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The HIV-1 genome contains a gene expressed in the opposite, or antisense, direction to all other genes. The protein product of this antisense gene, called ASP, is poorly characterized, and its role in viral replication remains unknown. We... more
The HIV-1 genome contains a gene expressed in the opposite, or antisense, direction to all other genes. The protein product of this antisense gene, called ASP, is poorly characterized, and its role in viral replication remains unknown. We provide evidence that the antisense protein, ASP, of HIV-1 is found within the cell nucleus in unstimulated cells. In addition, we show that after PMA treatment, ASP exits the nucleus and localizes on the cell membrane. Moreover, we demonstrate that ASP is present on the surfaces of viral particles. Altogether, our studies identify ASP as a new structural component of HIV-1 and show that ASP is an accessory protein that promotes viral replication. The presence of ASP on the surfaces of both infected cells and viral particles might be exploited therapeutically.
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Introduction: The antisense strand of the HIV-1 genome encodes a 189-aa, highly hydrophobic protein (ASP) with no known homologs. Humoral and cellular immune responses against ASP in HIV-1 infected individuals demonstrate its expression... more
Introduction: The antisense strand of the HIV-1 genome encodes a 189-aa, highly hydrophobic protein (ASP) with no known homologs. Humoral and cellular immune responses against ASP in HIV-1 infected individuals demonstrate its expression invivo. However, whether ASP plays a role in viral replication is still unknown. We studied the expression and subcellular localization of ASP in various chronically infected cell lines. In addition, we investigated the impact of ASP expression on viral fitness. Methods: For intracellular and nuclear stainings, we used BD Cytofix/Cytoperm and eBioscience FoxP3 kits. Flow cytometry data were acquired on a Millipore Guava and analyzed with FlowJo. Confocal and super-resolution microscopy images were acquired on Zeiss LSM 800 and Nikon N-STORMTi-E microscopes, and analyzed with Zen Blue and Nikon Elements Software Version 3.1. For virion-capture assays, antibodies against ASP and gp120 were immobilized on Protein G-dynabeads. For Fluorescence Correlatio...
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Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters,... more
Various epigenetic marks at the HIV-1 5'LTR suppress proviral expression and promote latency. Cellular antisense transcripts known as long noncoding RNAs (lncRNAs) recruit the polycomb repressor complex 2 (PRC2) to gene promoters, which catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3), thus promoting nucleosome assembly and suppressing gene expression. We found that an HIV-1 antisense transcript expressed from the 3'LTR and encoding the antisense protein ASP promotes proviral latency. Expression of ASP RNA reduced HIV-1 replication in Jurkat cells. Moreover, ASP RNA expression promoted the establishment and maintenance of HIV-1 latency in Jurkat E4 cells. We show that this transcript interacts with and recruits PRC2 to the HIV-1 5'LTR, increasing accumulation of the suppressive epigenetic mark H3K27me3, while reducing RNA Polymerase II and thus proviral transcription. Altogether, our results suggest that the HIV-1 ASP transcript promotes epigenetic silencin...
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Resumen En varios trabajos se ha publicado la existencia de asociación estadística entre polimorfismos del HLA y el pronóstico de individuos seropositivos al virus de la hepatitis C (VHC) pero no existen estudios que demuestren asociación... more
Resumen En varios trabajos se ha publicado la existencia de asociación estadística entre polimorfismos del HLA y el pronóstico de individuos seropositivos al virus de la hepatitis C (VHC) pero no existen estudios que demuestren asociación entre genes y ser infectado ...
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Summary The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte–macrophage... more
Summary The humanized NOD/SCID/IL-2 receptor γ-chainnull (NSG) mouse model has been widely used for the study of HIV pathogenesis. Here, NSG mice with transgenic expression of human stem cell factor (SCF), granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 (NSG-SGM3) were injected with peripheral blood leukocytes (PBL mice) from two HIV-infected (HIV+) patients who were under anti-retroviral therapy (ART; referred as HIV+ mice) or one HIV-seronegative healthy volunteer (HIV−). Such mice are either hu-PBL-NSG-SGM3 HIV+ or HIV− mice, depending on the source of PBL. The kinetics of HIV replication and T cell responses following engraftment were evaluated in peripheral blood and secondary lymphoid tissues. High HIV replication and low CD4 : CD8 ratios were observed in HIV+ mice in the absence of anti-retroviral therapy (ART). Consistent with high activation and skewed differentiation of T cells from the HIV-infected donor, HIV+ mice exhibited a higher T cel...
