Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART

Abstract

Depletion and functional impairment of circulating plasmacytoid dendritic cells (pDCs) are characteristic attributes of HIV-1-infection. The mechanism of dysfunction of pDCs is unclear. Here, we studied the development of phenotype of pDCs in a cohort of HIV-1-infected individuals monitored before the initiation and during a 9-month follow up with antiretroviral therapy (ART). Using polychromatic flow cytometry, we detected significantly higher pDC-surface expression of the HIV-1 receptor CD4, regulatory receptor BDCA-2, Fcγ receptor CD32, pDC dysfunction marker TIM-3, and the marker of killer pDC, TRAIL, in treatment-naïve HIV-1-infected individuals before initiation of ART when compared to healthy donors. After 9 months of ART, all of these markers approached but did not reach the expression levels observed in healthy donors. We found that the rate of decline in HIV-1 RNA level over the first 3 months of ART negatively correlated with the expression of TIM-3 on pDCs. We conclude that immunogenic phenotype of pDCs is not significantly restored after sustained suppression of HIV-1 RNA level in ART-treated patients and that the level of the TIM-3 expressed on pDCs in treatment naïve patients could be a predictive marker of the rate of decline in the HIV-1 RNA level during ART.

Tissue-specific transcriptional profiling of plasmacytoid dendritic cells reveals a hyperactivated state in chronic SIV infection

“…TIGIT is highly expressed on resting and activated NK cells[ 82 ] and has been shown to mark exhausted CD8+ T cells in HIV and SIV infection [ 83 ], and is enriched on CD4+ T cells harboring latent virus in ART treated patients [ 84 ]. In contrast, the expression of TIM3, an exhaustion marker that has been shown to be highly expressed on HIV-1 infected human pDCs [ 85 , 86 ], was negligible in PB and LN pDCs from SIV-infected RMs.…”

Plasmacytoid Dendritic Cells as Cell-Based Therapeutics: A Novel Immunotherapy to Treat Human Immunodeficiency Virus Infection?

“…During ART, the TLR7/8 response appears to remain intact (Chang et al, 2012;Bam et al, 2017;Tsai et al, 2017) but IFN production upon TLR9 signaling is reduced, potentially due to continuous HIV-induced activation of pDCs in vivo or the interaction of CD40 with CD40L (Feldman et al, 2001;Tilton et al, 2008;Cavaleiro et al, 2009;Donhauser et al, 2012). Additionally, pDCs in the blood of PLWH display an exhausted phenotype and this may interfere with TLR signaling and subsequent IFN production (Cavaleiro et al, 2009;Schwartz et al, 2017;Font-Haro et al, 2018). However, administration of the TLR9 agonist MGN1703 to PLWH on ART enhances pDC activation, as measured by activation markers CD86 and CD40.…”

Immunopathogenetic role of plasmocytoid dendritic cells in Epstein-Barr virus infection

“…Тем не менее индуцированная вирусом иммунодефицита человека гибель CD4 + -T-клеток сдерживается, несмотря на повышенную вирусную нагрузку, что позволяет предположить, что pDCs подавляют репликацию ВИЧ [49]. При дальнейшем изучении pDCs сделан вывод о том, что иммуногенный фенотип этих клеток достоверно не восстанавливается после устойчивого подавления уровня РНК ВИЧ у пациентов на антиретровирусной терапии (АРТ) и что pDCs могут служить прогностическим маркером снижения уровня РНК ВИЧ во время проведения АРТ [48].…”