PLoS Articles
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UNC-authored articles published by the Public Library of Science (PLoS)
Works (2111)
1731. Validation of Multiplex Serology detecting human herpesviruses 1-5
- Title Tesim:
- Validation of Multiplex Serology detecting human herpesviruses 1-5
- Creator:
- Prager, K., Breuer, J., Mentzer, A.J., Brenner, N., Allen, N., Butt, J., Brozy, J., Almond, R., Waterboer, T., Weißbrich, B., Aiello, A.E., Meier, H.C.S., Michel, A., and Pawlita, M.
- Date of publication:
- 2018
- Abstract Tesim:
- Human herpesviruses (HHV) cause a variety of clinically relevant conditions upon primary infection of typically young and immunocompetent hosts. Both primary infection and reactivation after latency can lead to more severe disease, such as encephalitis, congenital defects and cancer. Infections with HHV are also associated with cardiovascular and neuro-degenerative disease. However, most of the associations are based on retrospective case-control analyses and well-powered prospective cohort studies are needed for assessing temporality and causality. To enable comprehensive investigations of HHV-related disease etiology in large prospective population-based cohort studies, we developed HHV Multiplex Serology. This methodology represents a low-cost, high-throughput technology that allows simultaneous measurement of specific antibodies against five HHV species: Herpes simplex viruses 1 and 2, Varicella zoster virus, Epstein-Barr virus, and Cytomegalovirus. The newly developed HHV species-specific (‘Monoplex’) assays were validated against established gold-standard reference assays. The specificity and sensitivity of the HHV species-specific Monoplex Serology assays ranged from 92.3% to 100.0% (median 97.4%) and 91.8% to 98.7% (median 96.6%), respectively. Concordance with reference assays was very high with kappa values ranging from 0.86 to 0.96 (median kappa 0.93). Multiplexing the Monoplex Serology assays resulted in no loss of performance and allows simultaneous detection of antibodies against the 5 HHV species in a high-throughput manner.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Epidemiology
- DOI:
- https://doi.org/10.17615/jnxr-3613
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0209379
- ISSN:
- 1932-6203
- Journal Issue:
- 12
- Journal Title:
- PLoS ONE
- Journal Volume:
- 13
- ORCID:
- Other Affiliation:
- German Cancer Research Center, University College London, University of Oxford, Heidelberg University, UK Biobank, Julius-Maximilians-Universität Würzburg, , and University of Wisconsin-Milwaukee
- Person:
- Prager, K., Breuer, J., Mentzer, A.J., Brenner, N., Allen, N., Butt, J., Brozy, J., Almond, R., Waterboer, T., Weißbrich, B., Aiello, A.E., Meier, H.C.S., Michel, A., and Pawlita, M.
- Rights Statement Label:
- In Copyright
- Source:
- cr56n644t and allison_aiello_36
1732. Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study
- Title Tesim:
- Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study
- Creator:
- Ritchie, K., Ishii, H., Numbers, K., Lima-Costa, M.F., van Boxtel, M., Trollor, J.N., Kumagai, S., Jacobsen, E.P., Ferri, C.P., Lo, J.W., Thalamuthu, A., Valhuerdi-Cepero, A.J., Hughes, T.F., Makkar, S.R., Riedel-Heller, S.G., Leung, Y., Lipton, R.B., Ganguli, M., Crawford, J.D., Scarmeas, N., Vaccaro, R., Deckers, K., Fung, A., Gao, Q., Brayne, C., Derby, C.A., Carrière, I., Nyunt, M.S.Z., Lipnicki, D.M., Narazaki, K., Katz, M.J., Brodaty, H., Sachdev, P.S., Dang, K., Ancelin, M.-L., Pabst, A., Aiello, A.E., Llibre-Rodriguez, J.J., Yannakoulia, M., Davin, A., Cherbuin, N., Scazufca, M., Stephan, B., Ng, T.P., Popovic, G., Lam, L., Santabárbara, J., Chen, T., Chan, W.-C., Anstey, K.J., Köhler, S., Roehr, S., Meguro, K., Guaita, A., Kochan, N.A., Suh, S.W., Kim, K.W., Llibre-Guerra, J.J., Haan, M.N., Lopez-Anton, R., Lobo, A., Castro-Costa, E., Hadjigeorgiou, G.M., and Han, J.W.