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<p>N = Normal, I = increased, gp = guinea pigs. This table is modified from <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd.0002858-Chen1"... more
<p>N = Normal, I = increased, gp = guinea pigs. This table is modified from <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd.0002858-Chen1" target="_blank">[136]</a>.</p
Research Interests: Microbiology, Hematology, Medical Microbiology, Infectious Diseases, Biological Sciences, and 15 moreAnatomy, Platelets, Findings, Dengue fever, Blood, Neglected tropical diseases, Thrombocytopenia, Blood Coagulation, Coagulation Disorders, Disseminated Intravascular Coagulation, Coagulation, Hantavirus, Microbial Pathogens, Body Fluids, and Flaviviruses
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Background Cancer is a leading cause of death in HIV-infected patients in the era of combination antiretroviral therapy (cART). Yet, there are no specific guidelines for the combined use of cART and chemotherapy in HIV-infected cancer... more
Background Cancer is a leading cause of death in HIV-infected patients in the era of combination antiretroviral therapy (cART). Yet, there are no specific guidelines for the combined use of cART and chemotherapy in HIV-infected cancer patients. The cellular enzyme thymidylate synthase (TS) catalyses the conversion of dUMP to TMP, which is converted to TDP and ultimately to TTP, a building block in DNA synthesis. TS inhibitors are recommended in some cancers, particularly non-small cell lung cancer (NSCLC). Because TS inhibitors modulate intracellular concentrations of endogenous 2′-deoxynucleotides, we hypothesized that TS inhibitors could impact the anti-HIV activity of nucleoside analogue reverse transcriptase inhibitors (NRTIs). Methods We evaluated gemcitabine and pemetrexed, two approved TS inhibitors, on the anti-HIV activities of NRTIs in infectivity assays using peripheral blood mononuclear cells (PBMCs) and in humanized mice. Results Gemcitabine enhanced the anti-HIV activi...
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Abstract: Viral hemorrhagic fevers (VHF) are acute zoonotic diseases that, early on, seem to cause platelet destruction or dysfunction. Here we present the four major ways viruses affect platelet development and function and new evidence... more
Abstract: Viral hemorrhagic fevers (VHF) are acute zoonotic diseases that, early on, seem to cause platelet destruction or dysfunction. Here we present the four major ways viruses affect platelet development and function and new evidence of molecular factors that are preferentially induced by the more pathogenic members of the families Flaviviridae, Bunyaviridae, Arenaviridae, and Filoviridae. A systematic search was performed through the main medical electronic databases using as parame-ters all current findings concerning platelets in VHF. Additionally, the review contains information from con-ference proceedings.
<p>Platelets have multiple surface receptors, a cannalicular system, microtubules, mitochondria, three types of granules (lysosomal, alpha, and dense), and deposits of small factors like glycogen (<a... more
<p>Platelets have multiple surface receptors, a cannalicular system, microtubules, mitochondria, three types of granules (lysosomal, alpha, and dense), and deposits of small factors like glycogen (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd-0002858-g002" target="_blank">Figure 2</a> and <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd-0002858-g003" target="_blank">3</a>) <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd.0002858-George1" target="_blank">[54]</a>. Whereas dense granules contain factors that potentiate platelet activation, α-granules contain growth factors and clotting proteins that contribute to hemostasis <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002858#pntd.0002858-Blair2" target="_blank">[130]</a>.</p
Research Interests: Microbiology, Hematology, Medical Microbiology, Infectious Diseases, Veterinary Science, and 15 moreBiological Sciences, Anatomy, Platelets, Dengue fever, Blood, Neglected tropical diseases, Thrombocytopenia, Blood Coagulation, Tropical diseases, Coagulation Disorders, Disseminated Intravascular Coagulation, Hantavirus, Microbial Pathogens, Body Fluids, and Flaviviruses
BackgroundHepatitis B Virus (HBV) is a public health problem that causes chronic hepatitis, eventually evolving to cirrhosis and hepatocellular carcinoma. Given the low frequency of screening in the general population, blood banks... more
BackgroundHepatitis B Virus (HBV) is a public health problem that causes chronic hepatitis, eventually evolving to cirrhosis and hepatocellular carcinoma. Given the low frequency of screening in the general population, blood banks represent a key element for monitoring and controlling HBV transmission. The objective of this work was to evaluate the validity of the diagnosis of HBV in blood banks, based on studies published in the world scientific literature from 2000 to 2018.MethodsWe used a Meta-analysis of random effects with application of a search and selection protocol according to Cochrane and PRISMA guidelines. Reproducibility, completeness and quality assessment were affirmed with QUADAS, a tool for assessing diagnostics. The parameters of sensitivity, specificity, likelihood ratios, odds ratio and ROC curve were analyzed in MetaDisc with 95% confidence.ResultsFrom 4,061 studies screened, only 12 complied with the protocol, and the compliant studies included a population of ...
