Biology Commons^™

The Effect Of Caffeine On The Bacterial Populations In A Freshwater Aquarium System, Adrienne M. Gibson, Roderick M. Morgan, Alexey G. Nikitin

Alexey Nikitin

Caffeine is becoming a common chemical found in the environment but, little research has been done to understand the environmental effects of caffeine, including dissolved caffeine in aquatic systems. The goal of this research study was to begin to understand how caffeine may interact with aquatic environment, using the bacteria of the genus Pseudomonas, commonly found in the aquatic habitat. We found that Pseudomonas shows an increase in growth when exposed to caffeine, which results in a change in spectrophotometric absorbance, increase in bacterial colony count in the presence of caffeine, and in bio-film like sheen appearing on the glass …

Mitochondrial Dna Analysis Of Eneolithic Trypillians From Ukraine Reveals Neolithic Farming Genetic Roots, Alexey Nikitin, Inna Potekhina, Nadin Rohland, Swapan Mallick, Malcolm Lillie

Alexey Nikitin

The agricultural revolution in Eastern Europe began in the Eneolithic with the Cucuteni-Trypillia culture complex. In Ukraine, the Trypillian culture (TC) existed for over two millennia (ca. 5,400±2,700 BCE) and left a wealth of artifacts. Yet, their burial rituals remain a mystery and to date almost nothing is known about the genetic composition of the TC population. One of the very few TC sites where human remains can be found is a cave called Verteba in western Ukraine. This report presents four partial and four complete mitochondrial genomes from nine TC individuals uncovered in the cave. The results of this …

The Molecular Basis Of High-Altitude Adaptation In Deer Mice, Jay F. Storz, Stephen J. Sabatino, Federico G. Hoffmann, Eben Gering, Hideaki Moriyama, Nuno Ferrand, Bruno Monteiro, Michael W. Nachman

Eben Gering

Elucidating genetic mechanisms of adaptation is a goal of central importance in evolutionary biology, yet few empirical studies have succeeded in documenting causal links between molecular variation and organismal fitness in natural populations. Here we report a population genetic analysis of a two-locus α-globin polymorphism that underlies physiological adaptation to high-altitude hypoxia in natural populations of deer mice, Peromyscus maniculatus. This system provides a rare opportunity to examine the molecular underpinnings of fitness-related variation in protein function that can be related to a well-defined selection pressure. We surveyed DNA sequence variation in the duplicated α-globin genes of P. maniculatus …

Variation In Flight Morphology In A Damselfly With Female-Limited Polymorphism, Emily Jane Mctavish, Genevieve K. Smith, Rafael F. Guerrero, Eben Gering

Eben Gering

Background: Female-limited colour polymorphisms occur in many species of dragonflies and damselflies. Often one female morph appears male-like in coloration (androchromes) whereas one or more others are distinct from males (gynochromes). These androchromes are hypothesized to be male-mimics, thereby avoiding the harassment of excessive male mating attempts.

Organism: The damselfly Ischnura ramburii, Rambur’s forktail, is a widespread New World species with androchrome and gynochrome females. It was introduced to the Hawaiian Islands in the mid-1970s and females were thought to be exclusively gynochromatic there.

Questions: How do males and females differ in their flight apparatus? Do females with different …

Prevalence And Diversity Of Avian Hematozoan Parasites In Asia: A Regional Study, Farah Ishtiaq, Eben Gering, Jon H. Rappole, Asad R. Rahmani, Yadvendradev V. Jhala, Carla J. Dove, Christopher M. Milensky, Storrs L. Olson, Mike A. Peirce, Robert C. Fleischer

Eben Gering

Tissue samples from 699 birds from three regions of Asia (Myanmar, India, and South Korea) were screened for evidence of infection by avian parasites in the genera Plasmodium and Haemoproteus. Samples were collected from November 1994 to October 2004. We identified 241 infected birds (34.0%). Base-on-sequence data for the cytochrome b gene from 221 positive samples, 34 distinct lineages of Plasmodium, and 41 of Haemoproteus were detected. Parasite diversity was highest in Myanmar followed by India and South Korea. Parasite prevalence differed among regions but not among host families. There were four lineages of Plasmodium and one of …

