scholarly journals Simian Immunodeficiency Virus Infection Modulates CD94+ (KLRD1+) NK Cells in Rhesus Macaques

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Daniel R. Ram ◽  
Olivier Lucar ◽  
Brady Hueber ◽  
R. Keith Reeves
Keyword(s):  
Flow Cytometry ◽  
Nk Cells ◽  
Simian Immunodeficiency Virus ◽  
Crucial Role ◽  
Nonhuman Primates ◽  
Nk Cell ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Recently, we and others have shown that natural killer (NK) cells exhibit memory-like recall responses against cytomegalovirus (CMV) and human immunodeficiency/virus simian immunodeficiency virus (HIV/SIV) infections. Although the mechanism(s) have not been fully delineated, several groups have shown that the activating receptor NKG2C is elevated on NK cells in the context of rhesus CMV (rhCMV) or human CMV (hCMV) infections. CD94, which heterodimerizes with NKG2C is also linked to adaptive NK cell responses. Because nonhuman primates (NHP) play a crucial role in modeling HIV (SIV) infections, it is crucial to be able to assess and characterize the NKG2 family in NHP. Unfortunately, it is not possible to detect CD94 using commercially available antibodies in NHP. Our work, a first for NHP, has focused on developing RNA flow cytometry using mRNA transcripts as proxies distinguishing NKG2C from NKG2A. We have expanded the application of this technology and here we show the first characterization of CD94+ (KLRD1+) NK cells in NHP using multiparametric RNA flow cytometry. Peripheral blood mononuclear cells from naive and matched acutely (n = 4) or chronically (n = 12) SIV-infected rhesus macaques were analyzed by flow cytometry using commercially available antibodies, determining expression of transcripts for NKG2A, NKG2C, and CD94 (KLRC1, KLRC2, and KLRD1, respectively) on NK cells using RNA flow cytometry. Our data show that KLRC1+/− KLRC2+ KLRD1+ NK cells decrease following chronic, but not acute, infection with SIV. This approach will allow us to investigate the kinetics of infection and NK memory formation and will further improve our understanding of basic NK cell biology, especially in the context of SIV infection. IMPORTANCE Nonhuman primates play a crucial role in approximating human biology and many diseases that are difficult, if not impossible, to achieve in other animal models, notably HIV. Current advances in adaptive NK cell research positions us to address fundamental deficiencies in our fight against infection and disease at the earliest moments after infection or substantially earlier in disease progression. We show here that we can identify specific NK cell subpopulations that are modulated following chronic, but not acute, SIV infection. The ability to identify these subsets more precisely will inform therapeutic and vaccine strategies targeting an optimized NK cell response.

scholarly journals Accumulation of Cytotoxic CD16+NK Cells in Simian Immunodeficiency Virus-Infected Lymph Nodes Associated withIn SituDifferentiation and Functional Anergy

2015 ◽  
Vol 89 (13) ◽  
pp. 6887-6894 ◽  
Author(s):  
Jamie L. Schafer ◽  
Haiying Li ◽  
Tristan I. Evans ◽  
Jacob D. Estes ◽  
R. Keith Reeves
Keyword(s):  
Lymph Nodes ◽  
Nk Cells ◽  
Simian Immunodeficiency Virus ◽  
Nk Cell ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
K562 Cells ◽  
Viral Reservoir ◽  
Immunodeficiency Virus

ABSTRACTRecent evidence suggests that even in treated infections, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication may continue in lymph nodes (LN), serving as a potential virus reservoir. Here we investigated the effects of lentivirus infection on natural killer (NK) cell frequencies, phenotypes, and functions in naive and acutely or chronically SIVmac239-infected rhesus macaques. Compared to that in naive animals, we observed a 3-fold-greater frequency of cytotoxic CD16+CD56−NK cells in LN of chronically infected macaques. However, NK cells did not appear to be trafficking to LN, as homing markers CD62L and CCR7 did not increase on circulating NK cells during infection. LN NK cells demonstrated enhanced cytotoxicity in acute infection, with 2-fold increases in perforin expression and 3-fold increases in CD107a expression following mitogen stimulation. Lysis of K562 cells by LN NK cells from acutely infected animals was greater than lysis by preinfection samples from the same animals. LN NK cells from chronically infected animals lysed K562 cells more efficiently than LN NK cells from uninfected animals, but importantly, surrogate markers of cytotoxicity in infected macaques were disproportionately greater thanex vivokilling. Furthermore, Tim-3, an indicator of activation and/or exhaustion, was upregulated 3-fold on LN NK cells in chronically infected animals. Collectively, these data suggest that LN NK cells are skewed toward a cytotoxic phenotype during SIV infection but may become dysfunctional and exhausted in chronic disease.IMPORTANCEThe accumulation of CD16+CD56−NK cells in the SIV-infected lymph node without changes in NK homing to the LN could suggest that these cells are differentiatingin situ. Surprisingly, this increase in frequency of the cytotoxic subset of NK cells is not accompanied by an increase of similar magnitude in the cytolytic function of LN lymphocytes. This functional modulation, together with the higher Tim-3 expression observed on LN NK cells isolated from chronically infected animals than on those from naive macaques, is indicative of an exhausted phenotype. This exhaustion could contribute to the robust replication of HIV and SIV in the LN during acute and chronic stages of infection, allowing the survival of infected cells and maintenance of a viral reservoir.