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Research Interests: Immune response, Survival Analysis, Medicine, Biological Sciences, Safety, and 15 moreCercopithecus aethiops, Humans, Female, Animals, Male, Sterilization, DNA Array, Efficiency, T lymphocytes, Lassa Fever, Callithrix, Immunogenicity, Mono, Gene Expression Regulation, and Medical and Health Sciences
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Research Interests: Cellular Biology, Biological Sciences, Drosophila, Female, Animals, and 15 moreMale, Cell Death, Embryonic Development, Gene Targeting, Heat Shock, Heat Shock Proteins, Heat Shock Protein, Gestational Age, Base Sequence, Embryos, Cell Survival, Knockout Mice, DNA binding proteins, Inner Cell mass, and Medical and Health Sciences
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Research Interests: Immune response, Biology, Virology, Cytokines, Medicine, and 15 moreBiological Sciences, Cercopithecus aethiops, Escherichia coli, Mice, Animals, Immunization, Vaccine, Drug Delivery Systems, DNA vaccines, DNA vaccination, DNA vaccine, Intranasal Administration, Vero cells, Antigen, and Medical and Health Sciences
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Research Interests: West Africa, Flow Cytometry, Biology, Medicine, Signal Transduction, and 11 moreBiological Sciences, Humans, Microarray Analysis, Global Gene Expression, Human Subjects, Enzyme Linked Immunosorbent Assay, Gene expression profiling, Differential expression, reverse transcriptase polymerase chain reaction, High density, and Medical and Health Sciences
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Acute arenavirus disease in primates, like Lassa hemorrhagic fever in humans, begins with flu-like symptoms and leads to death approximately 2 weeks after infection. Our goal was to identify molecular changes in blood that are related to... more
Acute arenavirus disease in primates, like Lassa hemorrhagic fever in humans, begins with flu-like symptoms and leads to death approximately 2 weeks after infection. Our goal was to identify molecular changes in blood that are related to disease progression. Rhesus macaques ( Macaca mulatta ) infected intravenously with a lethal dose of lymphocytic choriomeningitis virus (LCMV) provide a model for Lassa virus infection of humans. Blood samples taken before and during the course of infection were used to monitor gene expression changes that paralleled disease onset. Changes in blood showed major disruptions in eicosanoid, immune response, and hormone response pathways. Approximately 12% of host genes alter their expression after LCMV infection, and a subset of these genes can discriminate between virulent and nonvirulent LCMV infection. Major transcription changes have been given preliminary confirmation by quantitative PCR and protein studies and will be valuable candidates for futu...
Research Interests: Immune response, Biology, Cytokines, Medicine, Gene expression, and 15 moreQuantitative PCR, Biological Sciences, Humans, United States, Animals, Blood sampling, Rhesus macaques, Macaca Mulatta, Lassa Fever, Disease Progression, Chemokines, Gene Expression Regulation, Gene expression profiling, Molecular Sequence Data, and Medical and Health Sciences
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Arenaviruses can cause hemorrhagic fever and death in primates and guinea pigs, but these viruses are not highly pathogenic for most rodent carriers. In the United States, arenaviruses precipitated outbreaks of hepatitis in captive... more
Arenaviruses can cause hemorrhagic fever and death in primates and guinea pigs, but these viruses are not highly pathogenic for most rodent carriers. In the United States, arenaviruses precipitated outbreaks of hepatitis in captive monkeys, and they present an emerging health threat in the tropical areas of Africa and South America. We describe infection of rhesus macaques with the prototype arenavirus, lymphocytic choriomeningitis virus (LCMV), using the WE strain that has been known to cause both encephalopathy and multifocal hemorrhage. Five macaques were inoculated: two by the intravenous (i.v.) and three by the intragastric (i.g.) route. Whereas the two i.v.-inoculated monkeys developed signs and lesions consistent with fatal hemorrhagic fever, the i.g.-inoculated monkeys had an attenuated infection with no disease. Pathological signs of the primate i.v. infection differ significantly from guinea pig arenavirus infections and make this a superior model for human viral hemorrhagic disease.
