Scientists Identify Key Factor That Controls HIV Latency

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ScienceDaily (June 27, 2009) — Scientists at the Gladstone Institutes of Virology and Immunology (GIVI) have found another clue that may lead to eradication of HIV from infected patients who have been on antiretroviral therapy. A real cure for HIV has been elusive because the virus can "hide" in a latent form in resting CD4-T cells. By understanding this "latency" effect, researchers can identify ways to reactivate the virus and enable complete clearance by current or future therapies.

Researchers in the laboratory of GIVI Associate Director Eric Verdin, MD have found that methylation of cytosine in the DNA of infected cells is associated with HIV latency and that inhibition of DNA methylation causes the reactivation of latent HIV. These observations offer a potential new strategy for inhibiting HIV latency and reactivating the virus. The discovery was reported in the current edition of PLoS Pathogens.
"While HIV-1 latency is likely to be a multifactorial process, we have shown that inhibiting the methylation of the provirus contributes to an almost complete reactivation of latent HIV-1," said lead author Steven E. Kauder.
The research team, which also included scientists from the University of Utah and Stockholm's Karolinska Institute, developed in vitro models of HIV-1 latency in T cells that harbor a full-length HIV genome. The provirus in the cell lines also encoded a fluorescent marker to illuminate HIV-1 transcriptional activity.
In addition to finding that DNA methylation is a mechanism of latency, the scientists also discovered that a host protein, called methlyl-CpG binding domain protein 2 (MBD2) binds to the methylated HIV DNA and is an important mediator of latency.
"Interfering with methylation greatly potentiates the reactivation of HIV," Kauder said. In this study, the researchers found that the drug 5-aza-2'deoxycytidine (aza-CdR) can inhibit HIV methylation and cause the virus to reactivate.
"Combined with other areas of our investigation into HIV latency, this research provides important new knowledge about the process and opens many new pathways for future study," said Dr. Verdin, senior author of the study.
The research team included Alberto Bosque and Vicente Planelles of the University of Utah and Annica Lindqvist of Karolinska University. The study was supported by the National Institutes of Health
Eric Verdin's primary affiliation is with the Gladstone Institute of Virology and Immunology, where his laboratory is located and all his research is conducted. He is also professor of medicine at the University of California, San Francisco.
Adapted from materials provided by Gladstone Institutes, via EurekAlert!, a service of AAAS.

Scientists Show Bacteria Can 'Learn' And Plan Ahead

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ScienceDaily (June 18, 2009) — Bacteria can anticipate a future event and prepare for it, according to new research at the Weizmann Institute of Science. In a paper that appeared June 17 in Nature, Prof. Yitzhak Pilpel, doctoral student Amir Mitchell and research associate Dr. Orna Dahan of the Institute's Molecular Genetics Department, together with Prof. Martin Kupiec and Gal Romano of Tel Aviv University, examined microorganisms living in environments that change in predictable ways.

