|
|
|
3i Initiative Weekly Updates
Welcome to the 3i Weekly Update, your source for 3i relevant news and events. Please send all items of interest to Nicole.Frank@hsc.utah.edu by the end of the day on Thursdays.
| |
|
|
9/7 - 9/11- TUESDAY, SEPTEMBER 8, 2020, 10AM – 12PM - BSL2 and BBP Training - Online Zoom
- TUESDAY, SEPTEMBER 8, 2020, 4PM – 5PM - Long-Term Effects of COVID Research Meeting
- WEDNESDAY, SEPTEMBER 9, 2020, 10 – 11AM - Advanced Consideration of the Criteria for IRB Approval of Research
- THURSDAY, SEPTEMBER 10, 2020, 10 – 11AM - Grant-Writing Consultation: The National Science Foundation (NSF)
- FRIDAY, SEPTEMBER 11, 2020, 12 – 1PM - Department of Pediatrics Research In Progress (Presenters: M. Dean & J. Yost)
- FRIDAY, SEPTEMBER 11, 2020, 12:15 – 1:15PM - Department of Pathology Seminar Series (Presenter Keke Fairfax)
| |
|
| 35 Years Of HIV/AIDS Research And Care In Utah
In commemoration of the 30th anniversary of the Ryan White CARE Act, which provides much-needed funding for medical services for people with AIDS, we celebrate more than three decades of policies, research and care in Utah that has helped turn HIV/AIDS from a death sentence to a chronic disease. read more
| |
|
|
3i Funding Opportunities
Current Federal and Private FOAs applicable to the 3is can be found on the U's pivot page. New FOAs posted this week:
A monthly funding newsletter from PIVOT is sent to 3i investigators on the 2nd Monday of the month. If you have not been receiving the newsletter and would like to be added, please email Nicole.Frank@hsc.utah.edu.
| |
|
3i Investigator PublicationsCongratulations to the teams who published this week. If you have a publication that you would like included, please email us.
| |
|
Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d-peptide HIV entry inhibitor
Prc Natl Acad Sci U S A. 2020 Aug 20;202009700
Authors: Yoshiaki Nishimura, J Nicholas Francis, Olivia K Donau, Eric Jesteadt, Reza Sadjadpour, Amanda R Smith, Michael S Seaman, Brett D Welch, Malcolm A Martin, Michael S KayAbstract
Cholesterol-PIE12-trimer (CPT31) is a potent d-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a simian-HIV chimeric virus AD8 (SHIVAD8) macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ∼2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising candidate for HIV prevention and treatment.
PMID: 32820072 [PubMed - as supplied by publisher]
Read more
Clinical targeting of HIV capsid protein with a long-acting small moleculeNature. 2020 Aug;584(7822):614-618
Authors: John O Link, Martin S Rhee, Winston C Tse, Jim Zheng, John R Somoza, William Rowe, Rebecca Begley, Anna Chiu, Andrew Mulato, Derek Hansen, Eric Singer, Luong K Tsai, Rujuta A Bam, Chien-Hung Chou, Eda Canales, Gediminas Brizgys, Jennifer R Zhang, Jiayao Li, Michael Graupe, Philip Morganelli, Qi Liu, Qiaoyin Wu, Randall L Halcomb, Roland D Saito, Scott D Schroeder, Scott E Lazerwith, Steven Bondy, Debi Jin, Magdeleine Hung, Nikolai Novikov, Xiaohong Liu, Armando G Villaseñor, Carina E Cannizzaro, Eric Y Hu, Robert L Anderson, Todd C Appleby, Bing Lu, Judy Mwangi, Albert Liclican, Anita Niedziela-Majka, Giuseppe A Papalia, Melanie H Wong, Stephanie A Leavitt, Yili Xu, David Koditek, George J Stepan, Helen Yu, Nikos Pagratis, Sheila Clancy, Shekeba Ahmadyar, Terrence Z Cai, Scott Sellers, Scott A Wolckenhaue, John Ling, Christian Callebaut, Nicolas Margot, Renee R Ram, Ya-Pei Liu, Rob Hyland, Gary I Sinclair, Peter J Ruane, Gordon E Crofoot, Cheryl K McDonald, Diana M Brainard, Latesh Lad, Swami Swaminathan, Wesley I Sundquist, Roman Sakowicz, Anne E Chester, William E Lee, Eric S Daar, Stephen R Yant, Tomas Cihlar
Abstract
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
PMID: 32612233 [PubMed - as supplied by publisher]
| |
|
BMC Med. 2020 Sep 03;18(1):229
Authors: Seyed Khoei N, Jenab M, Murphy N, Banbury BL, Carreras-Torres R, Viallon V, Kühn T, Bueno-de-Mesquita B, Aleksandrova K, Cross AJ, Weiderpass E, Stepien M, Bulmer A, Tjønneland A, Boutron-Ruault MC, Severi G, Carbonnel F, Katzke V, Boeing H, Bergmann MM, Trichopoulou A, Karakatsani A, Martimianaki G, Palli D, Tagliabue G, Panico S, Tumino R, Sacerdote C, Skeie G, Merino S, Bonet C, Rodríguez-Barranco M, Gil L, Chirlaque MD, Ardanaz E, Myte R, Hultdin J, Perez-Cornago A, Aune D, Tsilidis KK, Albanes D, Baron JA, Berndt SI, Bézieau S, Brenner H, Campbell PT, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Cotterchio M, Gallinger S, Gruber SB, Haile RW, Hampe J, Hoffmeister M, Hopper JL, Hsu L, Huyghe JR, Jenkins MA, Joshi AD, Kampman E, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Lindor NM, Martín V, Moreno V, Newcomb PA, Offit K, Ogino S, Parfrey PS, Pharoah PDP, Rennert G, Sakoda LC, Schafmayer C, Schmit SL, Schoen RE, Slattery ML, Thibodeau SN, Ulrich CM, van Duijnhoven FJB, Weigl K, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Zhang X, Ferrari P, Anton G, Peters A, Peters U, Gunter MJ, Wagner KH, Freisling H
Abstract
BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.
METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.
RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).
CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
PMID: 32878631 [PubMed - in process]
| |
|
|
|
|