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Research Interests: Biology, Medicine, Biological Sciences, Virulence, Animals, and 14 moreOld World, Liver Function, Liver regeneration, Time Factors, Hepatocytes, Rhesus macaques, Macaca Mulatta, Amino Acid Profile, Species Specificity, Amino Acid Sequence, Interleukin, Diagnostic Tool, Medical and Health Sciences, and Liver Enzyme
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Lymphocytic choriomeningitis virus (LCMV) and Lassa virus can cause hemorrhagic fever and liver disease in primates. The WE strain of LCMV (LCMV-WE) causes a fatal Lassa fever-like disease in rhesus macaques and provides a model for... more
Lymphocytic choriomeningitis virus (LCMV) and Lassa virus can cause hemorrhagic fever and liver disease in primates. The WE strain of LCMV (LCMV-WE) causes a fatal Lassa fever-like disease in rhesus macaques and provides a model for arenavirus pathogenesis in humans. LCMV-WE delivered intravenously or intragastrically to rhesus macaques targets hepatocytes and induces high levels of liver enzymes, interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), and soluble tumor necrosis factor receptors (sTNFRI and -II) in plasma during acute infection. Proinflammatory cytokines TNF-α and IL-1β were not detected in plasma of infected animals, but increased plasma gamma interferon was noted in fatally infected animals. Immunohistochemistry of acute liver biopsies revealed that 25 to 40% of nuclei were positive for proliferation antigen Ki-67. The increases in IL-6, sIL-6R, sTNFR, and proliferation antigen that we observe are similar to the profile of incipient liver regeneration after surgical...
Research Interests: Biology, Immunohistochemistry, Medicine, Cell Division, Biological Sciences, and 15 moreInflammatory Immune Response, Lipopolysaccharide, Cercopithecus aethiops, Animals, Liver regeneration, Hepatocytes, Macaca Mulatta, Liver Disease, Interleukin, Alanine Transaminase, Arenavirus, Inflammatory response, Liver biopsy, Medical and Health Sciences, and Liver Enzyme
Hantavirus cardiopulmonary syndrome (HPS) has gained importance in Latin America as an emerging disease, with reports of about 4000 HPS cases; however, this is probably an underestimate because of limited surveillance programs and... more
Hantavirus cardiopulmonary syndrome (HPS) has gained importance in Latin America as an emerging disease, with reports of about 4000 HPS cases; however, this is probably an underestimate because of limited surveillance programs and diagnostic tools to confirm HPS. In order to address this issue and develop better serosurveillance capability, we evaluated three recombinant peptides from the Necoclí virus (NECV) nucleocapsid in antibody-capture ELISA. We cloned and expressed antigens representing the whole NECV nucleocapsid protein (NECV-rN), the immunodominant domain (NECV-rN100), and a serospecific domain (NECV-rN428), and then we compared these antigens in ELISA to detect IgG antibodies to NECV in human sera. We evaluated human sera collected during two epidemiological studies from the area where NECV was discovered. The first group included 609 sera from healthy individuals, and the second one included 89 samples from patients with undifferentiated febrile illness. In these two gro...
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Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for... more
Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for disease. In addition to assessing mRNA changes, functional studies are also needed to discriminate causes of disease from mechanisms of host resistance. Host responses that drive pathogenesis are likely to be targets for prevention or therapy. Host responses to Lassa or its related arenaviruses have been monitored in cell culture, in animal models of hemorrhagic fever, in Lassa-infected nonhuman primates and, to a limited extent, in infected human beings. Here, we describe results from those studies and discuss potential targets for reducing virus replication and mitigating disease.
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Dengue is a major public health problem in hyperendemic countries like Colombia, the understanding of the epidemiological trends is important for the development of efficient public health policies. We conducted a systematic review of the... more
Dengue is a major public health problem in hyperendemic countries like Colombia, the understanding of the epidemiological trends is important for the development of efficient public health policies. We conducted a systematic review of the epidemiologic data on dengue in Colombia from 1971 to 2020. A total of 375 relevant citations were identified, 36 of which fulfilled the inclusion criteria. The data of dengue and severe dengue cases, infection fatality rate, and serotype distribution were used to understand and identify gaps in the epidemiological knowledge in Colombia. The epidemiology of dengue in this country was characterized by five main outbreaks in 1998, 2002, 2010, 2013, and 2019 with high fatality rates in comparison with the average values reported in the Americas. The case fatality rate of severe dengue exceeded 2% and all four serotypes co-circulate throughout the country with some regional variations. Overall, the behavior of dengue in Colombia is influenced by multip...
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Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome... more
Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The...
