'Silencing' HIV with small bits of RNA

Researchers have shown that they can effectively tackle HIV-1 with small bits of gene-silencing RNA by delivering them directly to infected T cells, the major targets of the virus. While earlier studies had shown such a strategy could fight against many viruses including HIV-1, the new study in mice with human blood cells, so-called humanized mice, is the first to demonstrate an effective approach to systemic delivery in a living animal.

The researchers, led by Premlata Shankar of Texas Tech University Health Sciences Center and Sang-Kyung Lee of Hanyang University in Korea, reported their findings online as an immediate early publication on August 8th in Cell, a Cell Press journal.

" RNA interference has great potential as an antiviral treatment," said Premlata Shankar of Texas Tech University Health Sciences Center. "Using a delivery method for T cells, we now show that siRNA treatment can dramatically suppress HIV infection. This is nice proof of principle that it could be used as a therapeutic strategy. We think it has real promise, but there is a lot more to be done."

" No one had demonstrated before that HIV infection can be stopped in vivo, not just in cell lines but in animal models. It implies it might work in humans," added Priti Kumar of Harvard Medical School and Hanyang University.

Small interfering RNAs (siRNAs), as they are called, can effectively silence specific genes by ridding cells of messenger RNA before it is translated into functional proteins. Many previous studies had shown the effectiveness of RNAi in suppressing HIV replication in cell lines as well as in primary human T cells and macrophages.

"The challenge is delivery to the right cell [within a living animal]," Shankar said. "How do you get it in, especially into T cell where HIV infects? It's a big challenge."

In the new study, the researchers found a way. They combined part of an antibody that targets a surface molecule on T cells to an "oligo-9-arginine" peptide that allows the construct to attach and deliver siRNA to T cells.

Another impediment to studies of this kind had been the lack of a suitable small animal model that simulated HIV infection, the researchers said. In other words, mice can't normally get HIV. A recent development made that problem easier. Study co-author Leonard Schultz of The Jackson Laboratory and Dale Greiner from the University of Massachussets created an immunodeficient mouse that takes engraftments of human blood or stem cells well, yielding mice with human blood cells that are prone to HIV infection.

The researchers treated immunodeficient mice transplanted with human white blood cells with siRNAs targeting CCR5, a coreceptor on blood cells that allows the virus to enter, challenged them with HIV and then treated them further with a mixture of CCR5 siRNA and two siRNAs aimed at conserved HIV genes. In untreated mice, HIV-infected CD4 T cell levels dropped sharply. In contrast, in three out of four antiviral siRNA-treated mice, CD4 T cell levels remained essentially normal even four weeks after infection, they report.

" When treated with the siRNA mix, the infected mice looked almost like uninfected controls," Shankar said. "They had negligible levels of virus and their CD4 counts were maintained."

They then took a different approach. Rather than transplanting the mice with human blood cells, they injected newborn mice with human stem cells taken from umbilical cord blood. That way, the human blood cells develop in the mouse itself, such that the rodents' immune system doesn't recognize them as foreign, more closely mimicking the situation in humans. In that case as well, they found, the siRNA treatment dramatically cut the viral load.

The treatment also suppressed the virus and restored CD4 T cell counts in mice reconstituted with HIV-infected peripheral human blood cells. The finding provides evidence that the strategy has potential against an established HIV infection, in which multiple HIV "quasispecies" are likely to be present.

Further study will examine whether the method can also be used to target siRNAs to other cell types important to HIV infection.

" The availability of a preclinical animal model for HIV infection, as shown in this study, should allow rapid testing of these strategies, as well as other potential problems, such as viral escape and toxicity, that have to be resolved before RNAi therapy can be translated for clinical use," the researchers said.

Ultimately, Kumar said, siRNA therapy might be important as an adjunct or addition to the highly active antiretroviral therapy (HAART) used today.

Source: Cell Press

Related stories:

Study sheds light on causes of HIV dementia
A new study led by researchers at Albert Einstein College of Medicine of Yeshiva University has clarified how two major variants of HIV differ in their ability to cause neurologic complications. The finding, published in Journal of Neuroscience, highlights a new target for drugs that could prevent HIV-associated dementia, an incurable and increasingly common complication in people with AIDS. Even with anti-retroviral drug therapies, up to one-half of people infected with HIV will develop mild to moderate neurological complications, according to some estimates.
Interferon needed for cells to 'remember' how to defeat a virus
Scientists at UT Southwestern Medical Center have determined that the immune-system protein interferon plays a key role in "teaching" the immune system how to fight off repeated infections of the same virus.
Research identifies cell receptor as target for anti-inflammatory immune response
(PhysOrg.com) -- Invading pathogens provoke a series of molecular heroics that, when successful, muster an army of antibodies to neutralize the threat. Like with any close-quarter combat, however, an aggressive immune response runs the risk of friendly fire accidents. For the last decade, immunologists have intensively studied mechanisms evolved by the immune system to avoid these accidents by shutting off the immune response once the invaders have been eliminated.
An emergency brake in the brain
Brain researchers at the University of Oslo in Norway have penetrated deeply into the innermost secrets of the brain to find out how brain cells can survive a stroke. Strokes are usually caused by occlusion of one of the blood vessels in the brain. When blood is prevented from supplying vital oxygen and energy to the brain cells, their electrochemical balance is upset, and they cause damage to themselves and to the surrounding brain cells before they collapse and die. Often this affects the memory centre, the hippocampus, where the cells are particularly vulnerable.
Researchers develop new strategy for broad spectrum anti-viral drugs
Bavituximab, an anti-viral drug developed by UT Southwestern Medical Center researchers, shows promise as a new strategy to fight viral diseases, including potential bioterrorism agents.
Researchers identify toehold for HIV's assault on brain
Scientists have unraveled in unprecedented detail the cascade of events that go wrong in brain cells affected by HIV, a virus whose assault on the nervous system continues unabated despite antiviral medications that can keep the virus at bay for years in the rest of the body.
Recovering antibodies from 1918 flu pandemic survivors
(PhysOrg.com) -- Ninety years after the sweeping destruction of the 1918 flu pandemic, researchers at the Monroe Carell Jr. Children's Hospital at Vanderbilt have recovered antibodies to the virus — from elderly survivors of the original outbreak.
New research on gene sheds light on T-cell production
New research, just published by researchers from the University of Georgia, provides the first evidence that a key gene may be crucial to maintaining the production of the thymus and its disease-fighting T-cells after an animal's birth.

News discussion:

Medicine & Health news