Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques

O’Connor, Megan A.; Munson, Paul V.; Tunggal, Hillary C.; Hajari, Nika; Lewis, Thomas B.; Bratt, Debra; Moats, Cassie; Smedley, Jeremy; Bagley, Kenneth C.; Mullins, James I.; Fuller, Deborah H.

doi:10.1089/aid.2018.0184

Cited by 11 publications

(23 citation statements)

References 58 publications

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“…In HIV infection, targeting Tregs may be a feasible strategy for reducing HIV latent reservoir. SIV‐infected animals that maintained a balanced mucosal Th17/Treg ratio at the time of starting antiretroviral therapy exhibited a better virological control and had a higher peripheral CD4 + T cell count . Therefore, balanced Treg/Th17 ratio seems crucial in determining the outcome of viral infections.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells and T helper 17 cells in viral infection

et al. 2020

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CD4 + T cells are the central element of the adaptive immune responses and protect the body from a variety of pathogens. Starting from naive cells, CD4 + T cells can differentiate into various effector cell subsets with specialized functions including T helper (Th) 1, Th2, Th17, regulatory T (Treg) and T follicular helper (Tfh) cells. Among them, Tregs and Th17 cells show a strong plasticity allowing the functional adaptation to various physiological and pathological environments during immune responses. Although they are derived from the same precursor cells and their differentiation pathways are interrelated, the terminally differentiated cells have totally opposite functions. Studies have shown that Tregs and Th17 cells have rather complex interplays in viral infection: Th17 cells may contribute to immune activation and disease progression while Tregs may inhibit this process and play a key role in the maintenance of immune homoeostasis, possibly at the cost of compromised viral control. In this review, we take respiratory syncytial virus (RSV), hepatitis B virus (HBV)/hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections as examples to discuss these interplays and their impacts on disease progression in viral infection. How to cite this article: Wan Z, Zhou Z, Liu Y, et al. Regulatory T cells and T helper 17 cells in viral infection. Scand J Immunol. 2020;91:e12873.

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Section: Discussionmentioning

confidence: 99%

Regulatory T cells and T helper 17 cells in viral infection

et al. 2020

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“…Of particular importance, in matched specimens from early ART-treated animals, systematic higher Treg frequencies and lower memory CCR6 + Th17 frequencies were observed in the MLNs compared to blood, which demonstrates clearly their differential dynamics in these tissues. A recent study showed that the later initiation of ARV treatment at 6 weeks postinfection was not able to recover the Th17/Treg ratio in the GALT during the acute SIV infection of RMs (57). The consistent increased frequencies of Tregs in MLNs could be linked to IDO-1 enzyme expression (4).…”

Section: Discussionmentioning

confidence: 99%

Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection

Yero

Farnós

Rabezanahary

et al. 2019

J Virol

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Increased frequencies of immunosuppressive regulatory T cells (Tregs) are associated with gut lymphoid tissue fibrosis and dysfunction which, in turn, contribute to disease progression in chronic simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. Mesenteric lymph nodes (MLNs), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. However, the dynamics of Tregs in MLNs are not well understood due to the lack of accessibility to these tissues in HIV-infected individuals. Here, the dynamics of Tregs in blood and MLNs were assessed in SIV-infected rhesus macaques (RMs) following early antiretroviral drug (ARV) initiation. Early ARV initiation reduced T-cell immune activation, as assessed by HLA-DR/CD39 expression, and prevented the depletion of memory CCR6+ Th17 cells in both blood and MLNs. Untreated animals showed higher frequencies of Tregs, CD39+ Tregs, thymic Tregs, and new memory CD4 populations sharing similarity with Tregs as CTLA4+ PD1– and CTLA4+ PD1– FoxP3+ T cells. Despite early ARV treatment, the frequencies of these Treg subsets remained unchanged within the MLNs and, in contrast to blood normalization, the Th17/Treg ratio remained distorted in MLNs. Furthermore, our results highlighted that the expressions of IDO-1, TGFβ1 and collagen-1 mRNA remained unchanged in MLN of ARV-treated RMs. ARV interruption did not affect T-cell immune activation and Th17/Treg ratios in MLN. Altogether, our data demonstrated that early ARV initiation within the first few days of SIV infection is unable to reduce the frequencies and homing of various subsets of Tregs within the MLNs which, in turn, may result in tissue fibrosis, impairment in MLN function, and HIV persistence. IMPORTANCE Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections.

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“…Blood was also collected 10 days post-boost (38 days post-prime) in the 50μg vaccinated animals. Serum and plasma were collected and PBMCs were isolated from whole blood as previously described ( 62 ). Animals were sedated with an intramuscular injection (10 mg/kg) of ketamine (Ketaset®; Henry Schein) prior to blood collection or vaccination.…”

Section: Methodsmentioning

confidence: 99%

An Alphavirus -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates

et al. 2020

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The COVID-19 pandemic, caused by infection with the SARS-CoV-2 coronavirus, is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale-up. Here, we developed an alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with Lipid InOrganic Nanoparticles (LION) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti-SARS-CoV-2 S protein IgG antibody isotypes indicative of a Type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in lung and spleen. Prime-only immunization of aged (17-month old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. Importantly, in nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in 5 intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.

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Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques

Cited by 11 publications

References 58 publications

Regulatory T cells and T helper 17 cells in viral infection

Regulatory T cells and T helper 17 cells in viral infection

Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection

An Alphavirus -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates

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