scholarly journals Downregulation of Robust Acute Type I Interferon Responses Distinguishes Nonpathogenic Simian Immunodeficiency Virus (SIV) Infection of Natural Hosts from Pathogenic SIV Infection of Rhesus Macaques

2010 ◽  
Vol 84 (15) ◽  
pp. 7886-7891 ◽  
Author(s):  
Levelle D. Harris ◽  
Brian Tabb ◽  
Donald L. Sodora ◽  
Mirko Paiardini ◽  
Nichole R. Klatt ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Type I ◽  
Acute Type ◽  
Type I Ifn ◽  
Immunodeficiency Virus ◽  
Natural Hosts ◽  
Siv Infection

ABSTRACT The mechanisms underlying the AIDS resistance of natural hosts for simian immunodeficiency virus (SIV) remain unknown. Recently, it was proposed that natural SIV hosts avoid disease because their plasmacytoid dendritic cells (pDCs) are intrinsically unable to produce alpha interferon (IFN-α) in response to SIV RNA stimulation. However, here we show that (i) acute SIV infections of natural hosts are associated with a rapid and robust type I IFN response in vivo, (ii) pDCs are the principal in vivo producers of IFN-α/β at peak acute infection in lymphatic tissues, and (iii) natural SIV hosts downregulate these responses in early chronic infection. In contrast, persistently high type I IFN responses are observed during pathogenic SIV infection of rhesus macaques.

scholarly journals Enteric Ganglionitis in Rhesus Macaques Infected with Simian Immunodeficiency Virus

2007 ◽  
Vol 81 (12) ◽  
pp. 6265-6275 ◽  
Author(s):  
Marlene S. Orandle ◽  
Ronald S. Veazey ◽  
Andrew A. Lackner
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Inflammatory Cells ◽  
Acute Stage ◽  
Infected People ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Double Label ◽  
Myenteric Ganglia

ABSTRACT Gastrointestinal (GI) disease is a debilitating feature of human immunodeficiency virus (HIV) infection that can occur in the absence of histopathological abnormalities or identifiable enteropathogens. However, the mechanisms of GI dysfunction are poorly understood. The present study was undertaken to characterize changes in resident and inflammatory cells in the enteric nervous system (ENS) of macaques during the acute stage of simian immunodeficiency virus (SIV) infection to gain insight into potential pathogenic mechanisms of GI disease. Ganglia from duodenum, ileum, and colon were examined in healthy and acutely infected macaques by using a combination of routine histology, double-label immunofluorescence and in situ hybridization. Evaluation of tissues from infected macaques showed progressive infiltration of myenteric ganglia by CD3+ T cells and IBA1+ macrophages beginning as early as 8 days postinfection. Quantitative image analysis revealed that the severity of myenteric ganglionitis increased with time after SIV infection and, in general, was more severe in ganglia from the small intestine than in ganglia from the colon. Despite an abundance of inflammatory cells in myenteric ganglia during acute infection, the ENS was not a target for virus infection. This study provides evidence that the ENS may be playing a role in the pathogenesis of GI disease and enteropathy in HIV-infected people.

scholarly journals Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys

2007 ◽  
Vol 81 (9) ◽  
pp. 4445-4456 ◽  
Author(s):  
L. E. Pereira ◽  
F. Villinger ◽  
N. Onlamoon ◽  
P. Bryan ◽  
A. Cardona ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
T Cell Response ◽  
Immunodeficiency Virus ◽  
Sooty Mangabeys ◽  
Siv Infection

