Friday, March 27, 2015

Major Evolutionary Event: Retrovirus Invading Koala DNA!

Koalas throughout Australia are being infected with a circulating endogenous retrovirus. [Source: Quanta Magazine]

In the 1990s, a large number of koalas in Dreamworld, an Australian theme park, started dying of cancer. When it comes to animals, cancer clusters like these are often caused by retroviruses. These viruses insert their genetic material into the host genome, sometimes leading to oncogenesis. However, as veterinarians tested koalas for a retrovirus, they were shocked to discover that almost every koala was infected with koala retrovirus (KoRV).

KoRV is still spreading throughout Australia. Nearly all of the koalas in Queensland have been infected and there are moderate levels of KoRV between Queensland and the Southern islands, where the virus has yet to be detected. However, it may only be a matter of time.

The pervasiveness of KoRV indicates that it is likely infected the koala germ-line. As an endogenous retrovirus, it would be passed on from parent koalas to their offspring along with the rest of the koalas's genetic information.

All vertebrates have retroviral DNA embedded in their genomes. In fact, about 8% of the human genome is made up of endogenous retrovirus. However, these retroviral jumps into the germ-line genome occurred way back in our evolutionary history (and sometimes even drove evolution  -- we have endogenous retroviruses to thank for our placentas!)

Regular vs. Endogenous retroviruses, an infographic. [Source: Quanta Magazine]

This discovery is so exciting not only because endogenous retroviruses are awesome (certainly reason enough), but also because this is the first time scientists can observe a recent retroviral jump and its affects on a species.

Currently, KoRV is found circulating in the blood of koalas as well as in their sperm and eggs. It is also quite deadly. Usually endogenous retroviruses have been silenced in the host genome and do not cause disease. The infection was likely introduced tens of thousands of years ago (not so long on an evolutionary timescale), and KoRV already has two mutations that lowered its virulence, so this may be a general trend.

Researchers hope that KoRV will help explain one of the great endogenous retrovirus mysteries: "How does a deadly virus become one with the host without killing off the host population entirely?" Studying KoRV and its coevolution with koalas may also provide critical insights into our own evolutionary history.



Promising New Antiviral - Coming Soon for Transplant Patients?

Brincidofovir is a prodrug of cidofovir, a very hepatotoxic nucleoside analog. [Source:] 

Adenovirus is not usually on the list of deadly viruses that Ebola and HIV-1 inhabit. However, in transplant patients who have suppressed immune systems, adenovirus infection has a 60-80% mortality rate. There are currently no FDA-approved drugs against adenovirus. The current standard of care is cidofovir, a nucleoside analog with a high risk of kidney damage. It was approved for use in cytomegalovirus retinitis in AIDS patients. 

The pharmaceutical company Chimerix has developed an experimental antiviral that may offer a safer alternative. Brincidofovir is a prodrug of cidofovir. Chimerix uses a new lipid delivery technology that involves binding cidofovir with a lipid molecule. This conferees two major advantages: (1) it makes the drug absorbable by the gut (you can take it in a pill!) and (2) it can help target specific cells, where the cidofovir can be released, greatly enhancing the safety of the drug. 

The question is how can Chimerix  test the safety and efficacy of this new antiviral? The gold standard for clinical trials is a double blind trial in which one group receives the drug and another receives a placebo. However, when adenovirus infection has such a high mortality rate, is it ethical to give patients placebos? In response to this issue, Chimerix has received approval to conduct a late-stage clinical trial using “historic controls” instead. This type of study enables Chimerix to give brincidofovir to all patients who need it and compare their results with historic data. To keep these comparisons consistent, adenovirus patients will only be compared with other patients who received the same type of transplants and were treated at the same sites. The early data looks promising as it shows brincidofovir reduced the mortality of adenovirus infections by more than half.

Brincidofovir is also one of several experimental drugs approved for emergency use in the Ebola epidemic. Late-stage clinical trials for both adenovirus and CMV infection are moving forward, and there have been indications that it is useful in treating other viruses too, which is great news for transplant patients who often have multiple opportunistic infections. 


Thursday, March 26, 2015

German Measles Denier Ordered to Pay $106,000

Stefan Lanker - the man who claims the measles virus does not exist. Was anti-vaccination too mainstream for him?
[Source: "Question Everything" Youtube channel]

It all started with a challenge. Stefan Lanka, a German biologist known for promoting pseudoscientific theories such as HIV denialism and anti-vaccination, insisted that the measles virus did not exist. He claimed that measles is caused by a “psychosomatic illness” because of “traumatic separation.” And, to put his money where his theory is, he offered 100,000 euros (roughly $106,000 USD) to anyone who could prove that measles is viral in origin. 

