Acne Drug Prevents HIV Breakout

Acne Drug Prevents HIV Breakout

  11:54:00 PM    Science Lover

---

Johns Hopkins scientists have found that a safe and inexpensive antibiotic in use since the 1970s for treating acne effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating.

Janice E. Clements, Ph.D. (Credit: Image courtesy of Johns Hopkins Medical Institutions)

The drug, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy), according to research published now online and appearing in print April 15 in The Journal of Infectious Diseases. "The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins," says Janice Clements, Ph.D., Mary Wallace Stanton Professor of Faculty Affairs, vice dean for faculty, and professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

"The big challenge clinicians deal with now in this country when treating HIV patients is keeping the virus locked in a dormant state," Clements adds. "While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus."

Unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. According to Clements, minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS.

If taken daily for life, HAART usually can protect people from becoming ill, but it's not a cure. The HIV virus is kept at a low level but isn't ever entirely purged; it stays quietly hidden in some immune cells. If a person stops HAART or misses a dose, the virus can reactivate out of those immune cells and begin to spread.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. The Hopkins group connected the dots between that study with previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.

"Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn't see any deleterious effect," says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins. "This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation."

The success with the animal model prompted the team to study in test tubes whether minocycline treatment affected latency in human T cells infected with HIV. Using cells from HIV-infected humans on HAART, the team isolated the "resting" immune cells and treated half of them with minocycline. Then they counted how many virus particles were reactivated, finding completely undetectable levels in the treated cells versus detectable levels in the untreated cells.

"Minocycline reduces the capability of the virus to emerge from resting infected T cells," Szeto explains. "It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person on HAART, and since it prevents virus activation it should maintain the level of viral latency or even lower it. That's the goal: Sustaining a latent non-infectious state."

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV.

"HIV requires T cell activation for efficient replication and reactivation of latent virus," Clement says, "so our new understanding about minocyline's effects on a T cell could help us to find even more drugs that target its signaling pathways."

The research was supported by grants from the National Institutes of Health.

Authors of the paper, in addition to Clements and Szeto, are Angela K. Brice, Sheila A. Barber and Robert F. Siliciano, all of Johns Hopkins. Also, Hung-Chih Yang of National Taiwan University Hospital.

Read More

Biologists Wake Dormant Viruses and Uncover Mechanism for Survival

Biologists Wake Dormant Viruses and Uncover Mechanism for Survival

  9:44:00 PM    Science Lover

---

It is known that viral "squatters" comprise nearly half of our genetic code. These genomic invaders inserted their DNA into our own millions of years ago when they infected our ancestors. But just how we keep them quiet and prevent them from attack was more of a mystery until EPFL researchers revived them.

This shows the functioning of Kap1 protein in mouse embrocation cells. (Credit: Pascal Coderay, pascal@salut.ch)

The reason we survive the presence of these endogenous retroviruses -- viruses that attack and are passed on through germ cells, the cells that give rise to eggs and sperm -- is because something keeps the killers silent. Now, publishing in the journal Nature, Didier Trono and his team from EPFL, in Switzerland, describe the mechanism. Their results provide insights into evolution and suggest potential new therapies in fighting another retrovirus -- HIV.

Read More

Goodbye Needle, Hello Smoothie: New Generation Oral Vaccine Uses Dairy Probiotics To Protect Against Disease

Goodbye Needle, Hello Smoothie: New Generation Oral Vaccine Uses Dairy Probiotics To Protect Against Disease

  1:55:00 AM    Science Lover

---

The dendritic cell (green) engulfs the lactobacilli (small blue dots),
which release the vaccine. The dendritic cells will induce the
proliferation and the activation of T and B cells which will
eliminate the infected cells. (Credit: Mansour Mohamadzadeh)

Instead of a dreaded injection with a needle, someday getting vaccinated against disease may be as pleasant as drinking a yogurt smoothie.

A researcher from the Northwestern University Feinberg School of Medicine has developed a new oral vaccine using probiotics, the healthy bacteria that are found in dairy products like yogurt and cheese. He has successfully used the approach in a preclinical study to create immunity to anthrax exposure. He also is using the method to develop a breast cancer vaccine and vaccines for various infectious diseases.

This new generation vaccine has big benefits beyond eliminating the "Ouch!" factor. Delivering the vaccine to the gut -- rather than injecting it into a muscle -- harnesses the full power of the body's primary immune force, which is located in the small intestine.

"This is potentially a great advance in the way we give vaccines to people," said Mansour Mohamadzadeh, the lead author and an associate professor of medicine in gastroenterology at the Feinberg School.

"You swallow the vaccine, and the bacteria colonize your intestine and start to produce the vaccine in your gut," Mohamadzadeh said. "Then it's quickly dispatched throughout your body. If you can activate the immune system in your gut, you get a much more powerful immune response than by injecting it. The pathogenic bacteria will be eliminated faster."

Most vaccines consist of protein and won't maintain their effectiveness after being digested by the stomach. However, the lactobacillus protects the vaccine until it is in the small intestine.

The Northwestern study was reported in a recent issue of the Proceedings of the National Academy of Science.

There are other advantages to the new oral vaccine. Probiotics, which are natural immune stimulators, eliminate the need for a chemical in traditional vaccines that inflames the immune system and triggers a local immune response. The chemical, called an adjuant, may cause side effects such as dizziness, arm swelling and vomiting. Probiotic vaccines also are inexpensive to produce.

The specially engineered vaccine gives more immune bang for the buck than an injected one because it induces a local and a systemic immune response. The vaccine targets the first line of gut immune cells called dendritic cells -- the commanders-in-chiefs of the immune system.

They engulf the vaccine then instruct the immune system's foot soldiers -- killer T-cells and B-cells -- to seek out and destroy any cells in the body infected with a particular bacterium or virus.

In the study, Mohamadzadeh fed mice the new oral anthrax vaccine, and then exposed them to anthrax bacteria. Eighty percent of the mice survived, which is comparable to the results when mice were injected with anthrax vaccine, he said.

"Their immune response was higher and more robust than with the injected vaccine," Mohamadzadeh said. The mice generated a much higher T and B immunity against the pathogenic bacteria.

Mohamadzadeh's vaccine technology can be applied to many other diseases. He is developing an oral vaccine for breast cancer using probiotics. The vaccine would use the Her2/neu breast cancer antigen, a protein highly produced by breast tumor cells, and train the immune system to destroy any cells producing Her2/neu, he said.

In addition, Mohamadzadeh has developed a "multi-tasking" cancer vaccine against breast, colon and pancreatic cancer that soon will be tested in mouse models.

The technology also can be used to develop a probiotic vaccine for HIV, hepatitis C and the flu, he said.

Terrence Barrrett, M.D., chief and professor of gastroenterology at the Feinberg School, said delivering a vaccine to the gut is the most logical route.

"Nature isn't used to seeing antigens injected into a muscle," said Barrett, who also is a physician at Northwestern Memorial Hospital. "The place where your immune system is designed to encounter and mount a defense against antigens is your gut."

======================================================

Journal reference:

1. M. Mohamadzadeh, T. Duong, S. J. Sandwick, T. Hoover, and T. R. Klaenhammer. Dendritic cell targeting of Bacillus anthracis protective antigen expressed by Lactobacillus acidophilus protects mice from lethal challenge. Proceedings of the National Academy of Sciences, 2009; DOI: 10.1073/pnas.0900029106

Adapted from materials provided by Northwestern University.

If you like this post, buy me a beer at $3!

Read More