An Unwelcome Gift from Gorillas

July 3, 2015

By Medical Discovery News


You probably know that Acquired Immunodeficiency Syndrome (AIDS), which has affected 79 million people and killed 39 million since 1981, is the result of Human Immunodeficiency Virus (HIV). What you may not know is that there are several different types of this virus and they did not all come from the same source, making the search for HIV’s origins lengthy and complicated.

There are four groups of HIV-1: M, N, O, and P. Each of them was transmitted between African primates as simian immunodeficiency viruses (SIVs) before infecting humans, and each crossed species to humans independently. More than 40 African primates carry SIVs, which emerged up to 6 million years ago. It is likely that transmission to humans has occurred many times when hunters where exposed to the blood and tissues of infected animals. However the isolation of humans in Africa limited the spread of SIVs that crossed into humans until the last century.

It was not until modern travel allowed infected humans to move from the bush to cities and from there to other cities and countries that an HIV strain such as M took hold among humans, leading to a global pandemic. Group M causes more than 90 percent of AIDS cases and currently affects 40 million people worldwide. We already know that it came from chimpanzees in southern Cameroon. Group N also came from chimpanzees, but has infected less than 20 people.

Group O has infected about 100,000 people in Cameroon, Chad, Gabon, Niger, Nigeria, Senegal, and Togo. Although anti-retroviral drug combinations have made HIV infections survivable, many in Africa and the developing world do not have access to these treatments. Group P has only been isolated from two people. The origins of groups O and P were previously unknown, but now their source has been definitely confirmed: gorillas.

Scientists gathered fecal samples from western lowland, eastern lowland, and mountain gorillas, screening them for SIV antibodies and genetic information. Despite testing many wild troops of gorillas throughout Cameroon, Gabon, the Democratic Republic of Congo, and Uganda, the virus was identified at only four sites. Two strains of SIVs from southwestern Cameroon resembled HIV Group P and one from central Cameroon resembled Group O.

Not only does this data prove that gorillas were the immediate source of groups O and P, but the genetic information revealed that the viruses originated through a cross-species transmission from chimpanzees to gorillas. These are the same chimpanzees that infected humans, leading to groups M and N. Chimpanzees and gorillas share the same habitat, so the virus could have infected a gorilla if it bit a chimpanzee with SIV or was exposed to its blood or tissues.

Understanding the origins of HIV in humans is crucial if we want to prepare for additional viruses, especially SIV variants, entering the human population in the future, which will remain a risk as long as humans continue to hunt and eat primates.

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The Bright Side of Black Death

April 17, 2015

By Medical Discovery News

Bright Side of Black Death

It’s easy to think that nothing good could come from a disease that killed millions of people. But Dr. Pat Shipman, an anthropologist at Pennsylvania State University, disputed that notion in his recent article in “American Scientist,” where he suggested the Black Death that ravaged Europe in the Middle Ages may have resulted in some positive effects on the human population. Considering that we are in the midst another significant plague (the Ebola virus in West Africa), we could certainly use more information about the role of pandemics on human populations.

The Black Death or Bubonic plague started in the mid-1300s and was caused by a bacterium called Yersinia pestis, which typically enters the body through the bite of a flea. Once inside, the bacterium concentrates in our lymph glands, which swell as the bacteria grow and overwhelm the immune system, and the swollen glands, called buboes, turn black. The bacteria can make their way to the lungs and are then expelled by coughing, which infects others who breathe in the bacteria. The rapid spread of the infection and high mortality rates wiped out whole villages, causing not only death from disease but starvation as crops were not planted or harvested. It killed somewhere between 100 million to 200 million people in Europe alone, which was one-third to one-half of the entire continent’s population at the time. The plague originated in the Far East and spread due to improved trade routes between these two parts of the world.

Today, global travel is easier than ever thanks to extensive international airline networks. Just like with the Black Death, our transportation systems could enhance the spread of a modern plague. Of course, modern healthcare is also more sophisticated and effective, but as the latest Ebola outbreak has reminded us, a pandemic is a realistic possibility.

