Life Sciences Commons^™

Increased Interactions And Engulfment Of Dendrites By Microglia Precede Purkinje Cell Degeneration In A Mouse Model Of Niemann Pick Type-C., Larisa Kavetsky, Kayla K Green, Bridget R Boyle, Fawad A K Yousufzai, Zachary M Padron, Sierra E Melli, Victoria L Kuhnel, Harriet M Jackson, Rosa E Blanco, Gareth R Howell, Ileana Soto Reyes

Ileana Soto Reyes

Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1nmf164 mouse cerebellum, microglia …

Meox2 Haploinsufficiency Increases Neuronal Cell Loss In A Mouse Model Of Alzheimer's Disease, Ileana Soto Reyes, Weronika A. Grabowska, Kristen D. Onos, Leah C. Graham, Harriet M. Jackson, Stephen N. Simeone, Gareth R. Howell

Ileana Soto Reyes

Evidence suggests that multiple genetic and environmental factors conspire together to increase susceptibility to Alzheimer's disease (AD). The amyloid cascade hypothesis states that deposition of the amyloid-β (Aβ) peptide is central to AD; however, evidence in humans and animals suggests that Aβ buildup alone is not sufficient to cause neuronal cell loss and cognitive decline. Mouse models that express high levels of mutant forms of amyloid precursor protein and/or cleaving enzymes deposit amyloid but do not show neuron loss. Therefore, a double-hit hypothesis for AD has been proposed whereby vascular dysfunction precedes and promotes Aβ toxicity. In support of this, …

Deficiency Of Complement Component 5 Ameliorates Glaucoma In Dba/2j Mice, Gareth R. Howell, Ileana Soto Reyes, Margaret Ryan, Leah C. Graham, Richard S. Smith, Simon W.M. John

Ileana Soto Reyes

Background Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including …

Chronic Consumption Of A Western Diet Induces Robust Glial Activation In Aging Mice And In A Mouse Model Of Alzheimer’S Disease, Leah C. Graham, Jeffrey M. Harder, Ileana Soto Reyes, Wilhelmine N. De Vries, Simon W. M. John, Gareth R. Howell

Ileana Soto Reyes

Studies have assessed individual components of a western diet, but no study has assessed the long-term, cumulative effects of a western diet on aging and Alzheimer’s disease (AD). Therefore, we have formulated the first western-style diet that mimics the fat, carbohydrate, protein, vitamin and mineral levels of western diets. This diet was fed to aging C57BL/6J (B6) mice to identify phenotypes that may increase susceptibility to AD, and to APP/PS1 mice, a mouse model of AD, to determine the effects of the diet in AD. Astrocytosis and microglia/monocyte activation were dramatically increased in response to diet and was further increased …

Dba/2j Mice Are Susceptible To Diabetic Nephropathy And Diabetic Exacerbation Of Iop Elevation, Ileana Soto Reyes, Gareth R. Howell, Cai W. John, Joseph L. Kief, Richard T. Libby, Simon W.M. John

Ileana Soto Reyes

Some pathological manifestations of diabetes in the eye include retinopathy, cataracts and elevated intraocular pressure (IOP). Loss of retinal ganglion cells (RGCs) in non-proliferative stages of diabetic retinopathy and small increases in IOP in diabetic patients has raised the possibility that diabetes affects the development and progression of ocular hypertension and glaucoma. The Ins2Akita mutation is known to cause diabetes and retinopathy on a C57BL/6J (B6) background by as early as 3 months of age. Here, the impact of the Akita mutation on glaucoma was assessed using DBA/2J (D2) mice, a widely used mouse model of ocular hypertension induced glaucoma. …

Apoe Stabilization By Exercise Prevents Aging Neurovascular Dysfunction And Complement Induction, Ileana Soto Reyes, Leah C. Graham, Hannah J. Richter, Stephen N. Simeone, Jake E. Radell, Weronika Grabowska, W. Keith Funkhouser, Megan C. Howell, Gareth R. Howell

Ileana Soto Reyes

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, …

Meox2 Haploinsufficiency Accelerates Axonal Degeneration In Dba/2j Glaucoma, Rebecca A Buchanan, Kate E Foley, Keating W Pepper, Alaina M Reagan, Kelly J Keezer, Amanda A Hewes, Cory A Diemler, Christoph Preuss, Ileana Soto Reyes, Simon W M John, Gareth R Howell

Ileana Soto Reyes

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma. Here, we use these data to identify and test regulators of early gene expression changes in DBA/2J glaucoma.