Mixed Ancestry And Admixture In Kauai's Feral Chickens: Invasion Of Domestic Genes Into Ancient Red Junglefowl Reservoirs, Eben Gering, M. Johnsson, P. Willis, T. Getty, D. Wright

Eben Gering

A major goal of invasion genetics is to determine how establishment histories shape non‐native organisms' genotypes and phenotypes. While domesticated species commonly escape cultivation to invade feral habitats, few studies have examined how this process shapes feral gene pools and traits. We collected genomic and phenotypic data from feral chickens (Gallus gallus) on the Hawaiian island of Kauai to (i) ascertain their origins and (ii) measure standing variation in feral genomes, morphology and behaviour. Mitochondrial phylogenies (D‐loop & whole Mt genome) revealed two divergent clades within our samples. The rare clade also contains sequences from Red Junglefowl (the …

Maladaptation In Feral And Domesticated Animals, Eben Gering, Darren Incorvaia, R. Henriksen, Dominic Wright

Eben Gering

Selection regimes and population structures can be powerfully changed by domestication and feralization, and these changes can modulate animal fitness in both captive and natural environments. In this review, we synthesize recent studies of these two processes and consider their impacts on organismal and population fitness. Domestication and feralization offer multiple windows into the forms and mechanisms of maladaptation. Firstly, domestic and feral organisms that exhibit suboptimal traits or fitness allow us to identify their underlying causes within tractable research systems. This has facilitated significant progress in our general understandings of genotype–phenotype relationships, fitness trade‐offs, and the roles of population …

Getting Back To Nature: Feralization In Animals And Plants, Eben Gering, Darren Incorvaia, R. Henriksen, Jeffrey Conner, Thomas Getty, Dominic Wright

Eben Gering

Formerly domesticated organisms and artificially selected genes often escape controlled cultivation, but their subsequent evolution is not well studied. In this review, we examine plant and animal feralization through an evolutionary lens, including how natural selection, artificial selection, and gene flow shape feral genomes, traits, and fitness. Available evidence shows that feralization is not a mere reversal of domestication. Instead, it is shaped by the varied and complex histories of feral populations, and by novel selection pressures. To stimulate further insight we outline several future directions. These include testing how ‘domestication genes’ act in wild settings, studying the brains and …

Feralisation Targets Different Genomic Loci To Domestication In The Chicken, M. Johnsson, Eben Gering, P. Willis, S. Lopez, L. Van Dorp, G. Hellenthal, R. Henriksen, U. Friberg, D. Wright

Eben Gering

Feralisation occurs when a domestic population recolonizes the wild, escaping its previous restricted environment, and has been considered as the reverse of domestication. We have previously shown that Kauai Island's feral chickens are a highly variable and admixed population. Here we map selective sweeps in feral Kauai chickens using whole-genome sequencing. The detected sweeps were mostly unique to feralisation and distinct to those selected for during domestication. To ascribe potential phenotypic functions to these genes we utilize a laboratory-controlled equivalent to the Kauai population—an advanced intercross between Red Junglefowl and domestic layer birds that has been used previously for both …

Aposematic Signal Variation Predicts Male-Male Interactions In A Polymorphic Poison Frog, Laura Crothers, Eben Gering, Molly Cummings

Eben Gering

Many species use conspicuous “aposematic” signals to communicate unpalatability/unprofitability to potential predators. Although aposematic traits are generally considered to be classic examples of evolution by natural selection, they can also function in the context of sexual selection, and therefore comprise exceptional systems for understanding how conspicuous signals evolve under multifarious selection. We used males from a highly territorial poison frog species in a dichotomous choice behavioral test to conduct the first examination of how aposematic signal variation influences male–male interactions. Our results reveal two behavioral patterns: (1) male dorsal brightness influences the behaviors of male conspecifics such that males approach …

