Correction: Minimally invasive monitoring of CD4 T cells at multiple mucosal tissues after intranasal vaccination in rhesus macaques

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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Functional Impairment of Central Memory CD4 T Cells Is a Potential Early Prognostic Marker for Changing Viral Load in SHIV-Infected Rhesus Macaques

PLoS ONE ◽

10.1371/journal.pone.0019607 ◽

2011 ◽

Vol 6 (5) ◽

pp. e19607 ◽

Cited By ~ 10

Author(s):

Hong He ◽

Pramod N. Nehete ◽

Bharti Nehete ◽

Eric Wieder ◽

Guojun Yang ◽

...

Keyword(s):

T Cells ◽

Viral Load ◽

Prognostic Marker ◽

Functional Impairment ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

Central Memory ◽

Memory Cd4 T Cells

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Effects of exosome on the activation of CD4+ T cells in rhesus macaques: a potential application for HIV latency reactivation

Scientific Reports ◽

10.1038/s41598-017-15961-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 12

Author(s):

Xiaowu Hong ◽

Blake Schouest ◽

Huanbin Xu

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Potential Application ◽

Rhesus Macaques ◽

Hiv Latency

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Probiotic Supplementation Reduces Inflammatory Profiles But Does Not Prevent Oral Immune Perturbations During SIV Infection

10.1101/2020.12.17.423321 ◽

2020 ◽

Author(s):

Rhianna Jones ◽

Kyle Kroll ◽

Courtney Broedlow ◽

Luca Schifanella ◽

Scott Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Rhesus Macaques ◽

Oral Microbiome ◽

Probiotic Supplementation ◽

Siv Infection ◽

Anti Inflammatory

ABSTRACTHIV/SIV infections lead to massive loss of mucosal CD4+ T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (Pbx), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4+ T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although Pbx therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4+ T cell populations, and also suggest that oral Pbx could be a simple therapy to improve anti-inflammatory states in addition to more traditional antivirals.

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Mitigation of endemic GI-tract pathogen-mediated inflammation through development of multimodal treatment regimen and its impact on SIV acquisition in rhesus macaques

PLoS Pathogens ◽

10.1371/journal.ppat.1009565 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1009565

Author(s):

Rachele M. Bochart ◽

Kathleen Busman-Sahay ◽

Stephen Bondoc ◽

David W. Morrow ◽

Alexandra M. Ortiz ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Barrier Function ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

Mucosal Barrier ◽

Reproducible Research ◽

Axillary Lymph ◽

Ki 67 ◽

Mucosal Barrier Function

Here, we assessed the efficacy of a short-course multimodal therapy (enrofloxacin, azithromycin, fenbendazole, and paromomycin) to eliminate common macaque endemic pathogens (EPs) and evaluated its impact on gastrointestinal (GI) microbiota, mucosal integrity, and local and systemic inflammation in sixteen clinically healthy macaques. Treatment combined with expanded practices resulted in successful maintenance of rhesus macaques (RM) free of common EPs, with no evidence of overt microbiota diversity loss or dysbiosis and instead resulted in a more defined luminal microbiota across study subjects. Creation of a GI pathogen free (GPF) status resulted in improved colonic mucosal barrier function (histologically, reduced colonic MPO+, and reduced pan-bacterial 16s rRNA in the MLN), reduced local and systemic innate and adaptive inflammation with reduction of colonic Mx1 and pSTAT1, decreased intermediate (CD14+CD16+) and non-classical monocytes (CD14-CD16+), reduced populations of peripheral dendritic cells, Ki-67+ and CD38+ CD4+ T cells, Ki-67+IgG+, and Ki-67+IgD+ B cells indicating lower levels of background inflammation in the distal descending colon, draining mesenteric lymph nodes, and systemically in peripheral blood, spleen, and axillary lymph nodes. A more controlled rate of viral acquisition resulted when untreated and treated macaques were challenged by low dose intrarectal SIVmac239x, with an ~100 fold increase in dose required to infect 50% (AID50) of the animals receiving treatment compared to untreated controls. Reduction in and increased consistency of number of transmitted founder variants resulting from challenge seen in the proof of concept study directly correlated with post-treatment GPF animal’s improved barrier function and reduction of key target cell populations (Ki-67+ CD4+T cells) at the site of viral acquisition in the follow up study. These data demonstrate that a therapeutic and operational strategy can successfully eliminate varying background levels of EPs and their associated aberrant immunomodulatory effects within a captive macaque cohort, leading to a more consistent, better defined and reproducible research model.

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Mucosal T follicular helper cells in SIV-infected rhesus macaques: contributing role of IL-27

Mucosal Immunology ◽

10.1038/s41385-019-0174-0 ◽

2019 ◽

Vol 12 (4) ◽

pp. 1038-1054 ◽

Cited By ~ 2

Author(s):

Félicien Moukambi ◽

Henintsoa Rabezanahary ◽

Yasmina Fortier ◽

Vasco Rodrigues ◽

Julien Clain ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

T Follicular Helper Cells ◽

Mesenteric Lymph Nodes ◽

Tfh Cells ◽

Helper Cells ◽

Follicular Helper ◽

Memory Cd4 T Cells

AbstractMesenteric lymph nodes (MLNs), that drain the large and small intestine, are critical sites for the induction of oral tolerance. Although depletion of CD4 T cells in the intestinal lamina propria is a hallmark of HIV infection, CD4 T cell dynamics in MLNs is less known due to the lack of accessibility to these LNs. We demonstrate the early loss of memory CD4 T cells, including T follicular helper cells (Tfh) and a remodeling of MLN architecture in SIV-infected rhesus macaques (RMs). Along with the loss of Tfh cells, we observe the loss of memory B cells and of germinal center B cells. Tfh cells display a Th1 profile with increased levels of the transcription factors that negatively impact on Tfh differentiation and of Stat5 phosphorylation. MLNs of SIV-infected RMs display lower mRNA transcripts encoding for IL-12, IL-23, and IL-35, whereas those coding for IL-27 are not impaired in MLNs. In vitro, IL-27 negatively impacts on Tfh cells and recapitulates the profile observed in SIV-infected RMs. Therefore, early defects of memory CD4 T cells, as well of Tfh cells in MLNs, which play a central role in regulating the mucosal immune response, may have major implications for Aids.

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Induction of a virus-specific effector–memory CD4+ T cell response by attenuated SIV infection

Journal of Experimental Medicine ◽

10.1084/jem.20060134 ◽

2006 ◽

Vol 203 (12) ◽

pp. 2661-2672 ◽

Cited By ~ 50

Author(s):

Marie-Claire Gauduin ◽

Yi Yu ◽

Amy Barabasz ◽

Angela Carville ◽

Mike Piatak ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

High Frequency ◽

Cd4 T Cells ◽

Rhesus Macaques ◽

T Cell Response ◽

Cd4 T Cell ◽

Effector Memory ◽

Specific Effector

We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVΔnef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4–10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5–10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4+ cells from SIVΔnef animals were predominantly CD27−CD28−CD45RAlowCCR7−CCR5−, consistent with an effector–memory subset, and included a fully differentiated CD45RA+CCR7− subpopulation. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD27+CD28+CD45RA−CCR7+CCR5+, consistent with an early central memory phenotype. The CD45RA+CCR7−CD4+ subset from SIVΔnef animals was highly enriched for effector CD4+ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4+ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector–memory T cell population. The ability of SIVΔnef to induce a high frequency virus-specific CD4+ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.

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