- Date of publication:
- 2019
- Abstract Tesim:
- Background: With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. Methods and findings: We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54–105 (mean = 72.7) years and without dementia at baseline. Studies had 2–15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = −0.1, SE = 0.01), APOE*4 carriage (B = −0.31, SE = 0.11), depression (B = −0.11, SE = 0.06), diabetes (B = −0.23, SE = 0.10), current smoking (B = −0.20, SE = 0.08), and history of stroke (B = −0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = −0.07, SE = 0.01), APOE*4 carriage (B = −0.41, SE = 0.18), and diabetes (B = −0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = −0.24, SE = 0.12), and between diabetes and cognitive decline (B = −0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. Conclusions: These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Epidemiology
- DOI:
- https://doi.org/10.17615/k8sn-p657
- Identifier:
- https://dx.doi.org/10.1371/journal.pmed.1002853
- ISSN:
- 1549-1277
- Journal Issue:
- 7
- Journal Title:
- PLoS Medicine
- Journal Volume:
- 16
- ORCID:
- Other Affiliation:
- Université de Montpellier, Tohoku University, University of New South Wales, Fundação Oswaldo Cruz, Maastricht University Medical Center, Kyushu University, University of Pittsburgh, Universidade Federal de São Paulo, Medical University of Matanzas, Youngstown State University, University of Leipzig, Yeshiva University, National and Kapodistrian University of Athens, Golgi Cenci Foundation, Hong Kong Polytechnic University, National University of Singapore, Cambridge University, Fukuoka Institute of Technology, University of California, San Francisco, , Medical University of Havana, Harokopio University, Australian National University, Universidade de São Paulo, Newcastle University, Chinese University of Hong Kong, Instituto de Investigación Sanitaria Aragón, University of Hong Kong, Seoul National University Bundang Hospital, Institute of Neurology and Neurosurgery, Universidad de Zaragoza, and University of Thessaly
- Person:
- Ritchie, K., Ishii, H., Numbers, K., Lima-Costa, M.F., van Boxtel, M., Trollor, J.N., Kumagai, S., Jacobsen, E.P., Ferri, C.P., Lo, J.W., Thalamuthu, A., Valhuerdi-Cepero, A.J., Hughes, T.F., Makkar, S.R., Riedel-Heller, S.G., Leung, Y., Lipton, R.B., Ganguli, M., Crawford, J.D., Scarmeas, N., Vaccaro, R., Deckers, K., Fung, A., Gao, Q., Brayne, C., Derby, C.A., Carrière, I., Nyunt, M.S.Z., Lipnicki, D.M., Narazaki, K., Katz, M.J., Brodaty, H., Sachdev, P.S., Dang, K., Ancelin, M.-L., Pabst, A., Aiello, A.E., Llibre-Rodriguez, J.J., Yannakoulia, M., Davin, A., Cherbuin, N., Scazufca, M., Stephan, B., Ng, T.P., Popovic, G., Lam, L., Santabárbara, J., Chen, T., Chan, W.-C., Anstey, K.J., Köhler, S., Roehr, S., Meguro, K., Guaita, A., Kochan, N.A., Suh, S.W., Kim, K.W., Llibre-Guerra, J.J., Haan, M.N., Lopez-Anton, R., Lobo, A., Castro-Costa, E., Hadjigeorgiou, G.M., and Han, J.W.