Dr. Sharon DeWitte, a biological anthropologist at the University of South Carolina, recently made several discoveries from comparing the skeletal remains of those who died from the Black Death and those who died from other causes during the same era. First, she found that older people, who were therefore already frail, died at higher rates. Killing this group at a higher rate created a strong source of natural selection, removing the weakest part of the population.

After the plague years, she found that in general people lived longer. In medieval times, living to 50 was considered old age. But the children and grandchildren of plague survivors lived longer, probably because their predecessors lived long enough to pass on advantageous genes. Today, a genetic variant in European people called the CCR5-D32 allele, which was favored during the natural selection initiated by the plague, is associated with a higher resistance to HIV/AIDS.

Microbes have an intimate relationship with human populations and have shaped human evolution through the ages. We may see survivors of the Ebola virus passing on similarly advantageous genes through natural selection as well.

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The Berlin Patient

Feb. 27, 2015

By Medical Discovery News

Millions of people around the world are infected with HIV, the virus that causes AIDS, but only one has ever been cured. Known as the “Berlin Patient,” Timothy Ray Brown is a 48-year-old American living in Germany. Scientists and physicians have wondered how he was cured, and some recently published studies in monkeys have provided one clue.

Brown had been HIV positive since 1995. When HIV infects the body’s cells, it integrates its genetic information into cells, making the virus a permanent part of the host’s genetic information. Brown’s HIV was held at bay by antiretroviral drugs that have made this infection survivable.  However, in 2006 he was diagnosed with acute myeloid leukemia (AML), a cancer unrelated to HIV. AML affects a group of blood cells in bone marrow called the myeloid cells. Brown underwent grueling chemotherapy that failed. In the hope of saving his life, he received two bone marrow transplants. The year of his first transplant, he stopped taking the antiretrovirals, which would normally cause a patient’s HIV levels to skyrocket.

Yet, years later, there is no sign of the virus returning. Only traces of HIV’s genetic material have been found in his blood, and those pieces are unable to replicate. The big question now is: how was this accomplished?

His treatment for AML included three different factors that could have individually or collaboratively resulted in curing his HIV infection. First, in preparation for a bone marrow transplant, a patient is treated with a combination of chemotherapy and whole body radiation to eliminate the entire immune system in preparation for receiving a new one. Second, Brown received blood stem cell transplants from a person with a defective cell surface protein, CCR5, which is what HIV uses to enter cells. People with a CCR5 mutation are resistant to HIV infection. Third, his new immune system may have eliminated the virus and remnants of his old immune system that harbored it in something called a graft versus host reaction.

In an experiment to determine how Brown was cured of HIV, scientists isolated blood stem cells from three Rhesus Macaque monkeys and put them into cold storage. They then infected those monkeys as well as three control monkeys with an engineered version of HIV. Soon after infection, all six monkeys were treated with a cocktail of drugs, and just like in humans, the levels of the virus soon declined. A few months later, the first three monkeys underwent radiation treatments to eliminate their immune systems, and then their immune systems were restored using their own stem cells from storage. Months later, the antiretroviral drugs were withheld from all six monkeys, and the virus came roaring back in five of them. One of the monkeys who underwent the stem cell transplant did not have the virus return in its blood, but it was detected in some tissues.

This experiment established that the destruction of immune system prior to bone marrow transplant was not sufficient to eliminate the virus, so the selection of bone marrow cells resistant to HIV infection and/or the graft versus host reaction may be the reason Brown was cured of HIV. Further studies are needed before we will know exactly how HIV can be cured.

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Fungal Drug Forces HIV Suicide

Feb. 21, 2014

By Medical Discovery News

Fungal Drug Forces HIV Suicide

What do nail fungus and HIV have in common? As it turns out, the same drug may cure them both. A topical drug called Ciclopirox, commonly prescribed to treat nail fungus, has been found to kill HIV-infected cells in the lab.