David Bardens, a German doctor, responded by compiling evidence from multiple medical journals that measles is indeed caused by a virus. Of course, Lanka refused to actually pay, so Bardens sued. A German court recently ruled that Bardens’s proof was sufficient and that Lanka must pay. Lanka says that he plans to appeal.

When I first read about this case, I thought it was a hilarious publicity stunt. Then I realized that Lanka represents an all too common refusal to believe scientific evidence. He is a so-called scientist who took anti-vaccination one step farther and started going anti-virus. Such beliefs have led to precipitous declines in vaccination rates, especially for childhood diseases such as measles. Serious measles epidemics have swept the US and Europe. As herd immunity declines, innocent children, even those who have been vaccinated, may die of entirely preventable diseases. And that’s not funny at all.


Innovative New Design for Herpes Simplex Vaccine

Negatively stained transmission electron micrograph of herpes simplex virions. [Source: HHMI]

William Jacobs, an HHMI investigator at the Albert Einstein College of Medicine, may have a new way to vaccinate against herpes simplex virus (HSV) by turning the old vaccine paradigm on its head. HSV-1 and HSV-2 are responsible for the unsightly cold sores and genital lesions many individuals must live with. As of now, there has been no effective vaccine against either virus, but that may soon change.

The old HSV vaccine approach focused on eliciting neutralizing antibodies against the specific envelope glycoprotein gD. This protein was promising for two reasons: (1) it mediates viral entry and cell to cell spread, and (2) it stimulates a powerful immune response from the host. However, despite many attempts, there has yet to be an effective gD-based subunit vaccine.

Jacobs and his group tried something new. Instead of focusing on gD, what would happen if they got rid of it all together? They created a gD-deleted mutant HSV-2. To make the vaccine, they grew HSV-1 gD in a cell culture and then added the HSV-2 mutant to the mix. The mutant viruses soon picked up HSV-1 gD, which enabled them to infect target cells and replicate efficiently. However, without its own gD, the newly produced mutant viruses were unable to infect other cells.

This new HSV-2 vaccine was administered intravaginally and by skin contact to mice models that were later infected with wild type HSV-2. No virus was found in the vagina or any sensory nerves, where HSV is known to go latent. This vaccine also conferred immunity against both HSV-1 and HSV-2, likely due to morphological similarities between the viruses. There were also no negative side effects in immune compromised mice.

Further investigations reveal that this new vaccine strategy elicits antibody-dependent cell cytotoxicity (ADCC) instead of neutralizing antibodies, challenging old vaccine paradigms and introducing a powerful new way to confer immunity. In fact, this technology could be a scalable strategy. The HSV-2 vector could perhaps be reengineered as a vaccine against HIV, tuberculosis and other difficult-to-vaccinate mucosal infections.


Herpes Simplex Cluster in Mexico?

An indigenous child from Mexico's Bocoyna region putatively infected with HSV [Source: El Heraldo de Chihuahua]

El Heraldo de Chihuahua, a local Mexican news source, reported a possible herpes simplex virus (HSV) cluster in 20 children in the Bocoyna region in Mexico. These children are suffering from festering sores and scabs all over their faces. They live in a small, isolated village in the mountains where it is very difficult to obtain medical assistance. Although their families have tried to take them to the hospital, doctors refused to see them because they had no money. Currently, the infected children cannot eat or sleep because their bodies are covered in painful lesions. 

At this time, ProMed is unsure how El Heraldo determined that this disease cluster was caused by HSV, given that the children have yet to receive medical care. It would be interesting if this were caused by HSV though, given that HSV usually results in more limited lesions on either the mouth (HSV-1) or genital region (HSV-2). More serious or systemic HSV infections may be a sign of an opportunistic infection in cases of immunodeficiency. Herpes gladiatorum, one of the most infectious forms of HSV that is transmitted by skin to skin contact, may also be another culprit. So far, without any definitive tests, the differential diagnosis also includes impetigo (Staphylococcus aureus or group A beta-hemolytic streptococcus), cutaneous leishmaniasis (leishmania parasites) and ringworm (skin fungus). 

