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The Merits of Attacking Cytomegalovirus

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#1 reason

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Posted 12 December 2018 - 08:49 PM

Today's research results, published a few months ago, are one of a number of examples from recent years of a possible way to suppress or destroy persistent herpesviruses such as cytomegalovirus (CMV). These viruses cannot be effectively cleared from the body by the immune system; they remain latent to reemerge time and again. CMV itself is of particular interest because it is strongly implicated in the age-related dysfunction of the immune system. Research suggests that in old age an unsustainable fraction of immune cells become devoted to CMV, and since the decline of the thymus and hematopoietic stem cells ensure that the supply of replacement immune cells is reduced to a trickle, too few capable immune cells remain to adequately address other threats.

A range of studies provide evidence for people with greater exposure to CMV have a worse prognosis in later life, but it is far from clear as to whether (a) this is a burden that accumulates over time, and length of exposure is important, as studies of childhood adversity suggest, or (b) the burden arrives near entirely in later life, despite life-long infection with CMV, and requires some initial decline in immune function to start the process in earnest. The interesting question is whether it is worth trying to clear CMV from the body, given that it is largely harmless to young people, or whether the real target is the damage done to the immune system.

That damage, in the form of too many specialized immune cells and too low a rate of generation of new immune cells, will remain in effect even if CMV can be banished from the body of an older individual. The deficits of the aged immune system will have to be addressed via other approaches, such as targeted removal of CMV-specialized cells and regeneration of thymus and hematopoietic stem cells to restore a more youthful supply of new immune cells. Achieving those goals may well make CMV irrelevant. That said, it is worth considering getting rid of CMV might be more or less effective as a way to improve health in later life depending on when and how rapidly the consequent immune damage emerges.

Scientists Find a New Way to Attack Herpesviruses

Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. Normally, when a virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, it releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread.

"The way the virus operates is pretty cool, but it also presents a problem we couldn't solve. The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus. So how can the virus successfully multiply even after these proteins are gone?" The researchers found that, while PP71 is still present in the cell, it activates another protein known as IE1. This happens within the first few hours of the virus entering the cell, allowing the IE1 protein to take over after PP71 dies and continue creating new virus. To confirm their findings, the team created a synthetic version of the virus that allowed them to adjust the levels of the IE1 proteins using small molecules.

"We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently. But if the protein breaks down faster, the virus can't multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate." The new study could lead to a new therapeutic target to attack cytomegalovirus and other herpesviruses.

Feedback-mediated signal conversion promotes viral fitness

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient - they undergo immediate proteolysis but delayed synthesis - and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear.

Using an HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals - akin to early electronic transistors - and expose a potential target for therapeutic intervention.

View the full article at FightAging

#2 zorba990

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Posted 13 December 2018 - 02:09 AM

Better get DRACO....

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#3 QuestforLife

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Posted 13 December 2018 - 09:34 AM

Do we have a thread on DRACO?

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