The drugs that are currently used to treat HIV and prevent the progression to AIDS unfortunately do not eliminate the virus from the body. If people stop taking the drugs, the virus will rapidly take control. That means HIV-infected people have to stay on a combination of anti-retroviral drugs for the rest of their lives. Current combination drug therapies are very successful in controlling the virus and have made HIV a survivable disease. But many of the current HIV therapeutics have significant side effects including diarrhea, nausea, vomiting, and even damage to the liver and kidneys. They are also expensive, about $10,000-12,000 per patient per year in the U.S. It has long been a dream to find drugs that could eliminate the virus and cure HIV patients.

HIV is one member of a family of viruses called Lentiviruses. When these viruses infect someone, they enter host cells by binding to specific receptors on their surfaces. Once inside the cell, the virus’s genetic information is converted into DNA, the same type of molecule that human genes made of. The virus has an enzyme that inserts its genetic information into the genomes of the human cells. From that moment, that cell is infected for its life. Then the virus replicates and infects other cells.

Since the virus’s genetic information is now permanently lodged in the host cell’s genome, it is expressed and passed on to daughter cells if and when infected cells divide. That is why HIV-infected people must stay on anti-HIV medication for life. Without the medications the virus would replicate and eventually lead to immunodeficiency, progression to AIDS, and death. One of the defense mechanisms against viral infections is a pathway that allows a damaged or infected cell to commit suicide, thereby limiting the amount of viruses produced and spread. Unfortunately, HIV has evolved a mechanism to block this suicide pathway.

A research team from the New Jersey School of Medicine demonstrated that Ciclopirox, which is used by dermatologists and gynecologists to treat fungal infections, inhibits HIV gene expression. The drug also blocks an essential function of the infected host cells, reactivating the suicide pathway and leading to the death of HIV-infected cells, at least in lab cultures. Remarkably, when the drug was removed from the cultures, there was no resurgence of HIV, indicating the cultures no longer harbored the virus.

Before such a treatment can be applied to humans, a form of Ciclopirox that can be given systemically, such as a pill or shot that would apply the drug to cells throughout the body, must be developed. There are also other classes of drugs that may trigger the suicide of HIV-infected cells. Used in combination, this approach may offer for the very first time not only a treatment for HIV infection but possibly a cure.

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Bringing HIV Out of Hiding

March 15, 2013

By Medical Discovery News

Still tall, strong, and vibrant, Magic Johnson radiates the good health he exuded while playing professional basketball more than two decades ago. Yet for all that time he has been living with HIV, an infection controlled with a mix of potent drugs.

Though these antiretroviral drugs are highly effective, finding a cure for the lifelong disease remains elusive mainly due to a hidden pool of HIV-infected cells unreachable by current therapies. Recently a group of scientists successfully activated these cells, raising the hope of finding a cure for AIDS.

When HIV, the virus that causes AIDS, infects a cell, a copy of its genetic information is inserted in the cell’s genome and becomes a permanent part of that cell’s genetic information. After that, all future generations of the cell also contain the virus. 

In particular, HIV infects CD4+T white blood cells that become activated during infections.  After a patient is treated, the HIV-infected cells that survive revert back to a resting state, allowing the virus to become latent, lying dormant and unreachable by the immune system and current HIV drugs. This latent reservoir of infected cells is a major barrier to curing the disease, because anytime they’re activated the once-dormant viruses trigger a new round of infection.

The current standard therapy for HIV is called HAART, Highly Active Antiretroviral Therapy, which consists of three anti-HIV drugs given in combination.  Though highly effective in controlling HIV replication and in prolonged suppression of HIV levels in the blood, HAART isn’t capable of killing the virus in dormant infected CD4+T cells.

In the new study led by David Margolis at the University of North Carolina at Chapel Hill, a drug called Zolinza (Vorinostat) activated the virus in dormant infected T-cells, which may allow the immune system to locate and target the cells for eradication. Recent studies by Margolis and others have also shown that the drug attacks enzymes that keep HIV hiding in certain CD4+T cells.  Zolinza is a histone deacetylase (HDAC) inhibitor that is normally prescribed for mood disorders, certain lymphomas, and epileptic seizures.

