http://www.eurekalert.org/pub_releases/2011-10/uonc-dav100311.php

"Public release date: 6-Oct-2011

Distinct AIDS viruses found in cerebrospinal fluid of people with HIV dementia

CHAPEL HILL, N.C. -- When the virus that causes AIDS infects the central nervous system, it can lead to the development of a severe neurological disease called HIV-associated dementia (HAD).

The advent of highly active antiretroviral therapy, or HAART, has helped reduce HAD. But some studies show that HAART may not offer complete protection from less severe HIV-associated neurological problems, nor might it always help to reverse it. As people live longer with AIDS, their risk of developing neurological problems may increase.

New research for the first time may have pinpointed a possible explanation for the problem, one that might also help predict who is at greatest risk for HAD.

Scientists led by researchers from the University of North Carolina at Chapel Hill School of Medicine have discovered that some people diagnosed with HAD have two genetically distinct HIV types in their cerebrospinal fluid (CSF), the clear fluid found in the spaces around and inside the brain and spinal cord. What's more, these variants are not detected in HIV circulating in the blood, and one of them could be present years before the onset of dementia. The detection of these viruses in the CSF is evidence that they are growing in the central nervous system..."

http://www.medicalnewstoday.com/releases/235486.php

"Article Date: 06 Oct 2011

Cell-Penetrating Peptides For Drug Delivery Act Like A Swiss Army Knife

Cell-penetrating peptides, such as the HIV TAT peptide, are able to enter cells using a number of mechanisms, from direct entry to endocytosis, a process by which cells internalize molecules by engulfing them.

Further, these cell-penetrating peptides, or CPPs, can facilitate the cellular transfer of various molecular cargoes, from small chemical molecules to nano-sized particles and large fragments of DNA. Because of this ability, CPPs hold great potential as in vitro and in vivo delivery vehicles for use in research and for the targeted delivery of therapeutics to individual cells.

But exactly how cell-penetrating peptides - and particularly the HIV TAT peptide - accomplish these tasks has so far been a mystery.

"The HIV TAT peptide is special. People discovered that one can attach almost anything to this peptide and it could drag it across the cell," said Gerard Wong, a professor of bioengineering and of chemistry and biochemistry at the UCLA Henry Samueli School of Engineering and Applied Science and the California NanoSystems Institute at UCLA. "So there are obvious beneficial drug-delivery and biotechnology applications."

In a new study published in Proceedings of the National Academy of Sciences, UCLA Engineering researchers, including Wong and bioengineering professors Timothy Deming and Daniel Kamei, identify how HIV TAT peptides can have multiple interactions with the cell membrane, the actin cytoskeleton and specific cell-surface receptors to produce multiple pathways of translocation under different conditions.

Moreover, because the researchers now understand how cell-penetrating peptides work, they say it is possible to formulate a general recipe for reprograming normal peptides into CPPs.

"Prior to this, people didn't really know how it all worked, but we found that the HIV TAT peptide is really kind of like a Swiss Army Knife molecule, in that it can interact very strongly with membranes, as well as with the cytoskeletons of cells," said Wong, the study's lead author. "The second part wasn't well appreciated by the field..."

I have read in the past that HIV's wicked TAT gene plays an important role in its ability to invade the Brain and cause HIV related dementia http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0003731 . Chinese research however suggests that there may be ways of trashing HIV TAT's ability to cause at least some of its mischief...

"HDAC1/NFκB pathway is involved in curcumin inhibiting of Tat-mediated long terminal repeat transactivation.
Zhang HS, Ruan Z, Sang WW. College of Life Science & Bioengineering, Beijing University of Technology, Beijing, China. zhanghs@bjut.edu.cn.