- Rights Statement Label:
- In Copyright
- Source:
- allison_aiello_16 and fb494f95q
1733. Environmental methods for dengue vector control – A systematic review and meta-analysis
- Title Tesim:
- Environmental methods for dengue vector control – A systematic review and meta-analysis
- Creator:
- Horstick Olaf, Buhler, Claudia, Runge-Ranzinger, Silvia, Boyce, Ross, and Winkler, Volker
- Date of publication:
- 2019
- Abstract Tesim:
- Background: Vector control remains the primary method to prevent dengue infections. Environmental interventions represent sustainable and safe methods as there are limited risks of environmental contamination and toxicity. The objective of this study is to perform a systematic review and meta-analysis of the effectiveness of the following environmental methods for dengue vector control. Methodology/Principal findings: Following the PRISMA guidelines, a systematic literature search was conducted using the databases PubMed, EMBASE, LILACS, the Cochrane Library and Google Scholar. Quality assessment was done using the CONSORT 2010 checklist. For the meta-analysis the difference-in-differences (DID) and the difference-of-endlines (DOE) were calculated according to the Schmidt-Hunter method for the Breteau index (BI) and the pupae per person index (PPI). Nineteen studies were eligible for the systematic review, sixteen contributed data to the meta-analysis. The following methods were evaluated: (a) container covers with and without insecticides, (b) waste management and clean-up campaigns, and (c) elimination of breeding sites by rendering potential mosquito breeding sites unusable or by eliminating them. Study quality was highest for container covers with insecticides, followed by waste management without direct garbage collection and elimination of breeding places. Both, systematic review and meta-analysis, showed a weak effect of the interventions on larval populations, with no obvious differences between the results of each individual method. For the meta-analysis, both, container covers without insecticides (BI: DID -7.9, DOE -5) and waste management with direct garbage collection (BI: DID -8.83, DOE -6.2) achieved the strongest reductions for the BI, whereas for the PPI results were almost opposite, with container covers with insecticides (PPI: DID -0.83, DOE 0.09) and elimination of breeding places (PPI: DID -0.95, DOE -0.83) showing the strongest effects. Conclusions: Each of the investigated environmental methods showed some effectiveness in reducing larval and pupal densities of Aedes sp. mosquitoes. However, there is a need for more comparable high-quality studies at an adequate standard to strengthen this evidence.
- Resource type:
- Article
- Affiliation Label Tesim:
- Division of Infectious Diseases
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/fngv-7y97
- Identifier:
- https://dx.doi.org/10.1371/journal.pntd.0007420
- ISSN:
- 1935-2727
- Journal Issue:
- 7
- Journal Title:
- PLoS Neglected Tropical Diseases
- Journal Volume:
- 13
- Keyword:
- dengue, waste disposal, House Index, human, Review, virus transmission, breeding, randomized controlled trial (topic), waste management, pyriproxyfen, systematic review, nonhuman, quality control, outcome assessment, public health campaign, vector control, health education, insecticide, and meta analysis
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- University of Heidelberg, Ludwig-Maximilians University Munich, and
- Person:
- Horstick Olaf, Buhler, Claudia, Runge-Ranzinger, Silvia, Boyce, Ross, and Winkler, Volker
- Rights Statement Label:
- In Copyright
- Source:
- 1v53k368w
1734. Community health workers trained to conduct verbal autopsies provide better mortality measures than existing surveillance: Results from a cross-sectional study in rural western Uganda
- Title Tesim:
- Community health workers trained to conduct verbal autopsies provide better mortality measures than existing surveillance: Results from a cross-sectional study in rural western Uganda
- Creator:
- Nabukalu, Doreen, Wiens, Matthew, Ntaro, Moses, Mulogo, Edgar, Seviiri, Mathias, Boyce, Ross M., Reyes, Raquel, and Sundararajan, Radhika
- Date of publication:
- 2019
- Abstract Tesim:
- Background: In much of sub-Saharan Africa, health facilities serve as the primary source of routine vital statistics. These passive surveillance systems, however, are plagued by infrequent and unreliable reporting and do not capture events that occur outside of the formal health sector. Verbal autopsies (VA) have been utilized to estimate the burden and causes of mortality where civil registration and vital statistics systems are weak, but VAs have not been widely employed in national surveillance systems. In response, we trained lay community health workers (CHW) in a rural sub-county of western Uganda to conduct VA interviews in order to assess the feasibility of leveraging CHW to measure the burden of disease in resource limited settings. Methods and findings: Trained CHWs conducted a cross-sectional survey of the 36 villages comprising the Bugoye sub-county to identify all deaths occurring in the prior year. The sub county has an estimated population of 50,249, approximately one-quarter of whom are children under 5 years of age (25.3%). When an eligible death was reported, CHWs administered a WHO 2014 VA questionnaire, the results of which were analyzed using the InterVA-4 tool. To compare the findings of the CHW survey to existing surveillance systems, study staff reviewed inpatient registers from neighboring referral health facilities in an attempt to match recorded deaths to those identified by the survey. Overall, CHWs conducted high quality VA interviews on direct observation, identifying 230 deaths that occurred within the sub-county, including 77 (33.5%) among children under five years of age. More than half of the deaths (123 of 230, 53.5%) were reported to have occurred outside a health facility and thus would not be captured by passive surveillance. More than two-thirds (73 of 107, 68.2%) of facility deaths took place in one of three nearby hospitals, yet only 35 (47.9%) were identified on our review of inpatient registers. Consistent with previous VA studies, the leading causes of death among children under five years of age were malaria (19.5%), prematurity (19.5%), and neonatal pneumonia (15.6%). while among adults, HIV/AIDS-related deaths illness (13.6%), pulmonary tuberculosis (11.4%) and malaria (8.6%) were the leading causes of death. No child deaths identified from inpatient registers listed HIV/AIDS as a cause of death despite 8 deaths (10.4%) attributed to HIV/AIDS as determined by VA. Conclusions: Lay CHWs are able to conduct high quality VA interviews to capture critical information that can be analyzed using standard methodologies to provide a more complete estimate of the burden and causes of mortality. Similar approaches can be scaled to improve the measurement of vital statistics in order to facilitate appropriate public health interventions in rural areas of sub-Saharan Africa.
- Resource type:
- Article
- Affiliation Label Tesim:
- Division of Infectious Diseases and Division of General Medicine and Clinical Epidemiology
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/p0kz-ta13
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0211482
- ISSN:
- 1932-6203
- Journal Issue:
- 2
- Journal Title:
- PLoS ONE
- Journal Volume:
- 14
- Keyword:
- cross-sectional study, hospital, disease burden, malaria, cause of death, Uganda, questionnaire, feasibility study, male, acquired immune deficiency syndrome, World Health Organization, female, intermethod comparison, verbal autopsy, neonatal pneumonia, Human immunodeficiency virus infection, medical education, lung tuberculosis, health survey, autopsy, health auxiliary, rural area, interview, prematurity, controlled study, human, and mortality
- Language Label:
- English
- License Label:
- CC0 1.0 Universal
- ORCID:
- Other Affiliation:
- Mbarara University of Science & Technology, BC Children's Hospital, Wakiso District Local Government, , and Weill Cornell Medical Center
- Person:
- Nabukalu, Doreen, Wiens, Matthew, Ntaro, Moses, Mulogo, Edgar, Seviiri, Mathias, Boyce, Ross M., Reyes, Raquel, and Sundararajan, Radhika
- Rights Statement Label:
- In Copyright
- Source:
- 6q182r74j
1735. Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: A randomized clinical trial
- Title Tesim:
- Artesunate dose escalation for the treatment of uncomplicated malaria in a region of reported artemisinin resistance: A randomized clinical trial
- Creator:
- Schaecher, K., Kuntawungin, W. , Smith, B., Lon, C. , Khemawoot, P. , Socheat, D., Ruttvisutinunt, W., Lin, J. , Saunders, D., Fukuda, M.M., Darapiseth, S. , Bethell, D., Sriwichai, S. , Se, Y., Gosi, P., Tyner, S., Timmermans, A., and Teja-Isavadharm, P.