Methods: Upstream regulator analysis (URA) in Ingenuity Pathway Analysis was performed to identify potential master regulators of differentially expressed genes. The function of one putative regulator, mesenchyme homeobox 2 (Meox2), was tested using a combination of …

Enhancing Face Validity Of Mouse Models Of Alzheimer's Disease With Natural Genetic Variation., Kristen D Onos, Asli Uyar, Kelly J Keezer, Harriet M Jackson, Christoph Preuss, Casey J Acklin, Rita O'Rourke, Rebecca Buchanan, Travis L Cossette, Stacey J Sukoff Rizzo, Ileana Soto Reyes, Gregory W Carter, Gareth R Howell

Ileana Soto Reyes

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were …

Testimoni Manfaat Minyak Bulus Untuk Wajah Memutihkan Dengan Harga Yang Murah, Ripan Maki

ripan maki

The Economic Impacts Of Blackbird (Icteridae) Damage To Sunflower In The Usa, Karina Ernst, Julie Elser, George Linz, Hans Kandel, Jason Holderieath, Samantha Degroot, Steven Shwiff, Stephanie Shwiff

Jason Holderieath

BACKGROUND: Blackbird (Icteridae) damage to ripening sunflower (Helianthus annuus L.) has been a persistent economic issue in the USA for the last five decades. To quantify losses, we surveyed blackbird damage from 2001 to 2013 (excluding 2004) to physiologically mature sunflower in eight states: North Dakota, South Dakota, Texas, Nebraska, Minnesota, Colorado, Kansas, and Vermont.

RESULTS:We pooled data gathered during the most recent 5 years (2009 to 2013) of the survey and found losses averaged $US2.5 million and $US11.3 million for confectionery and oilseed hybrids, respectively. Three states, North Dakota, South Dakota, and Nebraska, had sufficient acreage and bird damage …

A Belmont Report For Animals?, Hope Ferdowsian, L. Syd M. Johnson, Jane Johnson, Andrew Fenton, Adam Shriver, John Gluck

John P. Gluck, PhD

Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, …

The Land Of Meat And Potatoes? Exploring Ireland’S Vegan And Vegetarian Foodscape, Corey Lee Wrenn

Corey Lee Wrenn, PhD

While it would not be accurate to suggest that Ireland is a hub of veganism or vegetarianism, too often it is written off as inherently unsympathetic to the ethics of plant-based eating and anti-speciesist politics. While it is true that Irish culture is historically tied to speciesism and its economy is especially dependent upon “meat” and dairy production, Ireland’s relationship with other animals is complex and sometimes forgiving. This essay seeks to bring shape to the Irish vegan ethic, one that can be traced along its history of animism, agrarianism, ascendency, adaptation, and activism. From its pagan roots to its …

The Question Of Animal Awareness, Francoise Wemelsfelder

Françoise Wemelsfelder, PhD

The problem of animal awareness lies at the interface of science and philosophy. As a starting point for the study of phenomena such as awareness, mind, consciousness, etc., we hardly have any reference other than our own human experience and in the context of a nondualistic ontology this can be justified. In philosophy and psychology it appears to be very difficult to give direct operational definitions of terms such as consciousness, etc. So we might expect this to be even more difficult in the study of animals. A detailed knowledge of animals and their behaviour is necessary in order to …

Animal Boredom: Is A Scientific Study Of The Subjective Experiences Of Animals Possible?, Françoise Wemelsfelder

Françoise Wemelsfelder, PhD

The aim of this paper is to explore the relationship between different meta-scientific frameworks and the science of animal welfare. Animal Boredom 117 During the past few years, I have become more and more convinced that the great difficulty science has in studying subjective experience in its objects, might be related to the denial of any role to subjective experience in the observer as an interpretational guide. Can a quality in the world around us be observed, when this same quality is deliberately excluded from the process of observing?