Margolis’ team administered the drug to six HIV-infected men on HAART therapy. Within eight hours of taking Zolinza, all patients showed a five-fold increase in the amount of viral RNA, a marker of HIV replication in the CD4+T-cells. This means the latent HIV was activated, which will hopefully make it vulnerable to current treatment, but will more likely pave the way to a means of marking the infected cells for eradication by drugs or the body’s immune system.

The study also showed that while Zolinza promoted HIV replication, the viral loads in the blood did not go up since all the study patients were on the HAART regimen. Scientists will no doubt need to develop several treatment approaches to target latent HIV, but at least this latest discovery offers new hope for a cure.

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New Weapons Against TB

Jan. 18, 2013

By Medical Discovery News

Tuberculosis (TB), the world’s No. 2 killer from a single infectious agent, has a knack for resisting antibiotics. Doctors discovered combining antibiotics had better results, until recent years when TB evolved beyond existing antibiotic cocktails. That may change with a new drug combination that seems to work. 

The new therapy couldn’t come at a better time. Even though TB had been well controlled, it began to make a dramatic comeback in the 1980s. TB, caused by a bacterium called Mycobacterium tuberculosis, infects one person in the world every second. It’s among the top three killers of women and left 10 million children orphaned in 2009.

TB is also the leading cause of death for people with HIV because their weaker immune systems make them vulnerable to the disease. The rise of global HIV infections is largely to blame for the reemergence of TB. Currently, an estimated 14 million people worldwide are co-infected with HIV and TB, and most of them will die without treatment.

TB’s resurgence is also due to drug resistance. To treat people with active, extensively drug resistant strains of TB, doctors prescribe a combination of four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Yet in recent years completely drug resistant strains of TB have developed and pose a global threat.

TB is transmitted by inhaling the droplets of an infected person’s sneeze or cough, but also through ingestion. Most infections start in the lungs and initially have no symptoms or at worst feel like the flu. The immune system can wall off the bacteria in what is called a granuloma, a round structure with a core that encases the bacteria and infected cells. Nine out of 10 infections stop at this stage, but some people live with a latent infection for years.

In about 5 percent of cases, the latent TB bacteria reactivate after one to two years. The bacteria replicate rapidly and spread throughout the body. Signs and symptoms of active TB include long-lasting cough bringing up sputum and blood, unexplained weight loss, fatigue, fever, night sweats, chills, loss of appetite, pain with breathing or coughing, and chest pain. Though TB most often affects the lungs, it can also involve the genitourinary system, bones, joints, lymph nodes, and peritoneum.

If TB bacteria’s proliferation is not controlled by the immune system, a severe form of the disease called miliary TB develops. The bacteria eventually cause extensive and progressive damage to the structure of the lungs and ultimately death.

With the new drug combination, fewer people will suffer these ravaging consequences. One new cocktail is called PA-824 and consists of moxifloxacin, a relatively new antibiotic, and pyrazinamide, an older TB drug. The combination works faster than current therapies, and doesn’t seem to interact with HIV drugs.

At least three other drugs or combinations are in the testing phase, just in time to treat multiple-drug-resistant forms of this deadly disease. If effective, the drugs will help a global initiative to reverse the spread of TB by 2015.

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Lifesaving Venom

By Medical Discovery News

Sept. 1, 2012

Reversing Cerebral Palsy

People have evolved a fear of snakes out of necessity. One bite from a venomous snake can prove fatal, so it’s ironic that a number of remarkable drugs are derived not only from poisonous snakes, but other deadly creatures as well. Researchers increasingly prize this group of animals, believing their venom holds the promise of effective treatments for major disorders ranging from high blood pressure to heart disease to cancer.

Depending on the type of poisonous snake, a bite can cause a drop in platelets and lead to uncontrollable bleeding. Or it can, like the venom of the Brazilian pit viper, incapacitate victims by causing their blood pressure to plummet. But in smaller doses these same characteristics can reverse disease.