- Date of publication:
- 2011
- Abstract Tesim:
- Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. The currently recommended daily dose of artesunate (AS) is 4 mg/kg, and is administered for 3 days together with a partner antimalarial drug. This study investigated the impact of different AS doses on clinical and parasitological responses in malaria patients from an area of known artemisinin resistance in western Cambodia. Methods: Adult patients with uncomplicated P. falciparum malaria were randomized into one of three 7-day AS monotherapy regimens: 2, 4 or 6 mg/kg/day (total dose 14, 28 and 42 mg/kg). Clinical, parasitological, pharmacokinetic and in vitro drug sensitivity data was collected over a 7-day inpatient period and during weekly follow-up to 42 days. Results: 143 patients were enrolled (n = 75, 40 and 28 to receive AS 2, 4 and 6 mg/kg/day respectively). Cure rates were high in all treatment groups at 42 days despite almost half the patients remaining parasitemic on Day 3. There was no impact of increasing AS dose on median parasite clearance times, median parasite clearance rates or on the proportion of patients remaining parasitemic on Day 3. However at the lowest dose used (2 mg/kg/d) patients with parasitemia >10,000/μL had longer median (IQR) parasite clearance times than those with parasitemia <10,000/μL (63 (48-75) vs. 84 (66-96) hours, p<0.0001). 19% of patients in the high-dose arm developed neutropenia (absolute neutrophil count <1.0×109/L) by Day 14 and resulted in the arm being halted early. Conclusion: There is no pharmacodynamic benefit of increasing the daily dose of AS (4mg/kg) currently recommended for short-course combination treatment of uncomplicated malaria, even in regions with emerging artemisinin resistance, as long as the partner drug retains high efficacy.
- Resource type:
- Article
- Affiliation Label Tesim:
- Institute for Global Health and Infectious Diseases
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/4xf0-9v47
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0019283
- ISSN:
- 1932-6203
- Journal Issue:
- 5
- Journal Title:
- PLoS ONE
- Journal Volume:
- 6
- Keyword:
- artemisin, mefloquine, dihydroartemisinin, artesunate, and chloroquine
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- Armed Forces Research Institute of Medical Sciences, Armed Forces Research Institute of Medical Sciences , Center for Parasitology, Entomology and Malaria Control, and
- Person:
- Schaecher, K., Kuntawungin, W. , Smith, B., Lon, C. , Khemawoot, P. , Socheat, D., Ruttvisutinunt, W., Lin, J. , Saunders, D., Fukuda, M.M., Darapiseth, S. , Bethell, D., Sriwichai, S. , Se, Y., Gosi, P., Tyner, S., Timmermans, A., and Teja-Isavadharm, P.
- Rights Statement Label:
- In Copyright
- Source:
- 8623j388t
1736. New Metrics for Evaluating Viral Respiratory Pathogenesis
- Title Tesim:
- New Metrics for Evaluating Viral Respiratory Pathogenesis
- Creator:
- Menachery, Vineet D., Baric, Ralph S., Ferris, Martin T., and Gralinski, Lisa E.
- Date of publication:
- 2015
- Abstract Tesim:
- Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease. Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections. This methodology closely tracked with traditional pathogenesis metrics, distinguished both virusand dose-specific responses, and identified long-term respiratory changes following both SARS-CoV and Influenza A Virus infection. Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Epidemiology and Department of Genetics
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/7qq9-f010
- Identifier:
- https://doi.org/10.1371/journal.pone.0131451
- Journal Issue:
- 6
- Journal Title:
- PLoS ONE
- Journal Volume:
- 10
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- Person:
- Menachery, Vineet D., Baric, Ralph S., Ferris, Martin T., and Gralinski, Lisa E.
