Tuesday, April 29, 2008

A New Tactic Against HIV: T-Cell Tweaks

A New Tactic Against HIV: T-Cell Tweaks (from Wired.com)

By Brandon Keim Email


Scientists searching for anti-HIV drugs have been stymied by the fast-evolving, continuously adapting nature of the virus.

Some researchers are taking a different tack: rather than attacking the virus itself, they're targeting the cells that HIV infects.

In a study published yesterday in the Proceedings of the National Academy of Sciences, a team led by National Human Genome Research Institute cell biologist Pamela Schwartzberg turned off a protein that helps mobilize immune system cells against infection.

Once T-cells were stripped of the protein, HIV couldn't get traction: the signaling pathways it normally exploits to invade a cell and copy itself were short-circuited.


ITK, though targeted by some drug companies for its role in asthma and allergies, "has not been really thought about in the context of HIV," said Schwartzberg. "The work provides a model for finding novel targets that can affect HIV replication."

Selective Targeting of ITK blocks multiple steps of HIV Replication

Image: Courtesy of the Institut Cochin, a T-cell (blue) and a dendritic cell (yellow). The latter help calibrate immune response.

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1 comment:

Anonymous said...

Fascinating stuff Steve and very similar to the research stuff my wife has done. This is the link to her latest paper and copied below is the abstract from her Oxford D Phil.


Gayle Ritchie, Linacre College, submitted for the degree of DPhil, Trinity Term 2005.
Host-derived glycans on viral envelope spike glycoproteins can have several roles in the
virus lifecycle, including facilitating glycoprotein folding, in°uencing virus-cell interac-
tions, and evasion of host immunity. Ebola virus, HIV and SARS-CoV were used to
investigate these aspects of viral biology with the aim of using glycobiology to guide the
development of potential therapeutics.
The calnexin/calreticulin quality control folding pathway depends on the recognition
of monoglucosylated N-glycans. Inhibition of glycoprotein-chaperone interactions using
®-glucosidase inhibitors can result in a misfolded glycoprotein with altered biological
activity. Targeting this folding pathway may therefore be an e®ective means of viral
disease therapy. In this study, glucose- and galactose-based iminosugar compounds were
tested for antiviral activity against Ebola virus and SARS-CoV infection in vitro.
Viral glycoprotein carbohydrates can signi¯cantly in°uence viral tropism. Host-
derived glycan structures permit the virus to use host cell surface lectins for attachment
and entry. N- and O-glycosylation analysis of Ebola virus and SARS-CoV glycopro-
teins identi¯ed glycan epitopes speci¯c for host lectins, including the asialoglycoprotein
receptor, DC-SIGN and the human macrophage galactose lectin, and revealed the car-
bohydrate basis of viral tropism for these pathogens.
Glycoprotein-associated oligosaccharides can shield underlying antigenic protein epi-
topes from neutralising antibodies, thus facilitating evasion from host immunity. Re-
cently, however, the carbohydrate-speci¯c anti-HIV antibody 2G12 was isolated. Using
the structure of 2G12 as a template for immunogen design, the potent ®-mannosidase
inhibitor kifunensine was used to generate HIV-1 gp120 molecules with globally altered
N-glycosylation. The modi¯ed viral glycoproteins have two- to three-fold higher bind-
ing to 2G12, with at least two antibody binding sites per glycoprotein molecule. These
glycoproteins are potential novel anti-HIV immunogens.