As a practical example for the discussion described above, the phenomenon …

Incorporating New Technologies Into Toxicity Testing And Risk Assessment: Moving From 21st Century Vision To A Data-Driven Framework, Russell S. Thomas, Martin A. Philbert, Scott Auerbach, Barbara A. Wetmore, Michael J. Devito, Ila Cote, J. Craig Rowlands, Maurice Whelan, Sean M. Hays, Melvin E. Andersen, M.E. (Bette) Meek, Lawrence W. Reiter, Jason C. Lambert, Harvey J. Clewell Iii, Martin L. Stephens, Q. Jay Zhao, Scott C. Wesselkamper, Lynn Flowers, Edward W. Carney, Tim P. Pastoor, Dan D. Petersen, Carole L. Yauk, Andy Nong

Martin Stephens, PhD

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions …

Evidence-Based Toxicology For The 21st Century: Opportunities And Challenges, Martin L. Stephens, Melvin E. Andersen, Richard A. Becker, Kellyn Betts, Kim Boekelheide, Ed Carney, Robert Chapin, Dennis Devlin, Suzanne C. Fitzpatrick, John R. Fowle Iii, Patricia Harlow, Thomas Hartung, Sebastian Hoffman, Michael P. Holsapple, Abigail Jacobs, Richard Judson, Olga Naidenko, Tim Pastoor, Grace Patlewicz, Andrew Rowan, Roberta Scherer, Rashid Shaikh, Ted Simon, Douglas Wolf, Joanne Zurlo

Martin Stephens, PhD

The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on “Evidence-based Toxicology for the 21st Century: Opportunities and Challenges” in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathwaybased testing methods consistent with the 2007 National Research Council report on “Toxicity Testing in the 21st Century” as well as to adopt a governance structure and work processes to move that …

Beyond The 3rs: Expanding The Use Of Human-Relevant Replacement Methods In Biomedical Research, Kathrin Herrmann, Francesca Pistollato, Martin L. Stephens

Martin Stephens, PhD

This year marks the 60th anniversary of Russell and Burch’s pioneering book, The Principles of Humane Experimental Technique. Their 3Rs framework has helped to inspire humane and scientific progress in experimental technique. However, it is time to update its strategic application. The 21st century has already seen the development of promising, high-tech non-animal models, such as organs-on-a-chip and computational approaches that, in our view, will replace animals as the default option in biomedical experimentation. How fast this transition will take place will depend on the pace at which these new models are optimized to reflect the biology of humans, rather …

Adaptation Of The Systematic Review Framework To The Assessment Of Toxicological Test Methods: Challenges And Lessons Learned With The Zebrafish Embryotoxicity Test, Martin L. Stephens, Sevcan Gül Akgün-Ölmez, Sebastian Hoffman, Rob De Vries, Burkhard Flick, Thomas Hartung, Manoj Lalu, Alexandra Maertens, Hilda Witters, Robert Wright, Katya Tsaioun

Martin Stephens, PhD

Systematic review methodology is a means of addressing specific questions through structured, consistent, and transparent examinations of the relevant scientific evidence. This methodology has been used to advantage in clinical medicine, and is being adapted for use in other disciplines. Although some applications to toxicology have been explored, especially for hazard identification, the present preparatory study is, to our knowledge, the first attempt to adapt it to the assessment of toxicological test methods. As our test case, we chose the zebrafish embryotoxicity test (ZET) for developmental toxicity and its mammalian counterpart, the standard mammalian prenatal development toxicity study, focusing the …

Accelerating The Development Of 21st-Century Toxicology: Outcome Of A Human Toxicology Project Consortium Workshop, Martin L. Stephens, Craig Barrow, Melvin E. Andersen, Kim Boekelheide, Paul L. Carmichael, Michael P. Holsapple, Mark Lafranconi

Martin Stephens, PhD

The U.S. National Research Council (NRC) report on “Toxicity Testing in the 21st century” calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to “toxicity pathways,” i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report’s implementation, the Human Toxicology Project Consortium hosted a workshop on 9–10 November 2010 in Washington, …

United States Midwest Soil And Weather Conditions Influence Anaerobic Potentially Mineralizable Nitrogen, Jason D. Clark, Kristen S. Veum, Fabian G. Fernandez, James J. Camberato, Paul R. Carter, Richard B. Ferguson, David W. Franzen, Daniel E. Kaiser, Newell R. Kitchen, Carrie A.M. Laboski, Emerson D. Nafziger, John E. Sawyer, John F. Shanahan

Jason Clark

Nitrogen provided to crops through mineralization is an important factor in N management guidelines. Understanding of the interactive effects of soil and weather conditions on N mineralization needs to be improved. Relationships between anaerobic potentially mineralizable N (PMN_an) and soil and weather conditions were evaluated under the contrasting climates of eight US Midwestern states. Soil was sampled (0–30 cm) for PMN_an analysis before pre-plant N application (PP_0N) and at the V5 development stage from the pre-plant 0 (V5_0N) and 180 kg N ha⁻¹ (V5_180N) rates and incubated for 7, 14, …