- Rights Statement Label:
- In Copyright
- Source:
- x920g3098
1737. Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA
- Title Tesim:
- Human cytomegalovirus UL29/28 protein interacts with components of the NuRD complex which promote accumulation of immediate-early RNA
- Creator:
- Rout, Michael P., Moorman, Nathaniel J., Cuevas-Bennett, Christian, Shenk, Thomas, Chait, Brian T., Cristea, Ileana M., Terhune, Scott S., and Savaryn, John Paul
- Date of publication:
- 2010
- Abstract Tesim:
- Histone deacetylation plays a pivotal role in regulating human cytomegalovirus gene expression. In this report, we have identified candidate HDAC1-interacting proteins in the context of infection by using a method for rapid immunoisolation of an epitope-tagged protein coupled with mass spectrometry. Putative interactors included multiple human cytomegalo- virus-coded proteins. In particular, the interaction of pUL38 and pUL29/28 with HDAC1 was confirmed by reciprocal immunoprecipitations. HDAC1 is present in numerous protein complexes, including the HDAC1-containing nucleosome remodeling and deacetylase protein complex, NuRD. pUL38 and pUL29/28 associated with the MTA2 component of NuRD, and shRNA-mediated knockdown of the RBBP4 and CHD4 constituents of NuRD inhibited HCMV immediate-early RNA and viral DNA accumulation; together this argues that multiple components of the NuRD complex are needed for efficient HCMV replication. Consistent with a positive acting role for the NuRD elements during viral replication, the growth of pUL29/28- or pUL38-deficient viruses could not be rescued by treating infected cells with the deacetylase inhibitor, trichostatin A. Transient expression of pUL29/28 enhanced activity of the HCMV major immediate-early promoter in a reporter assay, regardless of pUL38 expression. Importantly, induction of the major immediate-early reporter activity by pUL29/28 required functional NuRD components, consistent with the inhibition of immediate-early RNA accumulation within infected cells after knockdown of RBBP4 and CHD4. We propose that pUL29/28 modifies the NuRD complex to stimulate the accumulation of immediate-early RNAs.
- Resource type:
- Article
- Affiliation Label Tesim:
- Department of Microbiology and Immunology
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/68de-g186
- Identifier:
- https://dx.doi.org/10.1371/journal.ppat.1000965
- ISSN:
- 1553-7366
- Journal Issue:
- 6
- Journal Title:
- PLoS Pathogens
- Journal Volume:
- 6
- Keyword:
- trichostatin A, RNA, virus protein, unclassified drug, short hairpin RNA, protein pUL29, histone deacetylase 1, and protein pul28
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- Person:
- Rout, Michael P., Moorman, Nathaniel J., Cuevas-Bennett, Christian, Shenk, Thomas, Chait, Brian T., Cristea, Ileana M., Terhune, Scott S., and Savaryn, John Paul
- Rights Statement Label:
- In Copyright
- Source:
- rv043107p
1738. β-globin LCR and intron elements cooperate and direct spatial reorganization for gene therapy
- Title Tesim:
- β-globin LCR and intron elements cooperate and direct spatial reorganization for gene therapy
- Creator:
- Hotta, Akitsu, Garcia-Martinez, J. Victor, Moffett, Angela, Pasceri, Peter, Fussner, Eden, Bazett-Jones, David P., Ellis, James, Buzina, Alla, Lo, Mandy Y. M., and Bharadwaj, Rikki R.
- Date of publication:
- 2008
- Abstract Tesim:
- The Locus Control Region (LCR) requires intronic elements within b-globin transgenes to direct high level expression at all ectopic integration sites. However, these essential intronic elements cannot be transmitted through retrovirus vectors and their deletion may compromise the therapeutic potential for gene therapy. Here, we systematically regenerate functional bglobin intron 2 elements that rescue LCR activity directed by 5′HS3. Evaluation in transgenic mice demonstrates that an Oct-1 binding site and an enhancer in the intron cooperate to increase expression levels from LCR globin transgenes. Replacement of the intronic AT-rich region with the Igμ 3′MAR rescues LCR activity in single copy transgenic mice. Importantly, a combination of the Oct-1 site, Igm 39MAR and intronic enhancer in the BGT158 cassette directs more consistent levels of expression in transgenic mice. By introducing intron-modified transgenes into the same genomic integration site in erythroid cells, we show that BGT158 has the greatest transcriptional induction. 3D DNA FISH establishes that induction stimulates this small 5′HS3 containing transgene and the endogenous locus to spatially reorganize towards more central locations in erythroid nuclei. Electron Spectroscopic Imaging (ESI) of chromatin fibers demonstrates that ultrastructural heterochromatin is primarily perinuclear and does not reorganize. Finally, we transmit intron-modified globin transgenes through insulated self-inactivating (SIN) lentivirus vectors into erythroid cells. We show efficient transfer and robust mRNA and protein expression by the BGT158 vector, and virus titer improvements mediated by the modified intron 2 in the presence of an LCR cassette composed of 5′HS2-4. Our results have important implications for the mechanism of LCR activity at ectopic integration sites. The modified transgenes are the first to transfer intronic elements that potentiate LCR activity and are designed to facilitate correction of hemoglobinopathies using single copy vectors.
