sábado, 14 de maio de 2011

Latência do HIV Publicado na Science de 13 de maio

Understanding HIV Latency to Undo It
Jon Cohen
With reservoirs of latently infected cells in the spotlight as the central obstacle to a cure, attention is focusing on the fine details of how HIV does this deep dive and stays submerged.

Twenty-five years ago, when HIV still went by the names of HTLV-III and LAV, researchers recognized that the AIDS virus could lie dormant inside human chromosomes, which they erroneously suggested might explain the time lag between infection and disease. Today, with reservoirs of latently infected cells in the spotlight as the central obstacle to a cure (see main text, p. 784), attention is focusing on the fine details of how HIV does this deep dive and stays submerged. “We really need to understand what maintains latency in order to figure out how to reverse it,” says Douglas Richman, a virologist at the University of California, San Diego. “Right now, it's sort of coarse guesses.”

HIV, unlike herpesviruses, carries no gene that pushes cells into a narcoleptic state. “Latency is not a biological property of the virus,” says Eric Verdin, who studies HIV dormancy at the Gladstone Institute of Virology and Immunology in San Francisco, California. “Latency only becomes relevant because drugs can now suppress 99% of HIV replication, and that's what is left.”

HIV typically stumbles into a latent state when it infects an actively dividing CD4 white blood cell that then downshifts into a “resting” gear. These resting CD4s can lounge around for years until they are called into action and start dividing, at which point the HIV genes will be expressed along with the CD4 cell's own genes. Much effort has gone into characterizing the specific subsets of memory cells that make up the reservoir, as the distinction could prove critical to purging them.

Virologist Nicolas Chomont and immunologist Rafick-Pierre Sékaly of the Vaccine & Gene Therapy Institute of Florida in Port St. Lucie reported in the August 2009 issue of Nature Medicine that 85% of the reservoir consists of two distinct lineages of CD4s known as “transitional” or “central” memory cells. This finding was hugely influential, as it showed that the reservoirs of each lineage persist by different mechanisms: Central memory cells live for decades, and infected transitional memory cells persist by cloning themselves through a process called homeostatic proliferation. “As we try to get rid of them, we'll have to use different strategies,” Chomont says.

Other researchers have probed the interior of cells to better understand how proteins, enzymes, and both human and viral DNA all work together to keep HIV silent. Chromosomes tightly pack DNA, wrapping it around proteins called histones. Expression of genes, including those inserted by trespassers like HIV, takes place when these complexes uncoil (see illustration). Specifically, as DNA unspools from histones, protein sherpas guide a suite of transcription factors to genes, which then make the amino acids that form proteins. The most popular purge strategies today aim to selectively induce HIV DNA to uncoil.

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Deep sleep. When HIV infects activated CD4s and integrates with chromosomes, some cells enter a resting state. These latently infected central memory cells can live for years. Interleukin-7 can also transform them into transitional memory cells that persist by cloning themselves. Purge drugs will likely have to attack these reservoirs with different strategies. One approach (inset) aims to kick-start transcription, waking up latently infected cells and triggering their demise.
One potential way to massage histones so they let loose and allow transcription to begin: protect the acetyl groups that bind to them. Enzymes known as histone deacetylases (HDACs) constantly remove these acetyl groups, which helps keep HIV latent. SAHA, a purge drug now in clinical studies (see table), inhibits HDACs.

A half-dozen other molecular mechanisms that contribute to latency are also possible targets to purge reservoirs. DNA methylation gums up histones, so blocking that process may unspool virus. Human protein complexes sequester critical transcription factors in different parts of the cell, and drugs might free the factors from bondage, allowing them to reach the viral DNA. After transcription begins, several other proteins elongate the new HIV being expressed, and spurring them along could help flush latent virus from cells, too.

Recent advances in laboratory models of latency, including artificial infection of memory CD4 cells and “humanized” mice, are clarifying finer points of how HIV stays quiescent and identifying novel purge drugs. “We have incredible tools now, and these technologies were not available 10 years ago,” says Vicente Planelles, a virologist at the University of Utah in Salt Lake City, who developed a new latent cell system.

Just as antiretroviral drugs had little impact against HIV until several compounds simultaneously attacked the virus at different stages of its life cycle, purging reservoirs may ultimately require a cocktail of interventions that undoes latency from multiple angles. “We have to find some combination to tickle the cell and the virus such that the virus can be expressed without vastly affecting all of the other uninfected cells in the body, and that's going to be tricky,” says David Margolis, a virologist at the University of North Carolina, Chapel Hill, who has done pioneering studies with HDAC inhibitors. “This is going to be a long, difficult thing to figure out.”

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