Breaking News
June 19, 2018 - Study finds elevated risk of congenital defects in lithium-exposed infants
June 19, 2018 - Test-Taking Can Be Tough for Kids With Vision Problems
June 19, 2018 - Injections for knee osteoarthritis—’subtle but significant’ impact of revisions in clinical practice guidelines
June 19, 2018 - Researchers develop new approach to assess effectiveness of Men B vaccine
June 19, 2018 - Study shows link between financial literacy and hospitalization risk in older adults
June 19, 2018 - New study examines how the brain plays role in rheumatoid arthritis inflammation
June 19, 2018 - Researchers discover new defense mechanism against oxygen radicals
June 19, 2018 - WVU researcher aims to produce updated whooping cough vaccine
June 19, 2018 - Scientists develop novel computational framework to support personalized cancer treatment
June 19, 2018 - Rate of dementia on the decline—but beware of growing numbers
June 19, 2018 - Microglia play protective role in response to retinal detachment, shows study
June 19, 2018 - Technology breakthrough could enable detection of fetal genetic abnormalities in early pregnancy
June 19, 2018 - Novel chip can be used to identify rhinovirus strains as cause of asthma
June 19, 2018 - Effects of in vitro fertilization depend on genetic variation inherited from parents
June 19, 2018 - Heart attack patients unable to resume work report depression and financial hardship
June 19, 2018 - Study combines gene editing and stem cell technologies to predict person’s risk for heart disease
June 19, 2018 - Weight loss of 20% or greater results in better outcomes for overweight, obese adults with knee osteoarthritis
June 19, 2018 - Alnylam Reports Updated Positive Results from Phase 1/2 Study of Lumasiran in Patients with Primary Hyperoxaluria Type 1 (PH1)
June 19, 2018 - Study predicts most people with earliest Alzheimer’s signs won’t develop dementia associated with the disease
June 19, 2018 - Abnormal sleep duration linked to metabolic syndrome in new study
June 19, 2018 - Researchers develop new method to preserve fertility in boys with prepubertal cancer
June 19, 2018 - Late onset of diabetes could be indicative of pancreatic cancer
June 19, 2018 - WHO releases new International Classification of Diseases (ICD-11)
June 19, 2018 - Skin tone makes big difference in diagnosis and treatment of dermatologic conditions
June 19, 2018 - After addiction, the long road back to good health
June 19, 2018 - High blood pressure could be an early sign of dementia
June 19, 2018 - Innovative drugs and new European treatment guidelines refine, improve MS therapy
June 19, 2018 - BIDMC scientists develop new tool to benefit patients with HCV-associated liver failure
June 19, 2018 - Diabetes diagnosis may come with increased risk of pancreatic cancer for African-Americans, Latinos
June 19, 2018 - Personalized Goals, Cash Motivate Heart Patients to Exercise
June 19, 2018 - Nipah Virus (NiV) | CDC
June 19, 2018 - Genomics offers new treatment options for infants with range of soft tissue tumors
June 18, 2018 - Study shows how moderate consumption of alcohol can protect the heart
June 18, 2018 - Gene editing technology predicts heart disease risk
June 18, 2018 - Who Will and Who Won’t Get the Flu?
June 18, 2018 - Research shows effective responses to online feedback
June 18, 2018 - Scientists to focus on big data and genetics to identify risk factors for dementia
June 18, 2018 - Ultrasound-based technology for assessing overweight adolescents with liver disease
June 18, 2018 - Osteochondral knee defect treated using cell technology
June 18, 2018 - New clinical trial finds no evidence to support use of tamsulosin for kidney stones
