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Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. King Khalid Univ, Saudi Arabia.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
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2018 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, article id 899Article in journal (Refereed) Published
Abstract [en]

Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2018. Vol. 9, article id 899
Keywords [en]
dendritic cells; natural killer cells; complement; HIV; cross talk; checkpoint inhibitors; CXCR3; CCR4
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-147922DOI: 10.3389/fimmu.2018.00899ISI: 000431174300002PubMedID: 29760706OAI: oai:DiVA.org:liu-147922DiVA, id: diva2:1209565
Note

Funding Agencies|Swedish Research Council; Swedish Physicians against AIDS Research Foundation; VINNMER for Vinnova; Linkoping University Hospital Research Fund; ALF Grants Region Ostergotland; FORSS; CERiA, University of Malaya [UM.C.625/1/HIR/139]

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2019-05-21
In thesis
1. Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
Open this publication in new window or tab >>Effects of Complement Opsonization of HIV on Dendritic Cells: and Implications for the Immune Response
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
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.  

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 65
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1640
Keywords
HIV, dendritic cells, complement, innate immune response, TLR signaling, T cell activation, NK cells, inflammation, antiviral response, immune evasion
National Category
Immunology
Identifiers
urn:nbn:se:liu:diva-151665 (URN)10.3384/diss.diva-151665 (DOI)9789176852217 (ISBN)
Public defence
2018-10-26, Berzeliussalen, Campus US, Linköping, 09:00 (English)
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Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2019-09-30Bibliographically approved

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