Lack of Interleukin-10-Mediated Anti-Inflammatory Signals and Upregulated Interferon Gamma Production Are Linked to Increased Intestinal Epithelial Cell Apoptosis in Pathogenic Simian Immunodeficiency Virus Infection

Pan, Diganta; Kenway-Lynch, Carys S.; Lala, Wendy; Veazey, Ronald S.; Lackner, Andrew A.; Das, Arpita; Pahar, Bapi

doi:10.1128/jvi.01757-14

Cited by 28 publications

(60 citation statements)

References 57 publications

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“…At least 20,000 events were collected by gating on lymphocytes. Data were acquired in a BD LSRII flow cytometer within 24 h after staining and analyzed further using FlowJo software (TreeStar Inc.) [5, 27]. Absolute count of CD4+ T-cell population was calculated using flow cytometry and CBC data.…”

Section: Methodsmentioning

confidence: 99%

Breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques

Pahar

Kenway-Lynch

Marx

et al. 2016

Virol J

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BackgroundIncreasing evidence suggests an unexpected potential for non-neutralizing antibodies to prevent HIV infection. Consequently, identification of functional linear B-cell epitopes for HIV are important for developing preventative and therapeutic strategies. We therefore explored the role of antigen-specific immune responses in controlling plasma viremia in SIV infected rhesus macaques.MethodsThirteen rhesus macaques were inoculated either intravaginally or intrarectally with SIVMAC251. Peripheral blood CD4+ T-cells were quantified. Plasma was examined for viremia, antigen specific IgG, IgA and IgM binding responses and neutralizing antibodies. Regions containing binding epitopes for antigen-specific IgG, IgM and IgA responses were determined, and the minimum size of linear Envelope epitope responsible for binding antibodies was identified.ResultsThe presence of neutralizing antibodies did not correlate the outcome of the disease. In a few SIV-infected macaques, antigen-specific IgG and IgM responses in plasma correlated with decreased plasma viremia. Early induction and the breadth of antigen-specific IgG responses were found to be significantly correlated with the control of plasma viral load. Immunoglobulin classes share similar functional linear B-cell epitopes. SIV-specific linear envelope B-cell epitopes were found to be 12 amino-acids in length.ConclusionsEarly induction of combination of peptide-specific IgG responses were found to be responsible for the control of plasma viral load and indicative of disease outcome in SIV-infected rhesus macaques and might be important for the development of therapeutic strategies for control or prevention of HIV/AIDS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0652-x) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques

Pahar

Kenway-Lynch

Marx

et al. 2016

Virol J

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“…This is reflected in a rapid increase in expression of the anti-inflammatory cytokines TGF-β and IL-10 following SIVagm infection of AGMs (Kornfeld et al, 2005). Furthermore, a recent study in RMs established a correlation with internalization of the IL-10 receptor (i.e., lowered responsiveness to IL-10) by mucosal lymphocytes in the gut epithelium with increased levels of apoptosis (Pan et al, 2014). …”

