scholarly journals Pegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection

2017 ◽  
Vol 13 (10) ◽  
pp. e1006692 ◽  
Author(s):  
Adam L. Bailey ◽  
Connor R. Buechler ◽  
Daniel R. Matson ◽  
Eric J. Peterson ◽  
Kevin G. Brunner ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Acute Phase ◽  
Immune Recognition ◽  
Macaque Model

scholarly journals Pegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection

2017 ◽  
Author(s):  
Adam L. Bailey ◽  
Connor R. Buechler ◽  
Daniel R. Matson ◽  
Eric J. Peterson ◽  
Kevin G. Brunner ◽  
...  
Keyword(s):  
Immune System ◽  
Hiv Infection ◽  
Protective Effect ◽  
Acute Phase ◽  
Human Population ◽  
Chronic Phase ◽  
Immune Recognition ◽  
Irreversible Damage ◽  
Macaque Model ◽  
High Prevalence

AbstractHuman pegivirus (HPgV) protects HIV+ people from HIV-associated disease, but the mechanism of this protective effect remains poorly understood. We sequentially infected cynomolgus macaques with simian pegivirus (SPgV) and simian immunodeficiency virus (SIV) to model HIV+HPgV co-infection. SPgV had no effect on acute-phase SIV pathogenesis – as measured by SIV viral load, CD4+ T cell destruction, and immune activation – suggesting that HPgV’s protective effect is exerted primarily during the chronic phase of HIV infection. We also examined the immune response to SPgV in unprecedented detail, and found that this virus elicits virtually no activation of the immune system despite persistently high titers in the blood over long periods of time. Overall, this study expands our understanding of the pegiviruses – an understudied group of viruses with a high prevalence in the global human population – and suggests that the protective effect observed in HIV+HPgV co-infected people occurs primarily during the chronic phase of HIV infection.One Sentence SummaryPegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection.Short TitlePegivirus and AIDS-virus co-infectionAccessible SummaryPeople infected with HIV live longer, healthier lives when they are co-infected with the human pegivirus (HPgV) – an understudied virus with a high prevalence in the global human population. To better understand how HPgV protects people with HIV from HIV-associated disease, we infected macaques with simian versions of these two viruses (SPgV and SIV). We found that SPgV had no impact on the incidence of SIV-associated disease early during the course of SIV infection – a time when SIV and HIV are known to cause irreversible damage to the immune system. Oddly, we found that the immune system did not recognize SPgV; a finding that warrants further investigation. Overall, this study greatly expands on our understanding of the pegiviruses and their interaction with the immune system.

scholarly journals SIV/Macaque Model of HIV Infection in Cocaine Users: Minimal Effects of Cocaine on Behavior, Virus Replication, and CNS Inflammation

2011 ◽  
Vol 7 (2) ◽  
pp. 401-411 ◽  
Author(s):  
Michael Weed ◽  
Robert J. Adams ◽  
Robert D. Hienz ◽  
Kelly A. Meulendyke ◽  
Michael E. Linde ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Virus Replication ◽  
Cns Inflammation ◽  
Macaque Model ◽  
Cocaine Users

scholarly journals HIV infection and drugs of abuse: role of acute phase proteins

2013 ◽  
Vol 10 (1) ◽  
Author(s):  
Thangavel Samikkannu ◽  
Kurapati VK Rao ◽  
Adriana Y Arias ◽  
Aarthi Kalaichezian ◽  
Vidya Sagar ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Acute Phase ◽  
Drugs Of Abuse ◽  
Acute Phase Proteins

scholarly journals Gene Editing of CCR5 in Hematopoietic Stem Cells in a Nonhuman Primate Model of HIV/AIDS

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4802-4802 ◽  
Author(s):  
Christopher W. Peterson ◽  
Jianbin Wang ◽  
Patricia Polacino ◽  
Michael C. Holmes ◽  
Shiu-Lok Hu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hiv Infection ◽  
Positive Selection ◽  
Functional Cure ◽  
Hematopoietic Stem ◽  
Macaque Model ◽  
Number Of Patients ◽  
Shiv Infection

