SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans

Abstract The host immune system is profoundly affected during the acute phase of progressive immunodeficiency lentiviral infections. Studies of these alterations have been quite restricted in humans because of the limited availability of samples from acutely HIV-infected persons. Therefore, numerous studies have turned attention to nonhuman primate models. Specifically, SIV-infected rhesus macaques (RMs) have been informative for understanding the pathogenesis of HIV infection in humans. Indeed, advantages of the nonhuman primate model include the ability to study the very early events after infection and the ability to retrieve copious amounts of tissues. In addition, nonhuman primates allow for comparative studies between non-natural and natural hosts for SIV, in which SIV infection results in progression, or not, to AIDS, respectively. Although SIV infection of RM is the best model for HIV infection, the immunologic and/or virologic phenomena in SIV-infected RM do not always reflect those seen in HIV-infected humans. Here virologic and immunologic aspects of acute HIV infection of humans and SIV infection of Asian and African nonhuman primates are discussed and compared in relation to how these aspects relate to disease progression.

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Faculty Opinions recommendation of Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718499019.793501303 ◽

2014 ◽

Author(s):

Allan Zajac

Keyword(s):

Disease Progression ◽

Type I Interferon ◽

Rhesus Macaques ◽

Type I ◽

Slow Disease Progression ◽

Siv Infection ◽

Interferon Responses

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

Cells ◽

10.3390/cells10040806 ◽

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.

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Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

Scientific Reports ◽

10.1038/s41598-021-93918-x ◽

2021 ◽

Vol 11 (1) ◽

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 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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Brain tissue transcriptomic analysis of SIV-infected macaques identifies several altered metabolic pathways linked to neuropathogenesis and poly (ADP-ribose) polymerases (PARPs) as potential therapeutic targets

Journal of NeuroVirology ◽

10.1007/s13365-020-00927-z ◽

2021 ◽

Author(s):

Carla Mavian ◽

Andrea S. Ramirez-Mata ◽

James Jarad Dollar ◽

David J. Nolan ◽

Melanie Cash ◽

...

Keyword(s):

Frontal Cortex ◽

Rhesus Macaques ◽

Lymphocyte Depletion ◽

Brain Infection ◽

Immunodeficiency Virus ◽

Significant Enrichment ◽

Siv Infection ◽

Polymerase Chain

Abstract Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals’ quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.

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Identification of MHC class I sequences in Chinese-origin rhesus macaques

Immunogenetics ◽

10.1007/s00251-007-0267-x ◽

2007 ◽

Vol 60 (1) ◽

pp. 37-46 ◽

Cited By ~ 70

Author(s):

Julie A. Karl ◽

Roger W. Wiseman ◽

Kevin J. Campbell ◽

Alex J. Blasky ◽

Austin L. Hughes ◽

...

Keyword(s):

Mhc Class I ◽

Rhesus Macaques ◽

Class I ◽

Chinese Origin

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Passive Immunization of Rhesus Macaques against SIV Infection and Disease

AIDS Research and Human Retroviruses ◽

10.1089/aid.1995.11.843 ◽

1995 ◽

Vol 11 (7) ◽

pp. 843-854 ◽

Cited By ~ 44

Author(s):

MURRAY GARDNER ◽

ANN ROSENTHAL ◽

MYRA JENNINGS ◽

JOANN YEE ◽

LINDA ANTIPA ◽

...

Keyword(s):

Rhesus Macaques ◽

Passive Immunization ◽

Siv Infection

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Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.01715-08 ◽

2008 ◽

Vol 83 (2) ◽

pp. 572-583 ◽

Cited By ~ 49

Author(s):

Mareike Meythaler ◽

Amanda Martinot ◽

Zichun Wang ◽

Sarah Pryputniewicz ◽

Melissa Kasheta ◽

...

Keyword(s):

Immune Response ◽

T Lymphocytes ◽

T Lymphocyte ◽

Immune Activation ◽

Rhesus Macaques ◽

Lymphocyte Apoptosis ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

Siv Infection ◽

Species Specific

ABSTRACT In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection.

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Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment

Retrovirology ◽

10.1186/s12977-018-0400-y ◽

2018 ◽

Vol 15 (1) ◽

Cited By ~ 1

Author(s):

Stephanie J. Bissel ◽

Kate Gurnsey ◽

Hank P. Jedema ◽

Nicholas F. Smith ◽

Guoji Wang ◽

...

Keyword(s):

Cognitive Impairment ◽

Rhesus Macaques ◽

Clinical Disease ◽

Chinese Origin

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

Journal of Virology ◽

10.1128/jvi.80.6.3083-3087.2006 ◽

2006 ◽

Vol 80 (6) ◽

pp. 3083-3087 ◽

Cited By ~ 21

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.

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