- Resource type:
- Article
- Affiliation Label Tesim:
- Center for AIDS Research
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/mj97-8v46
- Identifier:
- https://dx.doi.org/10.1371/journal.pgen.1000051
- ISSN:
- 1553-7390
- Journal Issue:
- 4
- Journal Title:
- PLoS Genetics
- Journal Volume:
- 4
- Keyword:
- lentivirus vector, primer DNA, octamer transcription factor 1, globin, protein, Pou2f1 protein, mouse, recombinant protein, messenger RNA, and beta globin
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- SickKids and University of Texas Southwestern Medical Center
- Person:
- Hotta, Akitsu, Garcia-Martinez, J. Victor, Moffett, Angela, Pasceri, Peter, Fussner, Eden, Bazett-Jones, David P., Ellis, James, Buzina, Alla, Lo, Mandy Y. M., and Bharadwaj, Rikki R.
- Rights Statement Label:
- In Copyright
- Source:
- zs25xf55c
1739. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice
- Title Tesim:
- Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice
- Creator:
- Garcia, J. Victor, Othieno, Florence A., Powell, Daniel A., Wei, Bangdong L., Sun, Zhifeng, Haase, Ashley T., Denton, Paul W., Payne, Deborah, Wege, Anja K., and Estes, Jacob D.
- Date of publication:
- 2008
- Abstract Tesim:
- 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 CD4+ T and other relevant human cells, rendering these humanized mice susceptible to intravaginal infection by HIV-1. Effects of HIV-1 infection include CD4+ T cell depletion in gut-associated lymphoid tissue (GALT) that closely mimics what is observed in HIV-1-infected humans. We also show that pre-exposure prophylaxis with antiretroviral drugs is a highly effective method for preventing vaginal HIV-1 transmission. Whereas 88% (7/8) of BLT mice inoculated vaginally with HIV-1 became infected, none of the animals (0/5) given pre-exposure prophylaxis of emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) showed evidence of infection (Chi square = 7.5, df = 1, p = 0.006). Conclusions: The fact that humanized BLT mice are susceptible to intravaginal infection makes this system an excellent candidate for preclinical evaluation of both microbicides and pre-exposure prophylactic regimens. The utility of humanized mice to study intravaginal HIV-1 transmission is particularly highlighted by the demonstration that pre-exposure prophylaxis can prevent intravaginal HIV-1 transmission in the BLT mouse model.
- Resource type:
- Article
- Affiliation Label Tesim:
- Center for AIDS Research
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/vqpf-py88
- Identifier:
- https://dx.doi.org/10.1371/journal.pmed.0050016
- ISSN:
- 1549-1277
- Journal Issue:
- 1
- Journal Title:
- PLoS Medicine
- Journal Volume:
- 5
- Keyword:
- tenofovir disoproxil, adenine, antiretrovirus agent, drug derivative, emtricitabine, emtricitabine plus tenofovir disoproxil, phosphonic acid derivative, deoxycytidine, and anti human immunodeficiency virus agent
- Language Label:
- English
- License Label:
- Attribution 3.0 United States
- ORCID:
- Other Affiliation:
- University of Texas Southwestern Medical Center at Dallas, University of Minnesota, Minneapolis, and University of Minnesota
- Page End:
- 89
- Page Start:
- 79
- Person:
- Garcia, J. Victor, Othieno, Florence A., Powell, Daniel A., Wei, Bangdong L., Sun, Zhifeng, Haase, Ashley T., Denton, Paul W., Payne, Deborah, Wege, Anja K., and Estes, Jacob D.