June 18, 2018 - Study demonstrates increased levels of gum disease in people at risk of rheumatoid arthritis
June 18, 2018 - Ebola & Marburg | NIH: National Institute of Allergy and Infectious Diseases
June 18, 2018 - Brains, eyes, testes: off-limits for transplants?
June 18, 2018 - Drug used to treat myelofibrosis can awaken ‘dormant’ lymphomas in the bone marrow
June 18, 2018 - New study focuses on best, cost effective practices to bridge treatment gap for brain disorders
June 18, 2018 - New study highlights predictors that prevent from achieving remission in early RA
June 18, 2018 - Neuroscientists map feeling of cool touch to the brain’s insula in mouse model
June 18, 2018 - Study highlights potential use of blood biomarkers as diagnostic tool for sleep apnea
June 18, 2018 - Eating plant-based diet can reduce risk for heart problems in people with type 2 diabetes
June 18, 2018 - Lenabasum has acceptable safety and tolerability in diffuse cutaneous systemic sclerosis
June 18, 2018 - Study shows link between risky opioid prescriptions and increased odds of death
June 18, 2018 - Bone density scans could help determine likelihood of cardiovascular disease
June 18, 2018 - Mechanical thrombectomy appears to be important therapy for acute stroke in very old patients
June 18, 2018 - Novel compound as effective as FDA-approved antibiotics for treating deadly infections
June 18, 2018 - Ironwood Pharmaceuticals Announces FDA Orphan Drug Designation for Olinciguat for the Treatment of Sickle Cell Disease
June 18, 2018 - Surgical outcomes equivalent whether physician anesthesiologist assisted by nurse anesthetist or AA
June 18, 2018 - Studies provide insight into molecular changes prior to onset of arthritis
June 18, 2018 - Dyaco unveils specialist medical and rehabilitation equipment range in the UK
June 18, 2018 - Engineers develop algorithm to monitor joints of patients with arthritis
June 18, 2018 - Women with higher vitamin D blood levels have lower risk for breast cancer
June 18, 2018 - New studies help elucidate role of sleep in chronic pain
June 18, 2018 - Researchers link red meat sensitivity spread by ticks with heart disease
June 18, 2018 - Research explores role of autopsy in cardiovascular medicine
June 18, 2018 - Motif Bio Submits NDA for Iclaprim
June 18, 2018 - NIH-funded researchers identify target for chikungunya treatment
June 18, 2018 - Negative emotions are murkier, less distinct in adolescence
June 18, 2018 - Gut microbiome may be potential contributor to depression, anxiety in people with obesity
June 18, 2018 - Canakinumab reduces gout rate by more than half in atherosclerosis patients, study shows
June 18, 2018 - What Does the Future Hold?
June 18, 2018 - FDA Approves Keytruda (pembrolizumab) for Treatment of Refractory or Relapsed Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
June 18, 2018 - School cliques don’t always click
June 18, 2018 - Three experts from The Tinnitus Clinic contribute to major review on pulsatile tinnitus
June 18, 2018 - Unwieldy health costs often stand between teachers and fatter paychecks
June 18, 2018 - Link between frailty and mortality remains unchanged despite lower death rates, study finds
June 18, 2018 - Sleep disorders appear to be first sign of serious neurological diseases
June 18, 2018 - Childhood, adult obesity raise risk of developing hip and knee osteoarthritis
June 18, 2018 - Study unravels ‘blood stem cell niche’ puzzle
June 18, 2018 - People with heart problems do not take enough exercise, shows study
June 18, 2018 - Strong Link Identified Between T2DM and Parkinson’s Disease
June 18, 2018 - Early childhood interventions show mixed results on child development
Discovery puts the brakes on HIV’s ability to infect