A Method For Rearing Large Quantities Of The Damselfly, Ischnura Ramburii (Odonata: Coenagrionidae), In The Laboratory, Jason L. Locklin, Joshua S. Huckabee, Eben Gering

Eben Gering

Laboratory based experimental designs typically require large sample sizes of genetically related organisms at the same developmental stage. Several described methods for rearing damselflies have been published, but these methods require laborious techniques when rearing large quantities of damselflies simultaneously. We have developed a relatively easy and inexpensive method for rearing large quantities of a coenagrionid damselfly that streamlines previously published methods and employs new techniques that increase efficiency and yield. Culturing large numbers of damselflies in the laboratory is manageable and opens diverse research avenues.

Promises And Challenges Of Eco-Physiological Genomics In The Field: Tests Of Drought Responses In Switchgrass. Plant Physiology, John T. Lovell, Eugene V. Shakirov, Scott Schwartz, David B. Lowry, Michael J. Aspinwall, Samuel H. Taylor, Jason Bonnette, Juan Diego Palacio-Mejia, Christine V. Hawkes, Philip A. Fay, Thomas E. Juenger

Yevgeniy (Eugene) Shakirov

Identifying the physiological and genetic basis of stress tolerance in plants has proven to be critical to understanding adaptation in both agricultural and natural systems. However, many discoveries were initially made in the controlled conditions of greenhouses or laboratories, not in the field. To test the comparability of drought responses across field and greenhouse environments, we undertook three independent experiments using the switchgrass reference genotype Alamo AP13. We analyzed physiological and gene expression variation across four locations, two sampling times, and three years. Relatively similar physiological responses and expression coefficients of variation across experiments masked highly dissimilar gene expression responses …

Drought Responsive Gene Expression Regulatory Divergence Between Upland And Lowland Ecotypes Of A Perennial C4 Grass, John T. Lovell, Scott Schwartz, David B. Lowry, Eugene V. Shakirov, Jason E. Bonnette, Xiaoyu Weng, Mei Wang, Jenifer Johnson, Avinash Sreedasyam, Christopher Plott, Jerry Jenkins, Jeremy Schmutz, Thomas E. Juenger

Yevgeniy (Eugene) Shakirov

Climatic adaptation is an example of a genotype-by-environment interaction (G×E) of fitness. Selection upon gene expression regulatory variation can contribute to adaptive phenotypic diversity; however, surprisingly few studies have examined how genome-wide patterns of gene expression G×E are manifested in response to environmental stress and other selective agents that cause climatic adaptation. Here, we characterize drought-responsive expression divergence between upland (drought-adapted) and lowland (mesic) ecotypes of the perennial C₄ grass, Panicum hallii, in natural field conditions. Overall, we find that cis-regulatory elements contributed to gene expression divergence across 47% of genes, 7.2% of which exhibit drought-responsive G×E. …

Microbial Phytases And Phytate: Exploring Opportunities For Sustainable Phosphorus Management In Agriculture, Nelly P. Balaban, Aliya D. Suleimanova, Lia R. Valeeva, Inna B. Chastukhina, Natalia L. Rudakova, Margarita R. Sharipova, Eugene V. Shakirov

Yevgeniy (Eugene) Shakirov

Myo-inositol phosphates (phytates) are important biological molecules produced largely by plants to store phosphorus. Phytate is very abundant in many different soils making up a large portion of all soil phosphorus. This review assesses current phytase science from the perspective of its substrate, phytate, by examining the intricate relationship between the phytate-hydrolyzing enzymes and phytate as their substrate. Specifically, we examine available data on phytate’s structural features, distribution in nature and functional roles. The role of phytases and their localization in soil and plant tissues are evaluated. We provide a summary of the current biotechnological advances in using industrial …