- Rights Statement Label:
- In Copyright
- Source:
- 8623j381w
1740. Systemic administration of antiretrovirals prior to exposure prevents rectal and intravenous HIV-1 transmission in humanized BLT mice
- Title Tesim:
- Systemic administration of antiretrovirals prior to exposure prevents rectal and intravenous HIV-1 transmission in humanized BLT mice
- Creator:
- Krisko, John F., Powell, Daniel A., Mathias, Melissa, Zou, Wei, Kwak, Youn Tae, Estes, Jacob D., Garcia, J. Victor, Martinez-Torres, Francisco, Denton, Paul W., and Payne, Deborah A.
- Date of publication:
- 2010
- Abstract Tesim:
- Successful antiretroviral pre-exposure prophylaxis (PrEP) for mucosal and intravenous HIV-1 transmission could reduce new infections among targeted high-risk populations including discordant couples, injection drug users, high-risk women and men who have sex with men. Targeted antiretroviral PrEP could be particularly effective at slowing the spread of HIV-1 if a single antiretroviral combination were found to be broadly protective across multiple routes of transmission. Therefore, we designed our in vivo preclinical study to systematically investigate whether rectal and intravenous HIV-1 transmission can be blocked by antiretrovirals administered systemically prior to HIV-1 exposure. We performed these studies using a highly relevant in vivo model of mucosal HIV-1 transmission, humanized Bone marrow/Liver/Thymus mice (BLT). BLT mice are susceptible to HIV-1 infection via three major physiological routes of viral transmission: vaginal, rectal and intravenous. Our results show that BLT mice given systemic antiretroviral PrEP are efficiently protected from HIV-1 infection regardless of the route of exposure. Specifically, systemic antiretroviral PrEP with emtricitabine and tenofovir disoproxil fumarate prevented both rectal (Chi square = 8.6, df = 1, p = 0.003) and intravenous (Chi square = 13, df= 1, p = 0.0003) HIV-1 transmission. Our results indicate that antiretroviral PrEP has the potential to be broadly effective at preventing new rectal or intravenous HIV transmissions in targeted high risk individuals. These in vivo preclinical findings provide strong experimental evidence supporting the potential clinical implementation of antiretroviral based pre-exposure prophylactic measures to prevent the spread of HIV/AIDS.
- Resource type:
- Article
- Affiliation Label Tesim:
- Center for AIDS Research
- Type:
- http://purl.org/dc/dcmitype/Text
- DOI:
- https://doi.org/10.17615/89bj-5p26
- Identifier:
- https://dx.doi.org/10.1371/journal.pone.0008829
- ISSN:
- 1932-6203
- Journal Issue:
- 1
- Journal Title:
- PLoS ONE
- Journal Volume:
- 5
- Keyword:
- high risk population, Human immunodeficiency virus 1, animal model, controlled study, Human immunodeficiency virus 1 infection, tenofovir disoproxil, mouse, animal experiment, animal tissue, acquired immune deficiency syndrome, virus transmission, infection sensitivity, exposure, bone marrow, antiretrovirus agent, human, human cell, drug efficacy, liver, thymus, nonhuman, and emtricitabine
- Language Label:
- English
- License Label:
- Public Domain Mark 1.0
- ORCID:
- Other Affiliation:
- University of Texas Southwestern Medical Center at Dallas, National Cancer Institute, and
- Person:
- Krisko, John F., Powell, Daniel A., Mathias, Melissa, Zou, Wei, Kwak, Youn Tae, Estes, Jacob D., Garcia, J. Victor, Martinez-Torres, Francisco, Denton, Paul W., and Payne, Deborah A.
- Rights Statement Label:
- In Copyright
- Source:
- 08612v11b
Collection Details
- Total items
-
2111
- Size
-
unknown
- Date created
-
February 2, 2022