One group of drugs, called ACE inhibitors, brings down blood pressure by decreasing chemicals that tighten blood vessels so that blood flows more smoothly. Another drug, called tirofiban, comes from the saw-scaled viper, which has venom that thins the blood and causes victims to bleed out. As a drug, it’s an anticoagulant used to dissolve blood clots in people with a minor or impending heart attack.

Another venom with similar mechanisms comes from the Malayan pit viper, except it also possesses a protein that may dissolve clots for as long as six hours after stroke symptoms start. An international study is targeting this venom’s potential to expand the three-hour window required for current drugs to be effective. Allowing people more time to get to a hospital for evaluation and treatment makes a significant difference on their prognosis.

Other deadly creatures also have lifesaving potential. Scientists are studying the fatal Deathstalker scorpion native to North Africa and the Middle East. Yet, its venom contains Chlorotoxin, which just happens to attach to cancer cells by binding strongly to a cancer-specific protein called matrix metalloproteinase-2. By fluorescently labeling Chlorotoxin, surgeons can easily identify cancer tissues and remove them. Scientists also figured out that by radioactively labeling Chlorotoxin, the toxin targets tumor cells and the radiation kills them.

Another example is Cobratoxin, which Western pharmacists began experimenting with as early as the 1930s on patients with diseases such as multiple sclerosis (MS) and asthma. More recently, a modified form of Cobratoxin has been shown to block the development of induced MS in 90 percent of lab rats. Cobratoxin seems to stimulate a molecule called interleukin 27, which slows an overactive immune response that scientists believe may be causing the disease. A related toxin molecule called Cobrotoxin has been shown in studies to impede the spread of HIV by blocking the receptors the virus uses to infect cells.

While the field of venom study has grown, researchers are concerned that negative environmental impacts on some of the threatened venomous species will limit their work. Ultimately that reduces the number of potential life saving or life changing drugs that are possible.

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Slowing the Spread of HIV

By Medical Discovery News

Jan. 21, 2012

Slowing the Spread of HIV

Imagine living in a community where a third of the people have HIV. In parts of Uganda, Kenya and Botswana, people face that reality daily.

Even though money and resources are being used to educate the public there, social, political and cultural barriers continue to hinder efforts to control the epidemic. That’s why scientists around the world have spent years trying yet failing to come up with an HIV vaccine.

A new treatment approach using existing HIV drugs can prevent HIV infection. Studies out of the University of Washington and the Centers for Disease Control show treating uninfected individuals with anti-HIV drugs can prevent HIV infection.

These studies were done on couples where one person is infected with HIV and the other is HIV free. The uninfected partner is given a pill daily, either Tenofovir or Truvada, which combines Tenofovir and emetricitabine.

One study involved 1,219 Botswana couples where half the couples took Truvada and the other half took a placebo. The results showed that nine out of 601 participants taking Truvada contracted HIV during the study period, compared to 24 out of 599 participants taking a placebo. That’s a 63 percent reduction in HIV transmission.

In the second study, of the 4,758 couples, one third of the HIV-negative partners took Tenofovir once daily, one third took Truvada once daily, and the remaining third received a placebo. Results showed 18 partners taking Tenofovir became infected, 13 in partners taking Truvada, and 47 among those taking a placebo. That means the infection risk was 62 percent lower for those taking Tenofovir, and 73 percent lower with Truvada.

Additionally, a study of gay male couples taking Truvada showed a 44 percent lower transmission risk. These results are considered successful enough that although the U.S. Food and Drug Administration hasn’t approved Truvada for HIV-prevention, the Centers for Disease Control has already issued a guideline for those interested in starting the regimen.

Yet some AIDS groups in the United States are opposed to gay men using the drugs as a preventative, citing the 44 percent success rate as not effective enough because it could lead to riskier sexual practices and possibly create a drug-resistant HIV.

What’s clear now is Truvada and Tenofovir have the ability to make a tremendous impact on communities in sub-Saharan Africa, an area with nearly 70 percent of the world’s HIV cases. Since the side effects of these drugs are few, it will be easier to convince people not only to take them daily but to continue for the foreseeable future.

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