NIH Scientists Advance Understanding of Herpesvirus Infection
Herpes simplex virus (HSV) infections last a lifetime. Once a person has been infected, the virus can remain dormant (latent) for years before periodically reactivating to cause disease. This poorly understood cycle has frustrated scientists for years. Now, NIH scientists have identified a set of protein complexes that are recruited to viral genes and stimulate both initial infection and reactivation from latency. Environmental stresses known to regulate these proteins also induce reactivation.
Globally, the World Health Organization estimates that 500 million people are infected with HSV-2 while two-thirds of the population are infected with HSV-1. These viruses cause human diseases ranging from oral cold sores to genital lesions to serious eye conditions that can lead to blindness. In infants, HSV can cause neurological and developmental problems.
People infected with HSV also have an enhanced risk of acquiring or transmitting human immunodeficiency virus (HIV).
Scientists at NIAID previously made progress toward understanding the role of cellular protein HCF-1 in initiating HSV infection and reactivation. HCF-1 and associated proteins are recruited to the viral genome to enable the virus to replicate and spread. This previous work identified targets for the development of therapeutics to suppress infection and reactivation.
Their latest work, with collaborators from Princeton University, identifies new HCF-1 protein complexes that play additional roles in initiating viral infection and reactivation. Reporting in Cell Host & Microbe, the scientists found they could reactivate latent HSV in a mouse model using compounds that turn on components of these HCF-1 protein complexes. Interestingly, some of these HCF-1-associated proteins also are involved in HIV reactivation from latency.
The researchers are continuing to investigate the protein complexes involved in promoting HSV gene expression, infection and reactivation from latency. Identifying these complexes and understanding the mechanisms by which they function can potentially reveal additional targets for the development of new therapeutics.
Researchers Discover Mitochondrial ‘Circuit Breaker’ That Protects Heart from Damage
A team of scientists from NIH has discovered biological mechanisms that appear to prevent damage to the heart muscle’s “power grid,” the network of mitochondrial circuits that provide energy to cells. One of those mechanisms, the researchers found, acts much like a circuit breaker, allowing energy to continue moving throughout the heart muscle cells even when individual components of those cells—the mitochondria—have been damaged.
Such protective mechanisms could one day help better understand how heart and skeletal muscle function under both healthy and unhealthy conditions, such as with heart disease, mitochondrial diseases and muscular dystrophy, the researchers say.
Their study appears in Cell Reports. The lead author of the study is Dr. Brian Glancy, an investigator with the Muscle Energetics Laboratory, NHLBI.
In 2015, members of this same NIH research team announced the discovery of the so-called mitochondrial power grid in the skeletal muscle. Since that pivotal discovery, some scientists have raised questions about how such a grid would protect itself from damage to the muscle cells. This new finding offers some key insights.
Using high-resolution 3-D images and special light-activated probes, the scientists revealed a two-part system protecting the heart muscle’s power grid from disease-related damage. Instead of being organized as one large, grid-like network such as in skeletal muscle, the mitochondrial circuits in the heart are arranged in parallel rows that form several smaller subnetworks, the researchers found.
This subnetwork acts as a mechanism to prevent damage by limiting the spread of electrical dysfunction to smaller regions.
The researchers compared the newly discovered circuit breaker mechanism to lightning striking a city power grid: Lights may flicker over the whole city, but once the circuit breaker activates, only part of the city loses power.
In addition to primary support by NHLBI, this study is also supported by NCI.
Gene Silencing Shows Promise for Treating Two Fatal Neurological Disorders
In two studies of mice, researchers showed that a drug, engineered to combat the gene that causes spinocerebellar ataxia type 2 (SCA2), might also be used to treat amyotrophic lateral sclerosis (ALS). Both studies were published in the journal Nature with funding from NINDS.
“Our results provide hope that we may one day be able to treat these devastating disorders,” said Dr. Stefan Pulst, professor and chair of neurology at the University of Utah and a senior author of one of the studies. In 1996, Pulst and other researchers discovered that mutations in the ataxin 2 gene cause SCA2, a fatal inherited disorder that primarily damages a part of the brain called the cerebellum, causing patients to have problems with balance, coordination, walking and eye movements.
For this study, his team found that they could reduce problems associated with SCA2 by injecting mouse brains with a drug programmed to silence the ataxin 2 gene. In the accompanying study, researchers showed that injections of the same type of drug into the brains of mice prevented early death and neurological problems associated with ALS, a paralyzing and often fatal disorder.
“Surprisingly, the ataxin 2 gene may act as a master key to unlocking treatments for ALS and other neurological disorders,” said Dr. Aaron Gitler of Stanford University, senior author of the second study. In 2010, Gitler and colleagues discovered a link between ataxin 2 mutations and ALS.
“Many years of research on yeast and flies laid the groundwork for these exciting results,” said Dr. Daniel Miller, a program director at NINDS. “They demonstrate that rigorous studies on simple disease models can lead to powerful insights that help us understand and potentially treat seemingly untreatable disorders.”