The Genomic Landscape Of Molecular Responses To Natural Drought Stress In Panicum Hallii., John T. Lovell, Jerry Jenkins, David B. Lowry, Sujan Mamidi, Avinash Sreedasyam, Xiaoyu Weng, Kerrie Barry, Jason Bonnette, Brandon Campitelli, Chris Daum, Sean P. Gordon, Billie A. Gould, Albina Khasanova, Anna Lipzen, Alice Macqueen, Juan Diego Palacio-Mejía, Christopher Plott, Eugene V. Shakirov, Shengqiang Shu, Yuko Yoshinaga, Matt Zane, Dave Kudrna, Jason D. Talag, Daniel Rokhsar, Jane Grimwood, Jeremy Schmutz, Thomas E. Juenger

Yevgeniy (Eugene) Shakirov

Environmental stress is a major driver of ecological community dynamics and agricultural productivity. This is especially true for soil water availability, because drought is the greatest abiotic inhibitor of worldwide crop yields. Here, we test the genetic basis of drought responses in the genetic model for C4 perennial grasses, Panicum hallii, through population genomics, field-scale gene-expression (eQTL) analysis, and comparison of two complete genomes. While gene expression networks are dominated by local cis-regulatory elements, we observe three genomic hotspots of unlinked trans-regulatory loci. These regulatory hubs are four times more drought responsive than the genome-wide average. Additionally, cis- and trans-regulatory …

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. …

Cryptopatches Are Essential For The Development Of Human Galt, Tomonori Nochi, Paul W. Denton, Angela Wahl, J. Victor Garcia

Paul W. Denton

Abnormal gut-associated lymphoid tissue (GALT) in humans is associated with infectious and autoimmune diseases, which cause dysfunction of the gastrointestinal (GI) tract immune system. To aid in investigating GALT pathologies in vivo, we bioengineered a human-mouse chimeric model characterized by the development of human GALT structures originating in mouse cryptopatches. This observation expands our mechanistic understanding of the role of cryptopatches in human GALT genesis and emphasizes the evolutionary conservation of this developmental process. Immunoglobulin class switching to IgA occurs in these GALT structures, leading to numerous human IgAproducing plasma cells throughout the intestinal lamina propria. CD4+ T cell depletion …

Hypogammaglobulinemia In Blt Humanized Mice – An Animal Model Of Primary Antibody Deficiency, Francisco Martinez-Torres, Tomonori Nochi, Angela Wahl, J. Victor Garcia, Paul W. Denton

Paul W. Denton

Primary antibody deficiencies present clinically as reduced or absent plasma antibodies without another identified disorder that could explain the low immunoglobulin levels. Bone marrow-liver-thymus (BLT) humanized mice also exhibit primary antibody deficiency or hypogammaglobulinemia. Comprehensive characterization of B cell development and differentiation in BLT mice revealed other key parallels with primary immunodeficiency patients. We found that B cell ontogeny was normal in the bone marrow of BLT mice but observed an absence of switched memory B cells in the periphery. PC-KLH immunizations led to the presence of switched memory B cells in immunized BLT mice although plasma cells producing PCor …

Humanized Mouse Models Of Hiv Infection, Paul W. Denton, J. Victor Garcia

Paul W. Denton

Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses such as SIV that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in non-human hosts. For these reasons much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34+ hematopoietic progenitor cell transplanted immunodeficient mice and in particular mice also implanted with …

Antiretroviral Pre-Exposure Prophylaxis Prevents Vaginal Transmission Of Hiv-1 In Humanized Blt Mice, Paul W. Denton, Jacob D. Estes, Zhifeng Sun, Florence A. Othieno, Bangdong L. Wei, Anja K. Wege, Daniel A. Powell, Deborah A. Payne, Ashley T. Haase, J. Victor Garcia

Paul W. Denton

Background: Worldwide, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. Despite the urgency to develop and implement novel approaches capable of preventing HIV transmission, this process has been hindered by the lack of adequate small animal models for preclinical efficacy and safety testing. Given the importance of this route of transmission, we investigated the susceptibility of humanized mice to intravaginal HIV-1 infection.

