http://molpharm.aspetjournals.org/content/76/4/824.full

"An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule

Jacques J. Kessl, Jocelyn O. Eidahl, Nikolozi Shkriabai, Zhuojun Zhao 1' Christopher J. McKee, Sonja Hess, Terrence R. Burke, Jr and Mamuka Kvaratskhelia

An Allosteric Mechanism for Inhibiting HIV-1 Integrase with a Small Molecule

HIV-1 integrase (IN) is a validated target for developing antiretroviral inhibitors. Using affinity acetylation and mass spectrometric (MS) analysis, we previously identified a tetra-acetylated inhibitor (2E)-3-[3,4-bis(acetoxy)phenyl]-2-propenoate-N-[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propenyl]-l-serine methyl ester; compound 1] that selectively modified Lys173 at the IN dimer interface. Here we extend our efforts to dissect the mechanism of inhibition and structural features that are important for the selective binding of compound 1. Using a subunit exchange assay, we found that the inhibitor strongly modulates dynamic interactions between IN subunits. Restricting such interactions does not directly interfere with IN binding to DNA substrates or cellular cofactor lens epithelium-derived growth factor, but it compromises the formation of the fully functional nucleoprotein complex. Studies comparing compound 1 with a structurally related IN inhibitor, the tetra-acetylated-chicoric acid derivative (2R,3R)-2,3-bis[[(2E)-3-[3,4-bis(acetyloxy)phenyl]-1-oxo-2-propen-1-yl]oxy]-butanedioic acid (compound 2), indicated striking mechanistic differences between these agents. The structures of the two inhibitors differ only in their central linker regions, with compounds 1 and 2 containing a single methyl ester group and two carboxylic acids, respectively. MS experiments highlighted the importance of these structural differences for selective binding of compound 1 to the IN dimer interface. Moreover, molecular modeling of compound 1 complexed to IN identified a potential inhibitor binding cavity and provided structural clues regarding a possible role of the central methyl ester group in establishing an extensive hydrogen bonding network with both interacting subunits. The proposed mechanism of action and binding site for the small-molecule inhibitor identified in the present study provide an attractive venue for developing allosteric inhibitors of HIV-1 IN..."

U.S. Gamers Crack Puzzle in AIDS Research that Stumped Scientists for Years

http://www.foxnews.com/health/2011/09/19/us-g...ped-scientists-for-years/

http://news.wustl.edu/news/Pages/25061.aspx

Nanoparticles loaded with bee venom kill HIV
March 7, 2013

[...] Bee venom contains a potent toxin called melittin that can poke holes in the protective envelope that surrounds HIV, and other viruses. Large amounts of free melittin can cause a lot of damage. Indeed, in addition to anti-viral therapy, the paper’s senior author [...] has shown melittin-loaded nanoparticles to be effective in killing tumor cells.

The new study shows that melittin loaded onto these nanoparticles does not harm normal cells. That’s because Hood added protective bumpers to the nanoparticle surface. When the nanoparticles come into contact with normal cells, which are much larger in size, the particles simply bounce off. HIV, on the other hand, is even smaller than the nanoparticle, so HIV fits between the bumpers and makes contact with the surface of the nanoparticle, where the bee toxin awaits.

“Melittin on the nanoparticles fuses with the viral envelope,” Hood says. “The melittin forms little pore-like attack complexes and ruptures the envelope, stripping it off the virus.”

According to Hood, an advantage of this approach is that the nanoparticle attacks an essential part of the virus’ structure. In contrast, most anti-HIV drugs inhibit the virus’s ability to replicate. But this anti-replication strategy does nothing to stop initial infection, and some strains of the virus have found ways around these drugs and reproduce anyway.

“We are attacking an inherent physical property of HIV,” Hood says. “Theoretically, there isn’t any way for the virus to adapt to that. The virus has to have a protective coat, a double-layered membrane that covers the virus.”

Beyond prevention in the form of a vaginal gel, Hood also sees potential for using nanoparticles with melittin as therapy for existing HIV infections, especially those that are drug-resistant. The nanoparticles could be injected intravenously and, in theory, would be able to clear HIV from the blood stream.

“The basic particle that we are using in these experiments was developed many years ago as an artificial blood product,” Hood says. “It didn’t work very well for delivering oxygen, but it circulates safely in the body and gives us a nice platform that we can adapt to fight different kinds of infections.”

Since melittin attacks double-layered membranes indiscriminately, this concept is not limited to HIV. Many viruses, including hepatitis B and C, rely on the same kind of protective envelope and would be vulnerable to melittin-loaded nanoparticles. [...]

This article leads me to wonder how recent research concerning using probiotic bacteria to help improve the digestive systems of the HIV positive is going...

http://www.medicalnewstoday.com/releases/250660.php

"Article Date: 26 Sep 2012

Risk For Esophageal, Stomach Cancers Increased In Patients With AIDS

People with AIDS are at increased risk for developing esophageal and stomach carcinoma as well as non-Hodgkin lymphomas (NHLs), according to a new study in Gastroenterology, the official journal of the American Gastroenterological Association.

"People diagnosed with AIDS are living longer due to improved therapies. However, they remain at increased risk of developing a number of different cancers," said E. Christina Persson, PhD, of the National Cancer Institute and lead author of this study. "An elevated risk of esophageal and stomach cancers had been observed before, but we were able to look at risk for subtypes of these malignancies."

In this study, researchers analyzed data from the HIV/AIDS Cancer Match Study, which links data collected from 1980 to 2007 for 16 U.S. population-based HIV and AIDS and cancer registries. They compared risks of stomach and esophageal cancers in 596,955 people with AIDS with those of the general population.

Those with AIDS had a 69 percent and 44 percent increased risk of esophageal and stomach carcinomas, respectively. The risks of NHLs - tumors of immune cells - in the stomach and esophagus were also strongly elevated. Additionally, the researchers' analysis showed a significant 53 percent increased risk of cancer of the lower stomach in people with AIDS. Since Helicobacter pylori infection is one of the causes of this type of stomach cancer, one explanation for an increased risk of this cancer might be an increased prevalence of H. pylori in people with AIDS..."

http://www.bbc.co.uk/news/magazine-21942921

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