Abstract

Chromatin remodeling, especially in relation to the transactivator Tat, is an essential event for human immunodeficiency virus-1 (HIV-1) transcription. Curcumin has been shown to suppress pathways linked to HIV-1 replication. We investigated whether curcumin had the potential to inhibit Tat-induced long terminal repeat region (LTR) transactivation. As we shown, curcumin inhibited Tat-induced LTR transcativation, while knockdown of histone deacetylase 1 (HDAC1) by siRNA potentiated Tat-induced HIV-1 transcativation. Curcumin reversed Tat-induced down-regulation of HDAC1 expression in multinuclear activation of galactosidase indicator (MAGI) cells. Treatment with curcumin reversed Tat-induced dissociation of HDAC1 from LTR; and curcumin caused a decline in the binding of p65/NFκB to LTR promoters stimulated by Tat. Curcumin attenuated Tat-induced p65 phosphorylation and IKK phosphorylation. Curcumin reversed Tat-mediated reduction in AMPK activation and downstream acetyl-CoA carboxylase (ACC) activation. Collectively, our data provide new insights into understanding of the molecular mechanisms of curcumin inhibited Tat-regulated transcription, suggesting that targeting AMPK/HDAC1/NFκB pathway could serve as new anti-HIV-1 agents. J. Cell. Physiol. 226: 3385-3391, 2011.

http://www.sciencedaily.com/releases/2011/10/111012113550.htm

[...] Human Immunodeficiency Virus infection remains incurable because HIV can sneak through the BBB -- a network of special blood vessels and cells that protects the brain from many harmful substances -- while many of the most powerful anti-viral medications cannot. A pump at the BBB suctions anti-viral medicines away like a biological vacuum cleaner, leaving a reservoir of HIV in the brain. To overcome this hurdle and get rid of the last footholds of HIV, the researchers set out to develop a new group of drugs that can plug up the vacuuming mechanism and then sneak across the BBB to fight HIV. Their approach involves gluing two anti-HIV drug molecules together with a "tether." This dual drug plugs up the BBB vacuum cleaner and can then sneak across the BBB. Once across, the tether disintegrates, freeing the two drug molecules to kill the virus. [...]

It seems that in addition to the Fight Against AIDS at Home computer based research project we are all contributing to, Scripps research Scientists are attacking HIV from other angles.

http://www.eurekalert.org/pub_releases/2011-10/sri-srs101211.php

"Public release date: 13-Oct-2011

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute

Scripps Research scientists reveal surprising picture of how powerful antibody neutralizes HIV
The findings advance AIDS vaccine development

LA JOLLA, CA, October 13, 2011 – Researchers at The Scripps Research Institute have uncovered the surprising details of how a powerful anti-HIV antibody grabs hold of the virus. The findings, published in Science Express on October 13, 2011, highlight a major vulnerability of HIV and suggest a new target for vaccine development.

"What's unexpected and unique about this antibody is that it not only attaches to the sugar coating of the virus but also reaches through to grab part of the virus's envelope protein," said the report's co-senior author Dennis Burton, a professor at The Scripps Research Institute and scientific director of the International AIDS Vaccine Initiative's (IAVI) Neutralizing Antibody Center, based on the Scripps Research La Jolla campus.

"We can now start to think about constructing mimics of these viral structures to use in candidate vaccines," said co-senior author Ian Wilson, who is Hansen Professor of Structural Biology and member of the Skaggs Institute for Chemical Biology at Scripps Research.

Other institutions in the United States, United Kingdom, Japan, and the Netherlands contributed to the research as part of an ongoing global HIV vaccine development effort.

Getting a Better Grip on HIV

Researchers from the current team recently isolated the new antibody and 16 others from the blood of HIV-infected volunteers, in work they reported online in the journal Nature on August 17, 2011. Since the 1990s, Burton, Wilson, and other researchers have been searching for such "broadly neutralizing" antibodies against HIV—antibodies that work against many of the various strains of the fast-mutating virus—and by now have found more than a dozen. PGT 128, the antibody described in the new report, can neutralize about 70 percent of globally circulating HIV strains by blocking their ability to infect cells. It also can do so much more potently—in other words, in smaller concentrations of antibody molecules—than any previously reported broadly neutralizing anti-HIV antibody.