Their findings show that these microorganisms' genetic networks are hard-wired to 'foresee' what comes next in the sequence of events and begin responding to the new state of affairs before its onset.
E. coli bacteria, for instance, which normally cruise harmlessly down the digestive tract, encounter a number of different environments on their way. In particular, they find that one type of sugar – lactose – is invariably followed by a second sugar – maltose – soon afterward. Pilpel and his team of the Molecular Genetics Department, checked the bacterium's genetic response to lactose, and found that, in addition to the genes that enable it to digest lactose, the gene network for utilizing maltose was partially activated. When they switched the order of the sugars, giving the bacteria maltose first, there was no corresponding activation of lactose genes, implying that bacteria have naturally 'learned' to get ready for a serving of maltose after a lactose appetizer.
Another microorganism that experiences consistent changes is wine yeast. As fermentation progresses, sugar and acidity levels change, alcohol levels rise, and the yeast's environment heats up. Although the system was somewhat more complicated that that of E. coli, the scientists found that when the wine yeast feel the heat, they begin activating genes for dealing with the stresses of the next stage. Further analysis showed that this anticipation and early response is an evolutionary adaptation that increases the organism's chances of survival.
Ivan Pavlov first demonstrated this type of adaptive anticipation, known as a conditioned response, in dogs in the 1890s. He trained the dogs to salivate in response to a stimulus by repeatedly ringing a bell before giving them food. In the microorganisms, says Pilpel, 'evolution over many generations replaces conditioned learning, but the end result is similar.' 'In both evolution and learning,' says Mitchell, 'the organism adapts its responses to environmental cues, improving its ability to survive.' Romano: 'This is not a generalized stress response, but one that is precisely geared to an anticipated event.'
To see whether the microorganisms were truly exhibiting a conditioned response, Pilpel and Mitchell devised a further test for the E. coli based on another of Pavlov's experiments. When Pavlov stopped giving the dogs food after ringing the bell, the conditioned response faded until they eventually ceased salivating at its sound. The scientists did something similar, using bacteria grown by Dr. Erez Dekel, in the lab of Prof. Uri Alon of the Molecular Cell Biology Department, in an environment containing the first sugar, lactose, but not following it up with maltose. After several months, the bacteria had evolved to stop activating their maltose genes at the taste of lactose, only turning them on when maltose was actually available.
'This showed us that there is a cost to advanced preparation, but that the benefits to the organism outweigh the costs in the right circumstances,' says Pilpel. What are those circumstances? Based on the experimental evidence, the research team created a sort of cost/benefit model to predict the types of situations in which an organism could increase its chances of survival by evolving to anticipate future events. They are already planning a number of new tests for their model, as well as different avenues of experimentation based on the insights they have gained.
Pilpel and his team believe that genetic conditioned response may be a widespread means of evolutionary adaptation that enhances survival in many organisms – one that may also take place in the cells of higher organisms, including humans. These findings could have practical implications, as well. Genetically engineered microorganisms for fermenting plant materials to produce biofuels, for example, might work more efficiently if they gained the genetic ability to prepare themselves for the next step in the process.
Prof. Yitzhak Pilpel's research is supported by the Ben May Charitable Trust and Madame Huguette Nazez, Paris, France.
Adapted from materials provided by Weizmann Institute of Science, via EurekAlert!, a service of AAAS.

Breakthrough in the treatment of bacterial meningitis

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It can take just hours after the symptoms appear for someone to die from bacterial meningitis. Now, after years of research, experts at The University of Nottingham have finally discovered how the deadly meningococcal bacteria is able to break through the body's natural defence mechanism and attack the brain.

The discovery could lead to better treatment and vaccines for meningitis and could save the lives of hundreds of children.
Bacterial meningitis in childhood is almost exclusively caused by the respiratory tract pathogens Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. The mechanism used by these lethal germs to break through the blood brain barrier (BBB) has, until now, been unknown.
The team led by Dlawer Ala'Aldeen, Professor of Clinical Microbiology and Head of the Molecular Bacteriology and Immunology Group at the Centre for Biomolecular Sciences, recently discovered that all three pathogens target the same receptor on human cerebrovascular endothelial cells — the specialised filtering system that protects our brain from disease — enabling the organisms to cross the blood-brain barrier.
Their findings, published today in The Journal of Clinical Investigation, suggest that disruption or modulation of this interaction of bacterial adhesins with the receptor might offer unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.
Professor Ala'Aldeen, who has been studying meningitis and its causes for over 20 years, said: "This is a significant breakthrough which will help us design novel strategies for the prevention and treatment of bacterial meningitis. Identification of the human receptor and bacterial ligands is like identifying a mysterious key and its lock, which will open new doors and pave the way for new discoveries."
The research, carried out in collaboration with the Department of Infectious Diseases at St. Jude Children's Research Hospital in Memphis Tennessee, also involved students from the University who have been regular and willing volunteers in the research programme.
Professor Ala'Aldeen said: "The ultimate aim is to save lives by protecting the healthy and curing the sick. We are one step closer to new breakthroughs that would prevent disease or its complications. There still is a long way to go before we have the ultimate vaccine and the ultimate treatment of bacterial meningitis."
Source: University of Nottingham (news : web)

Fighting Malaria By Tricking Mosquito's Sense Of Smell

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http://www.sciencedaily.com/releases/2007/08/070830122259.htm

Science Daily — By mapping a specialized sensory organ that the malaria mosquito uses to zero in on its human prey, an international team of researchers has taken an important step toward developing new and improved repellents and attractants that can be used to reduce the threat of malaria, generally considered the most prevalent life-threatening disease in the world.