Methods and Findings: We show that the female reproductive tract of humanized bone marrow–liver–thymus (BLT) mice is reconstituted with human CD4þ T and other relevant human cells, rendering these humanized mice …

Human Breast Milk And Antiretrovirals Dramatically Reduce Oral Hiv-1 Transmission In Blt Humanized Mice, Angela Wahl, Michael D. Swanson, Tomonori Nochi, Rikke Olesen, Paul W. Denton, Morgan Chateau, J. Victor Garcia

Paul W. Denton

Currently, over 15% of new HIV infections occur in children. Breastfeeding is a major contributor to HIV infections in infants. This represents a major paradox in the field because in vitro, breast milk has been shown to have a strong inhibitory effect on HIV infectivity. However, this inhibitory effect has never been demonstrated in vivo. Here, we address this important paradox using the first humanized mouse model of oral HIV transmission. We established that reconstitution of the oral cavity and upper gastrointestinal (GI) tract of humanized bone marrow/liver/thymus (BLT) mice with human leukocytes, including the human cell types important for …

Painted Bunting (Passerina Ciris) Caught In The Web Of A Giant Lichen Orb-Weaver Spider (Araneus Bicentenarius), Philip Queller, Troy G. Murphy

Troy G Murphy

Orb-weaver spiders weave large webs that are capable of entrapping various species of birds. We report a case of a male Painted Bunting (Passerina ciris) caught in the web of a giant lichen orb-weaver (Araneus bicentenarius). Most cases of bird entrapment in spider webs involve spiders with larger webs (often Nephila sp.) and very small birds, usually hummingbirds. Our case is noteworthy because we report a relatively large bird caught in a relatively small web. Furthermore, the geographic distribution of A. bicentenarius extends beyond the tropics and subtropics, which is where most reported cases of bird …

Tlr9 Agonist Mgn1703 Enhances B Cell Differentiation And Function In Lymph Nodes, Mariane H. Schleimann, Maria-Louise Kobberø, Line K. Vibholm, Katherine Kjær, Leila B. Giron, Kathleen Busman-Sahay, Chi Ngai Chan, Michael Nekorchuk, Manuel Schmidt, Burghardt Wittig, Tine E. Damsgaard, Peter Ahlburg, Michel B. Hellfritzsch, Kaja Zuwala, Frederik H. Rothemejer, Rikke Olesen, Phillipp Schommers, Florian Klein, Harsh Dweep, Andrew Kossenkov, Jens R. Nyengaard, Jacob D. Estes, Mohamed Abdel-Mohsen, Lars Østergaard, Ole S. Søgaard, Paul W. Denton

Paul W. Denton

Background

TLR9 agonists are being developed as immunotherapy against malignancies and infections. TLR9 is primarily expressed in B cells and plasmacytoid dendritic cells (pDCs). TLR9 signalling may be critically important for B cell activity in lymph nodes but little is known about the in vivo impact of TLR9 agonism on human lymph node B cells. As a pre-defined sub-study within our clinical trial investigating TLR9 agonist MGN1703 (lefitolimod) treatment in the context of developing HIV cure strategies (NCT02443935), we assessed TLR9 agonist-mediated effects in lymph nodes.