Here’s hoping that these children get the medical they need and that this outbreak is investigated and controlled. 


The Next Ebola Zones: Lessons and Predictions

Western doctors in spacesuits are not the answer to future epidemics.
[Source: NBC News] 

The Ebola epidemic, which has ravaged many countries in West Africa, is finally starting to be controlled. However, as the public health measures and practices have been set in place in Ebola-stricken countries, it’s time to think about where else it could strike next.

Save the Children has issued a report warning that at least 28 countries are vulnerable. Asides from cultural practices, one major reason that Ebola infections escalated from isolated outbreaks to a wide scale epidemic is a lack of established healthcare infrastructure. 

One of my favorite quotes is by David Satcher, the 16th US Surgeon General. On the back of my copy of the Control of Communicable Diseases Manual (20th edition), he says, 

“We can learn a lot from the agents of infectious diseases. They teach us the value of eternal vigilance and the price of neglect of our public health infrastucture. They highlight disparities in health and the impact of social determinants of health globally, as we continue to strive for global health equality.” 

So far, Ebola has infected almost 24,000 people and killed 10,000. The virus has been spread to not only neighboring West African countries, but also the US and Europe. 

Save the Children states that a “robust health system could have helped get Ebola under control much sooner, saving thousands of children's lives and billions of dollars.” Using the number of health care workers, government spending on health and mortality rates, Save the Children identified the world’s worst public health systems, which include Somalia, Chad, Nigeria, Afghanistan, Haiti, Ethiopia, Central Africa Republic, Guinea, Niger, and Mali. 

The group argues that building more effective public health systems would be cheaper than fighting full-blown epidemics. This would also save the lives of 17,000 children each day, who die of preventable diseases such as pneumonia and malaria. 

It’s essential to frame this epidemic as not only a horrifying tragedy, but also a tragic reality of global health inequality. To prevent this from occurring again, we must solve the root of the problem. 


B Cell Populations Cooperate in Creating Potent HIV-Fighting Antibodies

          When  individuals are infected with HIV, they carry the virus for life.  Inside their bodies, the virus is mutating and evolving and can develop into multiple separate strains.  Because humans acquire HIV from other humans in whom this process is already taking place, the initial HIV virus sample that infects a susceptible healthy individual often already contains a variety of slightly different versions of the virus, accelerating virus diversification within the new patient.  The diversity of HIV strains within a given individual represents one of several challenges the human immune system faces when attempting to battle HIV.
          With other non-HIV infections, when the immune system learns to recognize the pathogen it can mobilize a swarm of cells with specificity for that pathogen to attack it and clear the infection.  The diversity of HIV strains within a patient disrupts this process.  Typically an HIV patient will develop an immune response that targets some but not all of the HIV strains present in the body those strains are dissimilar.  One set of key molecules responsible for the “recognition” of pathogens are called antibodies.  Many research efforts aspiring to develop an HIV vaccine or cure target the development of broadly-neutralizing antibodies (bnAbs), antibodies that recognize a wide range of HIV strains rather than only a subset of the strains present in an infected individual.
          Research work published by Gao et al. in the July 2014 issue of Cell investigated the mechanisms that contribute to bnAb development in an HIV patient who naturally makes these antibodies.  They found that two different populations of an immune cell type called a B cell participate in this process.  Each B cell has a certain pathogen specificity and one key part of the immune response to an infection is the selective activation of B cells specific for pathogens the body is actively trying to fend off, which causes these B cells to mature into plasma cells that mass-produce antibodies with the same specificity as the B cells.  Gao et al. found the B cells that produced bnAbs were activated because they were successful at recognizing a particular variant of the virus with a mutation in part of its surface called Loop D.  These Loop D mutant viruses had been enriched in the population of HIV virus strains within this patient by a separate population of B cells that Gao et al. called the “helper B cells.”  Having more of these Loop D mutants due to the activity of the helper B cells increased activation of bnAB B cells and therefore increased bnAb production.  The helper B cells enriched the population of Loop D mutant HIV viruses because the Loop D mutants were resistant to the helper B cells.  Because the helper B cells could not recognize the Loop D mutants, the Loop D HIV population survived while the helper B cells targeted other variants of HIV in the patient’s body.  The activity of the helper B cells enriched the Loop D mutant population, which then activated the B cells that would mature into bnAb-producing plasma cells.
          View the original publication here:

I also made this diagram to help clarify the process of bnAb development described in this paper:

--Laurie Rumker