HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses

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dc.contributor.authorLumngwena, Evelyn N
dc.contributor.authorMetenou, Simon
dc.contributor.authorMasson, Lindi
dc.contributor.authorCicala, Claudia
dc.contributor.authorArthos, James
dc.contributor.authorWoodman, Zenda
dc.date.accessioned2020-07-10T09:13:14Z
dc.date.available2020-07-10T09:13:14Z
dc.date.issued2020-07-02
dc.date.updated2020-07-05T04:45:34Z
dc.description.abstractBackground Heterosexual transmission remains the main route of HIV-1 transmission and female genital tract (FGT) inflammation increases the risk of infection. However, the mechanism(s) by which inflammation facilitates infection is not fully understood. In rhesus macaques challenged with simian immunodeficiency virus, dendritic cell (DC) mediated recruitment of CD4+ T cells to the FGT was critical for infection. The aim of this study was to delineate the mechanisms underlying DC-mediated HIV infection by comparing chemokine and pro-inflammatory cytokine production in response to transmitted founder (TF) and chronic infection (CI) Envelope (Env) pseudotyped viruses (PSV). Results Monocyte-derived DCs (MDDCs) were stimulated with PSV and recombinant gp140 representing matched TF and CI pairs of four individuals and cytokine secretion measured by multiplex immuno-assay. We found that 4/9 Env induced robust MDDC inflammatory responses and of those, three were cloned from TFs. Overall, TF Env induced MDDCs from healthy donors to secrete higher concentrations of inflammatory cytokines and chemokines than those from CI, suggesting TF Env were better inducers of inflammation. Assessing the signalling pathway associated with inflammatory cytokines, we found that PSV of matched TF and CI variants and a gp140 clone activated ERK and JNK to similar levels. Recombinant soluble DC-SIGN inhibited cytokine release and activation of ERK by PSV, suggesting that Env-DC-SIGN binding was partly involved in MDDC stimulation. Therefore, Env clones might differentially stimulate MDDC immune responses via alternative, yet unidentified signalling pathways. Conclusion Overall, this could suggest that the genetics of the virus itself influences inflammatory responses during HIV infection. In the absence of pre-existing infections, induction of greater inflammatory response by TFs might favour virus survival within the healthy FGT by driving an influx of target cells to sites of infection while suppressing immune responses via IL-10.en_US
dc.identifier.apacitationLumngwena, E. N., Metenou, S., Masson, L., Cicala, C., Arthos, J., & Woodman, Z. (2020). HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses. <i>Retrovirology</i>, 17(1), 17. en_ZA
dc.identifier.chicagocitationLumngwena, Evelyn N, Simon Metenou, Lindi Masson, Claudia Cicala, James Arthos, and Zenda Woodman "HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses." <i>Retrovirology</i> 17, 1. (2020): 17. en_ZA
dc.identifier.citationLumngwena, E.N., Metenou, S., Masson, L., Cicala, C., Arthos, J. & Woodman, Z. 2020. HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses. <i>Retrovirology.</i> 17(1):17. en_ZA
dc.identifier.ris TY - Journal Article AU - Lumngwena, Evelyn N AU - Metenou, Simon AU - Masson, Lindi AU - Cicala, Claudia AU - Arthos, James AU - Woodman, Zenda AB - Background Heterosexual transmission remains the main route of HIV-1 transmission and female genital tract (FGT) inflammation increases the risk of infection. However, the mechanism(s) by which inflammation facilitates infection is not fully understood. In rhesus macaques challenged with simian immunodeficiency virus, dendritic cell (DC) mediated recruitment of CD4+ T cells to the FGT was critical for infection. The aim of this study was to delineate the mechanisms underlying DC-mediated HIV infection by comparing chemokine and pro-inflammatory cytokine production in response to transmitted founder (TF) and chronic infection (CI) Envelope (Env) pseudotyped viruses (PSV). Results Monocyte-derived DCs (MDDCs) were stimulated with PSV and recombinant gp140 representing matched TF and CI pairs of four individuals and cytokine secretion measured by multiplex immuno-assay. We found that 4/9 Env induced robust MDDC inflammatory responses and of those, three were cloned from TFs. Overall, TF Env induced MDDCs from healthy donors to secrete higher concentrations of inflammatory cytokines and chemokines than those from CI, suggesting TF Env were better inducers of inflammation. Assessing the signalling pathway associated with inflammatory cytokines, we found that PSV of matched TF and CI variants and a gp140 clone activated ERK and JNK to similar levels. Recombinant soluble DC-SIGN inhibited cytokine release and activation of ERK by PSV, suggesting that Env-DC-SIGN binding was partly involved in MDDC stimulation. Therefore, Env clones might differentially stimulate MDDC immune responses via alternative, yet unidentified signalling pathways. Conclusion Overall, this could suggest that the genetics of the virus itself influences inflammatory responses during HIV infection. In the absence of pre-existing infections, induction of greater inflammatory response by TFs might favour virus survival within the healthy FGT by driving an influx of target cells to sites of infection while suppressing immune responses via IL-10. DA - 2020-07-02 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - Retrovirology KW - HIV-subtype C Env KW - Transmitter/Founder Envelopes KW - Inflammatory responses KW - Virus survival KW - Immunosuppression KW - Transmission LK - https://open.uct.ac.za PY - 2020 T1 - HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses TI - HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses UR - ER - en_ZA
dc.identifier.urihttps://doi.org/10.1186/s12977-020-00526-0
dc.identifier.urihttps://hdl.handle.net/11427/32100
dc.identifier.vancouvercitationLumngwena EN, Metenou S, Masson L, Cicala C, Arthos J, Woodman Z. HIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responses. Retrovirology. 2020;17(1):17. .en_ZA
dc.language.isoenen_US
dc.language.rfc3066en
dc.publisher.departmentDivision of Cardiologyen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.holderThe Author(s)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceRetrovirologyen_US
dc.source.journalissue1en_US
dc.source.journalvolume17en_US
dc.source.pagination17en_US
dc.source.urihttps://retrovirology.biomedcentral.com/
dc.subjectHIV-subtype C Enven_US
dc.subjectTransmitter/Founder Envelopesen_US
dc.subjectInflammatory responsesen_US
dc.subjectVirus survivalen_US
dc.subjectImmunosuppressionen_US
dc.subjectTransmissionen_US
dc.titleHIV-1 subtype C transmitted founders modulate dendritic cell inflammatory responsesen_US
dc.typeJournal Articleen_US
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