Discovery puts the brakes on HIV’s ability to infect

image_pdfDownload PDFimage_print
Tatyana Polenova and Juan Perilla, professors in the Department of Chemistry and Biochemistry at the University of Delaware, with a computer-generated model of HIV, the virus that causes AIDS. Credit: University of Delaware/ Evan Krape and Jeffrey Chase

Viewed with a microscope, the virus faintly resembles a pineapple—the universal symbol of welcome. But HIV, the virus that causes AIDS, is anything but that. It has claimed the lives of more than 35 million people so far.

In a study led by the University of Delaware and the University of Pittsburgh School of Medicine, researchers discovered a “brake” that interferes with HIV’s development into an infectious agent. This mechanism prevents the capsid—the protein shell covering the virus—from forming.

The finding, which was published in Nature Communications, was made by an interdisciplinary research team from UD, the University of Pittsburgh School of Medicine, University of Illinois, National Cancer Institute, DFH Pharma and Vanderbilt University Medical Center. The results are based on seven years of excruciatingly detailed studies of the structure and dynamics of HIV early and late in its life cycle. The movements of the virus molecules were measured experimentally and simulated in quadrillionths of a second—that’s much faster than the blink of an eye or the flutter of a hummingbird’s wings.

“People used to be fixated on the static structures of viruses, but they are not rock solid,” said Tatyana Polenova, professor in UD’s Department of Chemistry and Biochemistry. She is an expert in nuclear magnetic resonance (NMR) spectroscopy, which helps scientists identify and pinpoint the location of every atom in a structure and how each atom moves.

“Viruses like HIV and their constituent protein and nucleic acid molecules are dynamic entities that are constantly expanding and shrinking,” she added. “Their motions are like breathing.”

Polenova said molecules in the HIV virus operate in concert, yet within each molecule motions occur over many different time scales, a difficult scenario to simulate, to be sure. But not too complex for Juan Perilla, who joined the UD faculty as an assistant professor this past June. A quantitative biophysicist, Perilla created the first structural models of HIV as a postdoctoral scientist at the University of Illinois. Today, at UD, he routinely uses some of the world’s largest supercomputers to generate simulations of the HIV virus and its many moving parts.

Stopping a virus from maturing

As the HIV virus develops, a cascade of events occurs, affecting its structure and ability to infect. Think of the TV cooking show “Chopped.” But in this case, protein building blocks get methodically “cleaved” or cut from a larger, master protein called Gag.

By integrating state-of-the-art techniques, including solid-state and solution NMR, high-end computer simulations, and cryo-electron microscopy (for which the Nobel Prize was awarded earlier this fall) the researchers answered a longstanding question about how the final step in the maturation of the virus occurs—a process in which a noninfectious immature virion turns into an infectious virus particle.

The team discovered that a key peptide—spacer peptide 1 (SP1)—has to be in a highly mobile structure to be cut by the virus protease, the enzyme that acts like a cleaver. In simulations, the peptide resembles a thin, yarn-like strand attached to corkscrews of curled ribbons in constant motion.

“This peptide is always there in the final maturation step, but we were surprised that it is so disordered and dynamic,” Polenova said.

Once the SP1 peptide is cut, the HIV virus forms its protective capsid and becomes infectious. But how do you stop that process? In team experiments at the University of Pittsburgh led by Angela Gronenborn, the anti-HIV inhibitor Bevirimat was shown to interact with the SPI peptide, thus preventing the development of the virus’s capsid “coat.”

Zeroing in on potential drug targets to stop HIV from becoming infectious by disrupting the virus’s maturation is an ongoing goal for the team.

“We have to have a sense of these short-lived molecular fluctuations and processes—of protein cleavage and capsid generation,” Perilla said. “To add a new generation of capsid inhibitors to prevent HIV, you have to have very specific times and rates at which these drugs will work.”

Perilla and Polenova also said an extensive team of people is critical, including experimentalists and computational scientists, who have expertise in multiple biophysical techniques, such as NMR and cryo-EM, and across the disciplines of structural biology, biophysics, biochemistry and virology.

“This work would be impossible without our combined strength—I tell my students they need to learn to collaborate with people in other fields,” said Polenova. Also critical, she said, is the availability of cutting edge infrastructure in high-field NMR at the University of Delaware and at ultra-high field NMR centers across the U.S., including the National High Magnetic Field Laboratory, and internationally, such as the National Center for Scientific Research in Lyon, France, where Polenova and her students travel to perform NMR experiments.

She and Perilla both credit Angela Gronenborn, their collaborator at the University of Pittsburgh, for transforming their work through the Pittsburgh Center for HIV Protein Interactions, a national research center that Gronenborn established about a decade ago with funding from the National Institutes of Health.

“Science is moving away from the single scientist being able to peer at things at atomic resolution,” Polenova said. “It’s no longer the situation of doing one thing as a single investigator. Now, we all come together.”


Explore further:
Research team finds that protein motions regulate HIV infectivity

Journal reference:
Nature Communications

Provided by:
University of Delaware

Tagged with:

About author

Related Articles