HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells

Caetano, Diogo Gama; Paula, Hury Hellen Souza de; Bello, Gonzalo; Hoagland, Brenda; Villela, Larissa M.; Grinsztejn, Beatriz; Veloso, Valdiléa G.; Morgado, Mariza G.; Guimarães, Monick Lindenmeyer; Côrtes, Fernanda Heloise

doi:10.1371/journal.pone.0228745

Cited by 20 publications

(24 citation statements)

References 102 publications

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“…The Th17/Treg ratio decay becomes severe at a late stage of HIV infection, with values ranging from 0.75 to 0.2. In contrast, data suggest that Th17/Treg balance may be preserved in long-term non-progressors and maintained at an average level in elite controllers (47,49). Tryptophan catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) could contribute to this difference in the Th17/Treg ratio (112).…”

Section: The Dynamic Of Th17/treg Balance During Hiv Infection and On...mentioning

confidence: 99%

Th17 CD4+ T-Cell as a Preferential Target for HIV Reservoirs

et al. 2022

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Among CD4+ T-cells, T helper 17 (Th17) cells play a sentinel role in the defense against bacterial/fungal pathogens at mucosal barriers. However, Th17 cells are also highly susceptible to HIV-1 infection and are rapidly depleted from gut mucosal sites, causing an imbalance of the Th17/Treg ratio and impairing cytokines production. Consequently, damage to the gut mucosal barrier leads to an enhanced microbial translocation and systemic inflammation, a hallmark of HIV-1 disease progression. Th17 cells’ expression of mucosal homing receptors (CCR6 and α4β7), as well as HIV receptors and co-receptors (CD4, α4β7, CCR5, and CXCR4), contributes to susceptibility to HIV infection. The up-regulation of numerous intracellular factors facilitating HIV production, alongside the downregulation of factors inhibiting HIV, helps to explain the frequency of HIV DNA within Th17 cells. Th17 cells harbor long-lived viral reservoirs in people living with HIV (PLWH) receiving antiretroviral therapy (ART). Moreover, cell longevity and the proliferation of a fraction of Th17 CD4 T cells allow HIV reservoirs to be maintained in ART patients.

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Section: The Dynamic Of Th17/treg Balance During Hiv Infection and On...mentioning

confidence: 99%

Th17 CD4+ T-Cell as a Preferential Target for HIV Reservoirs

et al. 2022

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“…Furthermore, gut mucosal fibrosis contributes to gut dysbiosis and progressive microbial translocation from the gut to the periphery, which promotes systemic chronic inflammation and accelerated comorbidities and non-AIDS malignancies [ 38 , 39 ]. Notably, gut mucosal fibrosis occurs even in HIV elite controllers (EC) while they exhibit similar peripheral Treg levels compared to healthy individuals [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection

et al. 2021

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Background: HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods: Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIVinfected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings: Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-b1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-b7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-b1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-b1) + Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-b1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation: Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding: This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the R eseau SIDA et maladies infectieuses du Fonds de recherche du Qu ebec-Sant e (FRQ-S).

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“…Furthermore, CCR4 + CCR6 + Th17 and CXCR3 + CCR6 + (Th1/Th17) cells that express the HIV coreceptors CCR5 and CXCR4 and secrete low levels of MIP-1b are highly susceptible to in vitro infection by R5 and X4 HIV viruses (Elhed and Unutmaz, 2010;Gosselin et al, 2010). Additionally, these Th17 subsets also exhibit gut-and lymph nodehoming potential that might relate to their significant depletion in the gastrointestinal tract of chronic HIV-infected individuals (Bixler and Mattapallil, 2013), but not in HIV-infected LTNPs (Ciccone et al, 2011;Caetano et al, 2020).…”

Section: Introductionmentioning

confidence: 99%