To achieve successful replication within dendritic cells without triggering danger signaling, HIV accomplishes a delicate balance where only a low level of transcription can be sustained without triggering antiviral responses that would harm the virus. Here, we describe how the presence of HSV2 coinfection, which is very common in geographic areas with a high HIV prevalence and almost triples the risk of HIV acquisition, alters dendritic cell state to support much higher levels of HIV infection. We found this effect to be mediated by the STING pathway, which is involved in the sensing of DNA in the cell cytosol. STING activation led to an upregulation of factors such as IRF3 and NFkB that can be used for HIV transcription and a degradation of factors that restrict HIV replication.

In addition, we describe how HIV exploits the human complement system, a group of proteins that usually help the human body to identify dangerous pathogens while avoiding reaction towards self. HIV can coat itself, i.e. become opsonized, in complement fragments that are typically only present on the body’s own cells, allowing it to activate signaling pathways that are associated with tolerance. Dendritic cells that come into contact with complement opsonized HIV do not mount danger responses, despite the fact that HIV-derived single stranded RNA triggers the pathogen recognition receptor TLR8. The suppression of danger responses is mediated by activation of complement receptor 3, and leads to an increased infection of the dendritic cell and affects its interactions with other immune cells. There is a lack of recruitment of NK cells to the site of infection, and an inhibition of NK cell killing, which plays an important role in the destruction of HIV-infected cells in vivo. T cells primed by dendritic cells exposed to complement opsonized HIV have a lower ability to develop towards effector phenotype, and have an increased expression of the markers PD1, TIM3 and LAG3 which are associated with T cell dysfunction and exhaustion. In addition, T cells primed by these dendritic cells in the presence of NK cells upregulate markers CD38, CXCR3 and CCR4, which have been linked to an increased susceptibility to HIV infection.

In summary, we add to the current knowledge on HIV immune evasion mechanisms that allow the virus to establish infection, as well as describing mechanisms that govern whether dendritic cells mount danger signaling and an immune response or not.  

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 65
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1640
Emneord
HIV, dendritic cells, complement, innate immune response, TLR signaling, T cell activation, NK cells, inflammation, antiviral response, immune evasion
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-151665 (URN)10.3384/diss.diva-151665 (DOI)9789176852217 (ISBN)
Disputas
2018-10-26, Berzeliussalen, Campus US, Linköping, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-09-28 Laget: 2018-09-28 Sist oppdatert: 2019-09-30bibliografisk kontrollert

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