Methods

Participants received MGN1703 for 24 weeks concurrent with antiretroviral therapy. Seven …

Art Influences Hiv Persistence In The Female Reproductive Tract And Cervicovaginal Secretions, Rikke Olesen, Michael D. Swanson, Martina Kovarova, Tomonori Nochi, Morgan Chateau, Jenna B. Honeycutt, Julie M. Long, Paul W. Denton, Michael G. Hudgens, Amy Richardson, Martin Tolstrup, Lars Østergaard, Angela Wahl, J. Victor Garcia

Paul W. Denton

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT …

Using Animal Models To Overcome Temporal, Spatial And Combinatorial Challenges In Hiv Persistence Research, Paul W. Denton, Ole S. Søgaard, Martin Tolstrup

Paul W. Denton

Research challenges associated with understanding HIV persistence during antiretroviral therapy can be categorized as temporal, spatial and combinatorial. Temporal research challenges relate to the timing of events during establishment and maintenance of HIV persistence. Spatial research challenges regard the anatomical locations and cell subsets that harbor persistent HIV. Combinatorial research challenges pertain to the order of administration, timing of administration and specific combinations of compounds to be administered during HIV eradication therapy. Overcoming these challenges will improve our understanding of HIV persistence and move the field closer to achieving eradication of persistent HIV. Given that humanized mice and non-human primate …

Interferon Priming Is Essential For Human Cd34+ Cell-Derived Plasmacytoid Dendritic Cell Maturation And Function, A. Lausten, R. O. Bak, C. Krapp, L. Kjær, J. H. Egedahl, C. C. Petersen, S. Pillai, H. Q. Tang, N. Uldbjerg, M. Porteus, N. R. Roan, M. Nyegaard, Paul W. Denton, M. R. Jakobsen

Paul W. Denton

Plasmacytoid dendritic cells (pDC) are essential for immune competence. Here we show that pDC precursor differentiated from human CD34+ hematopoietic stem and progenitor cells (HSPC) has low surface expression of pDC markers, and has limited induction of type I interferon (IFN) and IL-6 upon TLR7 and TLR9 agonists treatment; by contrast, cGAS or RIG-I agonists-mediated activation is not altered. Importantly, after priming with type I and II IFN, these precursor pDCs attain a phenotype and functional activity similar to that of peripheral blood-derived pDCs. Data from CRISPR/Cas9-mediated genome editing of HSPCs further show that HSPC-pDCs with genetic modifications can be …

Broad Activation Of Latent Hiv-1 In Vivo, Kirston Barton, Bonnie Hiener, Anni Winckelmann, Thomas Aagaard Rasmussen, Wei Shao, Karen Byth, Robert Lanfear, Ajantha Solomon, James Mcmahon, Sean Harrington, Maria Buzon, Mathias Lichterfeld, Paul W. Denton, Rikke Olesen, Lars Østergaard, Martin Tolstrup, Sharon R. Lewin, Ole Schmeltz Søgaard, Sarah Palmer

Paul W. Denton

The ‘shock and kill’ approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4+ T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically diverse, indicating activation of …

Treatment Of Hiv-Infected Individuals With The Histone Deacetylase Inhibitor Panobinostat Results In Increased Numbers Of Regulatory T Cells And Limits Ex Vivo Lipopolysaccharide-Induced Inflammatory Responses, Christel Rothe Brinkmann, Jesper Falkesgaard Højen, Thomas Aagaard Rasmussen, Anne Sofie Kjær, Rikke Olesen, Paul W. Denton, Lars Østergaard, Zhengyu Ouyang, Mathias Lichterfeld, Xu Yu, Ole Schmeltz Søgaard, Charles Dinarello, Martin Tolstrup

Paul W. Denton

Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex. Gene expression in purified peripheral blood mononuclear cells (PBMCs) was evaluated using an Affymetrix HTA 2.0 gene chip. We found that proportions of CD4+ …

Predicting Hiv Pre-Exposure Prophylaxis Efficacy For Women Using A Preclinical Pharmacokinetic-Pharmacodynamic In Vivo Model, Angela Wahl, Phong T. Ho, Paul W. Denton, Katy L. Garrett, Michael G. Hudgens, Glenn Swartz, Cynthia O'Neill, Fulvia Veronese, Angela D. Kashuba, J. Victor Garcia

Paul W. Denton

The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of …