ABSTRACT Differences in clinical outcome of simian immunodeficiency virus (SIV) infection in disease-resistant African sooty mangabeys (SM) and disease-susceptible Asian rhesus macaques (RM) prompted us to examine the role of regulatory T cells (Tregs) in these two animal models. Results from a cross-sectional study revealed maintenance of the frequency and absolute number of peripheral Tregs in chronically SIV-infected SM while a significant loss occurred in chronically SIV-infected RM compared to uninfected animals. A longitudinal study of experimentally SIV-infected animals revealed a transient increase in the frequency of Tregs from baseline values following acute infection in RM, but no change in the frequency of Tregs occurred in SM during this period. Further examination revealed a strong correlation between plasma viral load (VL) and the level of Tregs in SIV-infected RM but not SM. A correlation was also noted in SIV-infected RM that control VL spontaneously or in response to antiretroviral chemotherapy. In addition, immunofluorescent cell count assays showed that while Treg-depleted peripheral blood mononuclear cells from RM led to a significant enhancement of CD4+ and CD8+ T-cell responses to select pools of SIV peptides, there was no detectable T-cell response to the same pool of SIV peptides in Treg-depleted cells from SIV-infected SM. Our data collectively suggest that while Tregs do appear to play a role in the control of viremia and the magnitude of the SIV-specific immune response in RM, their role in disease resistance in SM remains unclear.

scholarly journals Simian Immunodeficiency Virus Infection Induces Expansion of α4β7+ and Cytotoxic CD56+ NK Cells

2010 ◽  
Vol 84 (17) ◽  
pp. 8959-8963 ◽  
Author(s):  
R. Keith Reeves ◽  
Tristan I. Evans ◽  
Jacqueline Gillis ◽  
R. Paul Johnson
Keyword(s):  
Nk Cells ◽  
Simian Immunodeficiency Virus ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Dual Function ◽  
Cd107a Expression ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Ifn Γ

ABSTRACT Herein we demonstrate that chronic simian immunodeficiency virus (SIV) infection induces significant upregulation of the gut-homing marker α4β7 on macaque NK cells, coupled with downregulation of the lymph node-trafficking marker, CCR7. Interestingly, in naïve animals, α4β7 expression was associated with increased NK cell activation and, on CD16+ NK cells, delineated a unique dual-function cytotoxic-CD107a+/gamma interferon (IFN-γ)-secreting population. However, while SIV infection increased CD107a expression on stimulated CD56+ NK cells, α4β7+ and α4β7− NK cells were affected similarly. These findings suggest that SIV infection redirects NK cells away from the lymph nodes to the gut mucosae but alters NK cell function independent of trafficking repertoires.

scholarly journals Heightened Cytotoxic Responses and Impaired Biogenesis Contribute to Early Pathogenesis in the Oral Mucosa of Simian Immunodeficiency Virus-Infected Rhesus Macaques

2008 ◽  
Vol 16 (2) ◽  
pp. 277-281 ◽  
Author(s):  
Michael D. George ◽  
David Verhoeven ◽  
Sumathi Sankaran ◽  
Tiffany Glavan ◽  
Elizabeth Reay ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Oral Mucosa ◽  
Gene Transcription ◽  
Nk Cell ◽  
Rhesus Macaques ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Cytotoxic Responses ◽  
Intravenous Inoculation

ABSTRACT Simian immunodeficiency virus (SIV) infection disseminated into the oropharyngeal tissues of rhesus macaques 6 weeks following intravenous inoculation. Severe local CD4+ T-cell depletion coincided with increases in NK cell and proinflammatory biomarkers and the disruption of growth-associated gene transcription, demonstrating the rapid establishment of pathogenesis in the oral mucosa.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals Perforin Expression in the Gastrointestinal Mucosa Is Limited to Acute Simian Immunodeficiency Virus Infection

2006 ◽  
Vol 80 (6) ◽  
pp. 3083-3087 ◽  
Author(s):  
Máire F. Quigley ◽  
Kristina Abel ◽  
Bartek Zuber ◽  
Christopher J. Miller ◽  
Johan K. Sandberg ◽  
...  
Keyword(s):  
T Cells ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Positive Response ◽  
Rhesus Macaques ◽  
Gastrointestinal Mucosa ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Perforin Expression ◽  
Important Site

ABSTRACT Perforin-mediated cytotoxicity is a major effector function of virus-specific CD8 T cells. We have investigated the expression of perforin in the gut, an important site of simian immunodeficiency virus (SIV) pathogenesis, during experimental SIV infection of rhesus macaques. We observed significant increases in perforin protein and mRNA expression levels in the colons of SIV-infected macaques as early as 21 days after infection. However, during chronic infection, despite ongoing viral replication, perforin expression returned to levels similar to those detected in SIV-naïve animals. These findings demonstrate the presence of a robust perforin-positive response in gastrointestinal CD8 T cells during acute, but not chronic, SIV infection.

scholarly journals Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

2012 ◽  
Vol 86 (16) ◽  
pp. 8835-8847 ◽  
Author(s):  
Fan Wu ◽  
Ilnour Ourmanov ◽  
Takeo Kuwata ◽  
Robert Goeken ◽  
Charles R. Brown ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Lavage Fluid ◽  
Vaccine Protection ◽  
Immunodeficiency Virus ◽  
Siv Infection ◽  
Intravenous Inoculation

Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4+T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

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