Abstract Background: Hematopoietic stem cell (HSC) transplantation remains the only clinically observed path to functional cure of HIV infection. To better understand the mechanism of HSC-driven HIV control, and apply this therapy to a greater number of patients, we have developed a model of combination antiretroviral therapy (cART)-suppressed HIV infection in the pigtailed macaque, applicable to both gene therapy- and allogeneic transplant-based cure strategies. Following transplantation of HIV-resistant, autologous cells into conditioned animals, we are evaluating the extent to which protected cell progeny impede infection by SIV/HIV (SHIV) chimeric virus in vivo. Methods: Animals are challenged with SHIV virus containing an HIV envelope, after which a 3-drug cART regimen is initiated. Autologous HSCs are engineered to resist infection through targeted disruption of the CCR5 genetic locus using Zinc Finger Nucleases (ZFNs). Engraftment, persistence, and SHIV response of these autologous stem cells, and stem cell-derived lymphoid and myeloid cells, are measured in vivo. Results: SHIV infection in the pigtailed macaque model results in sustained viremia with consequent reduction in CD4+ T cells. Moreover, administration of three-drug cART leads to rapid and durable suppression of plasma viremia to <30 copies/mL plasma - suggesting that this model recapitulates key features of HIV infection and treatment in humans. CCR5 targeting experiments yield up to 60% gene disruption in CD34+ cells ex vivo, translating to approximately 5% disruption in vivo following transplant. Importantly, up to 10% of transplanted cells carry two disrupted alleles of CCR5; these cells should preferentially reconstitute CD4+ T-cell pools and other susceptible subsets following SHIV challenge. Consistent with this prediction, our preliminary data suggest that CCR5-deleted cells undergo positive selection following SHIV challenge in vivo. Conclusions: Our pigtailed macaque model of HIV infection and cART represents a promising platform for modeling functional cure strategies. Here we show that CCR5 deletion does not impair HSC engraftment or differentiation, and that CCR5-deleted cells can undergo SHIV-dependent positive selection even when present at low levels. Our model enables the evaluation of novel therapeutic approaches in the clinically relevant context of cART controlled SHIV infection - a setting of particular importance to approaches aimed at addressing the viral reservoir. Disclosures Wang: Sangamo Biosciences: Employment. Holmes:Sangamo Biosciences: Employment. Gregory:Sangamo Biosciences: Employment.

scholarly journals Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Toxicology ◽  
2016 ◽  
Vol 368-369 ◽  
pp. 10-18 ◽  
Author(s):  
Yat Yee Wong ◽  
Eva G. Rakasz ◽  
David J. Gasper ◽  
Thomas C. Friedrich ◽  
Lauren A. Trepanier
Keyword(s):  
Hiv Infection ◽  
Macaque Model

Resistance to Simian HIV Infection Is Associated With High Plasma Interleukin-8, RANTES and Eotaxin in a Macaque Model of Repeated Virus Challenges

2010 ◽  
Vol 53 (5) ◽  
pp. 574-581 ◽  
Author(s):  
Nattawan Promadej-Lanier ◽  
Debra L Hanson ◽  
Priya Srinivasan ◽  
Wei Luo ◽  
Debra R Adams ◽  
...  
Keyword(s):  
Hiv Infection ◽  
High Plasma ◽  
Interleukin 8 ◽  
Macaque Model

scholarly journals Sensing of HIV-1 Infection in Tzm-bl Cells with Reconstituted Expression of STING

2015 ◽  
Vol 90 (4) ◽  
pp. 2064-2076 ◽  
Author(s):  
Maud Trotard ◽  
Nikolaos Tsopoulidis ◽  
Nadine Tibroni ◽  
Joschka Willemsen ◽  
Marco Binder ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Cell Line ◽  
Nuclear Translocation ◽  
Innate Immune ◽  
Target Cells ◽  
Immune Recognition ◽  
Reporter Cell ◽  
Cytokine Mrna ◽  
Innate Recognition ◽  
Hiv 1