Predicting Economic Optimal Nitrogen Rate With The Anaerobic Potentially Mineralizable Nitrogen Test, Jason D. Clark, Fabian G. Fernandez, Kristen S. Veum, James J. Camberato, Paul R. Carter, Richard B. Ferguson, David W. Franzen, Daniel E. Kaiser, Newell R. Kitchen, Carrie A.M. Laboski, Emerson D. Nafziger, Carl J. Rosen, John E. Sawyer, John F. Shanahan

Jason Clark

Estimates of mineralizable N with the anaerobic potentially mineralizable N (PMN_an) test could improve predictions of corn (Zea mays L.) economic optimal N rate (EONR). A study across eight US midwestern states was conducted to quantify the predictability of EONR for single and split N applications by PMN_an. Treatment factors included different soil sample timings (pre-plant and V5 development stage), planting N rates (0 and 180 kg N ha⁻¹), and incubation lengths (7, 14, and 28 d) with and without initial soil NH₄–N included with PMN_an. Soil was sampled …

A Public–Industry Partnership For Enhancing Corn Nitrogen Research And Datasets: Project Description, Methodology, And Outcomes, Newell R. Kitchen, John F. Shanahan, Curtis J. Ransom, Christopher J. Bandura, Gregory M. Bean, James J. Camberato, Paul R. Carter, Jason D. Clark, Richard B. Ferguson, Fabian G. Fernandez, David W. Franzen, Carrie A.M. Laboski, Emerson D. Nafziger, Zhisheng Qing, John E. Sawyer, Matt Shafer

Jason Clark

Due to economic and environmental consequences of N lost from fertilizer applications in corn (Zea mays L.), considerable public and industry attention has been devoted to the development of N decision tools. Needed are research and databases and associated metadata, at numerous locations and years to represent a wide geographic range of soil and weather scenarios, for evaluating tool performance. The goals of this research were to conduct standardized corn N rate response field studies to evaluate the performance of multiple public-domain N decision tools across diverse soils and environmental conditions, develop and publish new agronomic science for improved …

Phomopsis Stem Canker Of Sunflower In North America: Correlation With Climate And Solutions Through Breeding And Management, Brent S. Hulke, Samuel G. Markell, Nolan C. Kane, Febina M. Mathew

Febina Mathew

Climate change is occurring in the central US and is interacting with agroecological factors to increase biotic stress in sunflower. Certain species of Diaporthe cause Phomopsis stem canker in sunflower and other dicotyledonous weeds and crops. The increase in precipitation already observed in the states of North Dakota, South Dakota, and Minnesota have increased the chances of outbreaks of necrotrophic pathogens, like Diaporthe. We discuss how climate trends, combined with technological, management, and economic interactions, are correlated with increasing incidence of Phomopsis stem canker in these and adjacent areas in North America. Further, we discuss management options and the …

Welfare Challenges Influence The Complexity Of Movement: Fractal Analysis Of Behaviour In Zebrafish, Anthony G. Deakin, Joseph W. Spencer, Andrew R. Cossins, Iain S. Young, Lynne U. Sneddon

Lynne Sneddon, PhD

The ability to assess welfare is an important refinement that will ensure the good condition of animals used in experimentation. The present study investigated the impact of invasive procedures on the patterns of movement of zebrafish (Danio rerio). Recordings were made before and after fin clipping, PIT tagging and a standard pain test and these were compared with control and sham handled zebrafish. The fractal dimension (FD) from the 3D trajectories was calculated to determine the effect of these treatments on the complexity of movement patterns. While the FD of zebrafish trajectories did not differ over time in either the …

Risk Assessment Of Catch And Release, Rolf Erik Olsen, Tor Fredrik Næsje, Trygve Poppe, Lynne Sneddon, John Webb

Lynne Sneddon, PhD

The report was produced during most of 2009, and gives a state of art overview of current knowledge on the effects of catch and release practices on these fish species’ welfare, using accessible and peer reviewed published literature as basis for the assessment. Anecdotic and non-published reports have been used to a limited extent as they are regarded as untested or containing unverified statements. The Panel on Animal Health and Welfare discussed the full report in a meeting on the 9th of December, and gave its support to the conclusions drawn by the ad hoc-group. The report has concentrated on …

Report Of A Meeting On Contemporary Topics In Zebrafish Husbandry And Care, Nikki Osborne, Gregory Paull, Adam Grierson, Karen Dunford, Elisabeth M. Busch-Nentwich, Lynne U. Sneddon, Natalie Wren, Joe Higgins, Penny Hawkins

Lynne Sneddon, PhD

A meeting on Contemporary Topics in Zebrafish Husbandry and Care was held in the United Kingdom in 2014, with the aim of providing a discussion forum for researchers, animal technologists, and veterinarians from academia and industry to share good practice and exchange ideas. Presentation topics included protocols for optimal larval rearing, implementing the 3Rs (replacement, reduction, and refinement) in large-scale colony management, and environmental enrichment. The audience also participated in a survey of current practice relating to practical husbandry, cryopreservation, and the provision of enrichment.