Section: Post-transmission Features That May Impact Siv Pathogenesmentioning

confidence: 99%

The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression

Raehtz

Pandrea

Apetrei

2016

Infection, Genetics and Evolution

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African NHPs are infected by over 40 different simian immunodeficiency viruses. These viruses have coevolved with their hosts for long periods of time and, unlike HIV in humans, infection does not generally lead to disease progression. Chronic viral replication is maintained for the natural lifespan of the host, without loss of overall immune function. Lack of disease progression is not correlated with transmission, as SIV infection is highly prevalent in many African NHP species in the wild. The exact mechanisms by which these natural hosts of SIV avoid disease progression are still unclear, but a number of factors might play a role, including: (i) avoidance of microbial translocation from the gut lumen by preventing or repairing damage to the gut epithelium; (ii) control of immune activation and apoptosis following infection; (iii) establishment of an anti-inflammatory response that resolves chronic inflammation; (iv) maintenance of homeostasis of various immune cell populations, including NK cells, monocytes/macrophages, dendritic cells, Tregs, Th17 T-cells, and γδ T-cells; (v) restriction of CCR5 availability at mucosal sites; (vi) preservation of T-cell function associated with down-regulation of CD4 receptor. Some of these mechanisms might also be involved in protection of natural hosts from mother-to-infant SIV transmission during breastfeeding. The difficulty of performing invasive studies in the wild has prohibited investigation of the exact events surrounding transmission in natural hosts. Increased understanding of the mechanisms of SIV transmission in natural hosts, and of the early events post-transmission which may contribute to avoidance of disease progression, along with better comprehension of the factors involved in protection from SIV breastfeeding transmission in the natural hosts, could prove invaluable for the development of new prevention strategies for HIV.

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“…Colon specimens, 8 cm in length were collected in ice-cold HBSS and were processed as described earlier [14-16]. Two to four mm 2 fragments of colon explants were cultured for 6h in 2ml RPMI-1640 containing BSA (0.01%), fungizone (1%), HEPES (25mM), and antibiotics (200 μg/ml streptomycin and 200 U/ml penicillin) in the presence of 5% CO 2 at 37°C [15, 16].…”

Section: Methodsmentioning

confidence: 99%

“…Two to four mm 2 fragments of colon explants were cultured for 6h in 2ml RPMI-1640 containing BSA (0.01%), fungizone (1%), HEPES (25mM), and antibiotics (200 μg/ml streptomycin and 200 U/ml penicillin) in the presence of 5% CO 2 at 37°C [15, 16]. Mucosal explants were treated with either anti-TGF-β1 MAbs (15μg/ml, R&D Systems, USA), rTGF-β1 protein (50ng/ml, R&D Systems) or isotype MAbs (isotype control, 15μg/ml, Biolegend, USA).…”

Section: Methodsmentioning

confidence: 99%

Transforming growth factor-β1 regulated phosphorylated AKT and interferon gamma expressions are associated with epithelial cell survival in rhesus macaque colon explants

Pahar

Pan

Lala

et al. 2015

Clinical Immunology

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Transforming growth factor-β1 (TGF-β1) is an important immunoregulatory cytokine that plays an obligate role in regulating T-cell functions. Here, we demonstrated the role of TGF-β1 in regulating the survival of intestinal epithelial cells (ECs) in rhesus colon explant cultures using either anti-TGF-β1 antibody or recombinant TGF-β1 proteins. Neutralization of endogenous TGF-β1 using anti-TGF-β1 antibodies induced apoptosis of both intestinal ECs and lamina propria (LP) cells. Additionally, endogenous TGF-β1 blocking significantly increased expression of IFNγ, TNFα, CD107a and Perforin in LP cells compared to media and isotype controls. A significant decrease in pAKT expression was detected in anti-TGF-β1 MAbs treated explants compared to isotype and rTGF-β1 protein treated explants. Our results demonstrated TGF-β1 regulated pAKT and IFNγ expressions were associated with epithelial cell survival in rhesus macaque colon explants and suggest a potential role of mucosal TGF-β1 in regulating intestinal homeostasis and EC integrity.

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Lack of Interleukin-10-Mediated Anti-Inflammatory Signals and Upregulated Interferon Gamma Production Are Linked to Increased Intestinal Epithelial Cell Apoptosis in Pathogenic Simian Immunodeficiency Virus Infection

Abstract: Interleukin-10 (IL-10) is an immunomodulatory cytokine that is important for maintenance of epithelial cell (EC) survival and anti-inflammatory responses (AIR).

Cited by 28 publications

References 57 publications

Breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques

Breadth and magnitude of antigen-specific antibody responses in the control of plasma viremia in simian immunodeficiency virus infected macaques

The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression

Transforming growth factor-β1 regulated phosphorylated AKT and interferon gamma expressions are associated with epithelial cell survival in rhesus macaque colon explants

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