ABSTRACTProduction of proinflammatory cytokines indicative of potent recognition by the host innate immune system has long been recognized as a hallmark of the acute phase of HIV-1 infection. The first components of the machinery by which primary HIV target cells sense infection have recently been described; however, the mechanistic dissection of innate immune recognition and viral evasion would be facilitated by an easily accessible cell line model. Here we describe that reconstituted expression of the innate signaling adaptor STING enhanced the ability of the well-established HIV reporter cell line Tzm-bl to sense HIV infection and to convert this information into nuclear translocation of IRF3 as well as expression of cytokine mRNA. STING-dependent immune sensing of HIV-1 required virus entry and reverse transcription but not genome integration. Particularly efficient recognition was observed for an HIV-1 variant lacking expression of the accessory protein Vpr, suggesting a role of the viral protein in circumventing STING-mediated immune signaling. Vpr as well as STING significantly impacted the magnitude and breadth of the cytokine mRNA expression profile induced upon HIV-1 infection. However, cytoplasmic DNA sensing did not result in detectable cytokine secretion in this cell system, and innate immune recognition did not affect infection rates. Despite these deficits in eliciting antiviral effector functions, these results establish Tzm-bl STING and Tzm-bl STING IRF3.GFP cells as useful tools for studies aimed at dissecting mechanisms and regulation of early innate immune recognition of HIV infection.IMPORTANCECell-autonomous immune recognition of HIV infection was recently established as an important aspect by which the host immune system attempts to fend off HIV-1 infection. Mechanistic studies on host cell recognition and viral evasion are hampered by the resistance of many primary HIV target cells to detailed experimental manipulation. We describe here that expression of the signaling adaptor STING renders the well-established HIV reporter cell line Tzm-bl competent for innate recognition of HIV infection. Key characteristics reflected in this cell model include nuclear translocation of IRF3, expression of a broad range of cytokine mRNAs, and an antagonistic activity of the HIV-1 protein Vpr. These results establish Tzm-bl STING and Tzm-bl STING IRF3.GFP cells as a useful tool for studies of innate recognition of HIV infection.

scholarly journals Innate immune recognition and activation during HIV infection

Retrovirology ◽  
2010 ◽  
Vol 7 (1) ◽  
Author(s):  
Trine H Mogensen ◽  
Jesper Melchjorsen ◽  
Carsten S Larsen ◽  
Søren R Paludan
Keyword(s):  
Hiv Infection ◽  
Innate Immune ◽  
Immune Recognition

scholarly journals Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency ReversalEx Vivo

2018 ◽  
Vol 92 (12) ◽  
pp. e00235-18 ◽  
Author(s):  
Carolina Garrido ◽  
Maria Abad-Fernandez ◽  
Marina Tuyishime ◽  
Justin J. Pollara ◽  
Guido Ferrari ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Receptor Expression ◽  
Immune Recognition ◽  
Hiv Eradication ◽  
Infected Cells ◽  
Interleukin 15 ◽  
The Impact

ABSTRACTCurrent efforts toward human immunodeficiency virus (HIV) eradication include approaches to augment immune recognition and elimination of persistently infected cells following latency reversal. Natural killer (NK) cells, the main effectors of the innate immune system, recognize and clear targets using different mechanisms than CD8+T cells, offering an alternative or complementary approach for HIV clearance strategies. We assessed the impact of interleukin 15 (IL-15) treatment on NK cell function and the potential for stimulated NK cells to clear the HIV reservoir. We measured NK cell receptor expression, antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxicity, interferon gamma (IFN-γ) production, and antiviral activity in autologous HIV replication systems. All NK cell functions were uniformly improved by IL-15, and, more importantly, IL-15-treated NK cells were able to clear latently HIV-infected cells after exposure to vorinostat, a clinically relevant latency-reversing agent. We also demonstrate that NK cells from HIV-infected individuals aviremic on antiretroviral therapy can be efficiently stimulated with IL-15. Our work opens a promising line of investigation leading to future immunotherapies to clear persistent HIV infection using NK cells.IMPORTANCEIn the search for an HIV cure, strategies to enhance immune function to allow recognition and clearance of HIV-infected cells following latency reversal are being evaluated. Natural killer (NK) cells possess characteristics that can be exploited for immunotherapy against persistent HIV infection. We demonstrate that NK cells from HIV-positive donors can be strongly stimulated with IL-15, improving their antiviral and cytotoxic potential and, more importantly, clearing HIV-infected cells after latency reversal with a clinically relevant drug. Our results encourage further investigation to design NK cell-based immunotherapies to achieve HIV eradication.

Sign in / Sign up

Export Citation Format

Share Document