Physiological And Behavioural Evaluation Of Common Anaesthesia Practices In The Rainbow Trout, Kieran C. Pounder, Jennifer L. Mitchell, Jack S. Thomson, Tom G. Pottinger, Lynne U. Sneddon

Lynne Sneddon, PhD

Anaesthetic drugs are commonly administered to fish in aquaculture, research and veterinary contexts. Anaesthesia causes temporary absence of consciousness and may reduce the stress and/or pain associated with handling and certain invasive procedures. The rainbow trout (Oncorhynchus mykiss) is a widely-used model species with relevance to both aquaculture and natural ecosystems. This study sought to establish the relative acute impact of commonly used anaesthetics on rainbow trout when used for anaesthesia or euthanasia by exploring their effects on aversion behaviour and stress physiology. Five widely used anaesthetics were investigated at two concentrations reflective of common laboratory practises: MS-222, benzocaine, 2-phenoxyethanol, …

Reduction In Activity By Noxious Chemical Stimulation Is Ameliorated By Immersion In Analgesic Drugs In Zebrafish, Javier Lopez-Luna, Qussay Al-Jubouri, Waleed Al-Nuaimy, Lynne U. Sneddon

Lynne Sneddon, PhD

Research has recently demonstrated that larval zebrafish show similar molecular responses to nociception to those of adults. Our study explored whether unprotected larval zebrafish exhibited altered behaviour after exposure to noxious chemicals and screened a range of analgesic drugs to determine their efficacy to reduce these responses. This approach aimed to validate larval zebrafish as a reliable replacement for adults as well as providing a high-throughput means of analysing behavioural responses. Zebrafish at 5 days postfertilization were exposed to known noxious stimuli: acetic acid (0.01%, 0.1% and 0.25%) and citric acid (0.1%, 1% and 5%). The behavioural response of each …

Intrarectal Transmission, Systemic Infection, And Cd4+ T Cell Depletion In Humanized Mice Infected With Hiv-1, Zhifeng Sun, Paul W. Denton, Jacob D. Estes, Florence A. Othieno, Bangdong L. Wei, Anja K. Wege, Michael W. Melkus, Angela Padgett-Thomas, Mary Zupancic, Ashley T. Haase, J. Victor Garcia

Paul W. Denton

Intrarectal infection between men who have sex with men represents a predominant form of human immunodefi ciency virus (HIV) transmission in developed countries. Currently there are no adequate small animal models that recapitulate intrarectal HIV transmission. Here we demonstrate that human lymphocytes generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract of humanized mice with human CD4+ T cells rendering them susceptible to intrarectal HIV transmission. HIV infection after a single intrarectal inoculation results in systemic infection with depletion of CD4+ T cells in gut-associated lymphoid tissue and other pathologic sequela that closely mimics those observed in HIV …

Targeted Cytotoxic Therapy Kills Persisting Hiv Infected Cells During Art, Paul W. Denton, Julie M. Long, Stephen W. Wietgrefe, Craig Sykes, Rae Ann Spagnuolo, Olivia D. Snyder, Katherine Perkey, Nancie M. Archin, Shailesh K. Choudhary, Kuo Yang, Michael G. Hudgens, Ira Pastan, Ashley T. Haase, Angela D. Kashuba, Edward A. Berger, David M. Margolis, J. Victor Garcia

Paul W. Denton

Antiretroviral therapy (ART) can reduce HIV levels in plasma to undetectable levels, but rather little is known about the effects of ART outside of the peripheral blood regarding persistent virus production in tissue reservoirs. Understanding the dynamics of ART-induced reductions in viral RNA (vRNA) levels throughout the body is important for the development of strategies to eradicate infectious HIV from patients. Essential to a successful eradication therapy is a component capable of killing persisting HIV infected cells during ART. Therefore, we determined the in vivo efficacy of a targeted cytotoxic therapy to kill infected cells that persist despite long-term ART. …