The sensory organ is the maxillary palp. It is one of three structures extending from the mosquito's head that together provide it with its sense of smell and taste. The other two are the feathery antennae that serve as general-purpose olfactory organs and respond to a wide range of different chemicals and the proboscis that contains sensors designed for close-in odor and taste detection.
The detailed map of the maxillary palp, which was published online in the journal Current Biology on Aug. 30, has determined that it contains a unique array of highly specialized receptor cells that detect carbon dioxide and octenol, key chemical signals that the insects use to find human prey.
"These receptors are highly sensitive, which suggests that the maxillary palps may serve as the malaria mosquito's long-range detection system," says Tan Lu, a graduate student at Vanderbilt who is the paper's first author.
"We haven't proven it yet, but the implication is that if you took away the maxillary palp the mosquito would not do nearly as well at finding human prey," adds Laurence J. Zwiebel, professor of biological sciences at Vanderbilt, who headed the study.
The research was performed by collaborators from Vanderbilt, Yale and Wageningen University in the Netherlands. They are part of a team that also includes researchers from the Ifakara Health Research and Development Centre in Tanzania and the Medical Research Council Laboratories in the Gambia that is funded by a grant from the Foundation for the National Institutes of Health through the Grand Challenges to Global Health Initiative in 2005 to develop a chemical strategy to combat the spread of malaria by the Anopheles mosquito.
"This paper marks a threshold in our grand challenge project because it provides a biological context and then strips it down to a few molecular targets that we are using to develop chemical modifiers that should have direct impacts on the mosquito's behavior," says Zwiebel.
The study fills a major gap in the scientific understanding of the malaria mosquito's olfactory system. Although considerable research has been done on the physiology and molecular biology of Anopheles gambiae's antennae and proboscis, there have been few studies of its maxillary palps. Most of the previous work that had been done on this "accessory olfactory appendage" was performed in another species of mosquito, Aedes aeqypti, the carrier of dengue and yellow fever.
Previous work found that the maxillary palps of the A. aeqypti were sensitive to carbon dioxide and octenol. So the discovery that this was also the case in An. gambiae did not come as a big surprise. However, the researchers found that the malaria mosquito uses different sets of receptors for this purpose which help explain why it appears to rely less on carbon dioxide and more on human-specific chemical compounds in seeking out hosts than does A. aegypti.
The mosquito's elaborate "nose" consists of hundreds of hollow hair-like structures called sensilla attached to its antennae, maxillary palps and proboscis. The tips of these structures are perforated with thousands of tiny holes that let aromatic compounds penetrate to their interior, where they encounter thread-like extensions from neurons which are tuned to detect specific molecules.
Compared to the mosquito's antennae, which are designed to detect hundreds of different compounds, the study found that the maxillary palps are highly specialized. "The amazing thing that we found was that all the sensory hairs that line the bottom of the maxillary palps are identical," says Zwiebel. They are all attached to three neurons: one which is tuned to detect carbon dioxide; one which is tuned to detect octenol; and one which serves to enhance general olfactory reception.
In addition to Zwiebel and Lu, the Vanderbilt researchers who contributed to the study are Quirong Wang, Michael Rutzler, Hyung-Wook Kwon and R. Jason Pitts. The Wageningen team consists of Yu Tong Qiu, Joop J.A. van Loon and Willem Takken. The Yale contributors are Jae Young Kwon and John R. Carlson. The research was funded by a Gates Foundation Grand Challenges in Global Health Initiative grant and by grants from the National Institutes of Health. Note: This story has been adapted from a news release issued by Vanderbilt University.

Fausto Intilla

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