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The development of mouse models that mimic the kinetics of Human Immunodeficiency Virus (HIV) infection is critical for the understanding of the pathogenesis of disease and for the design of novel therapeutic strategies. Here, we describe... more
The development of mouse models that mimic the kinetics of Human Immunodeficiency Virus (HIV) infection is critical for the understanding of the pathogenesis of disease and for the design of novel therapeutic strategies. Here, we describe the dynamics of HIV infection in humanized NOD/Shi-scid-IL2rγnull (NOG) mice bearing the human genes for interleukin (IL)-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (NOG-EXL mice). The kinetics of viral load, as well as the frequencies of T-cells, B-cells, Natural killer cells (NK), monocytes, and dendritic cells in blood and secondary lymphoid organs were evaluated throughout the time of infection. In comparison with a non-transgenic humanized mouse (NSG) strain, lymphoid and myeloid populations were more efficiently engrafted in humanized NOG-EXL mice, both in peripheral blood and lymphoid tissues. In addition, HIV actively replicated in humanized NOG-EXL mice, and infection induced a decrease in the percentage of CD4+ T-cell...
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Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of... more
Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, muscle aches, and other associated symptoms that can progress to vascular leakage, bleeding and multi-organ failure. Most of these viruses are zoonotic causing asymptomatic infections in the primary host, but in human beings, the infection can be lethal. Clinical and experimental evidence suggest that the T-cell response is needed for protection against VHF, but can also cause damage to the host, and play an important role in disease pathogenesis. Here, we present a review of the T-cell immune responses to VHF and insights into the possible ways to improve counter-measures for these viral agents.
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In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world's foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was... more
In 2017, the global Coalition for Epidemic Preparedness (CEPI) declared Lassa virus disease to be one of the world's foremost biothreats. In January 2018, World Health Organization experts met to address the Lassa biothreat. It was commonly recognized that the diversity of Lassa virus (LASV) isolated from West African patient samples was far greater than that of the Ebola isolates from the West African epidemic of 2013⁻2016. Thus, vaccines produced against Lassa virus disease face the added challenge that they must be broadly-protective against a wide variety of LASV. In this review, we discuss what is known about the immune response to Lassa infection. We also discuss the approaches used to make broadly-protective influenza vaccines and how they could be applied to developing broad vaccine coverage against LASV disease. Recent advances in AIDS research are also potentially applicable to the design of broadly-protective medical countermeasures against LASV disease.
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Lymphocytic choriomeningitis virus strain WE (LCMV-WE), a Risk Group 3 virus, causes a disease in rhesus monkeys that closely resembles human infection with Lassa fever virus, a Risk Group 4 agent. Three stages of disease progression have... more
Lymphocytic choriomeningitis virus strain WE (LCMV-WE), a Risk Group 3 virus, causes a disease in rhesus monkeys that closely resembles human infection with Lassa fever virus, a Risk Group 4 agent. Three stages of disease progression have been defined and profiled in this model: pre-viremic, viremic, and terminal. The earliest or pre-viremic stage reveals changes in the blood profile predictive of the later stages of disease. In order to identify whether specific changes are pathognomonic, it was necessary to perform a parallel infection with an attenuated virus (LCMV-Armstrong). Here we review the use of nonhuman primates to model viral hemorrhagic fever and offer a step-by-step guide to using a rhesus macaque model for Lassa fever.
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Research Interests: Biology, Medicine, Multidisciplinary, HIV, Humans, and 6 moreMice, Animals, PLoS one, Oximes, Protein Kinase Inhibitors, and Viral Load
To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy. We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in... more
To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy. We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIV BaL . Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 μL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture. Drug-untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC 50 of <8 nM) and dolutegravir (EC 50 of <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viraemia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice developed mu...
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HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of... more
HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κ...
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The nature of our world is changing, inexorably and sometimes imperceptibly due to technological advanc-es, the growth of under-privileged populations, and the unstable dynamics of competing political systems. The new "information... more
The nature of our world is changing, inexorably and sometimes imperceptibly due to technological advanc-es, the growth of under-privileged populations, and the unstable dynamics of competing political systems. The new "information age" provides new ways of per-ceiving and interpreting the world. For instance, in the biological sciences, large data sets have been used to simulate biological systems in silico. Mankind is learn-ing to use information to predict and control complex events. Despite the fact that our world is continually being re-constructed, we are all responsible for preserving it for future human beings. Our new interpretive and pre-dictive tools, such as bioinformatics, quantum phys-ics, chaos theory, and new biology, give us the added responsibility of acting like planetary citizens, where there is no room for nationalism. No one owns the knowledge, and nobody owns the planet. As planetary citizens with specialized scientific knowledge we have the responsib...