The new report illuminates why PGT 128 is so effective at neutralizing HIV. Using the Wilson lab's expertise in X-ray crystallography, Robert Pejchal, a research associate in the Wilson lab, determined the structure of PGT 128 joined to its binding site on molecular mockups of the virus, designed in part by Robyn Stanfield and Pejchal in the Wilson group and Bill Schief, now an IAVI principal scientist and associate professor at Scripps Research, and his group. With these structural data, and by experimentally mutating and altering the viral target site, they could see that PGT 128 works in part by binding to glycans on the viral surface.

Thickets of these sugars normally surround HIV's envelope protein, gp120, largely shielding it from attack by the immune system. Nevertheless, PGT 128 manages to bind to two closely spaced glycans, and at the same time reaches through the rest of the "glycan shield" to take hold of a small part of structure on gp120 known as the V3 loop. This penetration of the glycan shield by PGT 128 was also visualized by electron microscopy with a trimeric form of the gp120/gp41 envelope protein of HIV-1 by Reza Kayat and Andrew Ward of Scripps Research; this revealed that the PGT 128 epitope appears to be readily accessible on the virus.

"Both of these glycans appear in most HIV strains, which helps explain why PGT 128 is so broadly neutralizing," said Katie J. Doores, a research associate in the Burton lab who was one of the report's lead authors. PGT 128 also engages V3 by its backbone structure, which doesn't vary as much as other parts of the virus because it is required for infection.

PGT 128's extreme potency is harder to explain. The antibody binds to gp120 in a way that presumably disrupts its ability to lock onto human cells and infect them. Yet it doesn't bind to gp120 many times more tightly than other anti-HIV antibodies. The team's analysis hints that PGT 128 may be extraordinarily potent because it also binds two separate gp120 molecules, thus tying up not one but two cell-infecting structures. Other mechanisms may also be at work.

Toward an AIDS Vaccine

Researchers hope to use the knowledge of these antibodies' binding sites on HIV to develop vaccines that stimulate a long-term—perhaps lifetime—protective antibody response against those same vulnerable sites.

"We'll probably need multiple targets on the virus for a successful vaccine, but certainly PGT 128 shows us a very good target," said Burton.

Intriguingly, the basic motif of PGT 128's target may mark a general vulnerability for HIV. "Other research is also starting to suggest that you can grab onto two glycans and a beta strand and get very potent and broad neutralizing antibodies against HIV," Wilson said.

###

In addition to Pejchal, Doores, and Khayat, Laura M. Walker of Scripps Research and Po-Ssu Huang of University of Washington at Seattle were co-first authors of the study, "A potent and broad neutralizing antibody recognizes and penetrates the HIV glycan shield." Along with Wilson, Burton, and Ward, additional contributors were Sheng-Kai Wang, Chi-Huey Wong, Robyn L. Stanfield, Jean-Philippe Julien, Alejandra Ramos, Ryan McBride, and James C. Paulson of Scripps Research, and Pascal Poignard, and William R. Schief of Scripps Research, IAVI and University of Washington at Seattle; Max Crispin and Christopher N. Scanlan of the University of Oxford; Rafael Depetris and John P. Moore of Weill Medical College of Cornell University; Umesh Katpally, Andre Marozsan, Albert Cupo, and William C. Olson of Progenics Pharmaceuticals; Sebastien Maloveste of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health; Yan Liu and Ten Feizi of Imperial College, London; Yukishige Ito of the RIKEN Advanced Science Institute in Japan; and Cassandra Ogohara of University of Washington at Seattle.

The research was supported by the International AIDS Vaccine Initiative, National Institutes of Health, the U.S. Department of Energy, the Canadian Institutes of Health Research, the UK Research Councils, the Ragon Institute, and other organizations.