Fighting HIV With HIV,Researchers at the University of Pennsylvania School of Medicine report the first clinical test of a new gene therapy based on a disabled AIDS virus carrying genetic material that inhibits HIV replication. For the first application of the new vector five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were given a single infusion of their own immune cells that had been genetically modified for HIV resistance.

The researchers, led by Carl June, MD, and Bruce Levine, PhD, of the Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, along with Rob Roy MacGregor, MD, Professor of Medicine, report their findings in the online edition of the Proceedings of the National Academy of Sciences. Viral loads of the patients remained stable or decreased during the study, and one subject showed a sustained decrease in viral load. T-cell counts remained steady or increased in four patients during the nine-month trial. Additionally, in four patients, immune function specific to HIV improved.

Overall, the study results are significant, say the researchers, because it is the first demonstration of safety in humans for a lentiviral vector (of which HIV is an example) for any disease. Additionally, the vector, called VRX496, produced encouraging results in some patients where other treatments have failed.

"The goal of this phase I trial was safety and feasibility and the results established that," says June. "But the results also hint at something much more."

Each patient received one infusion of his or her own gene-modified T cells. The target dose was 10 billion cells, which is about 2 to 10 percent of the number of T cells in an average person. The T-cell count was unchanged early after the infusions. "We were able to detect the gene-modified cells for months, and in one or two patients, a year or more later," says Levine. "That's significant - showing that these cells just don't die inside the patient. The really interesting part of the study came when we saw a significant decrease in viral load in two patients, and in one patient, a very dramatic decrease.

But, cautions Levine, "just because this has produced encouraging results in one or two patients doesn't mean it will work for everyone. We have much more work to do." In the current study, each patient will be followed for 15 years.

Trojan Horses
"The new vector is a lab-modified HIV that has been disabled to allow it to function as a Trojan horse, carrying a gene that prevents new infectious HIV from being produced," says Levine. "Essentially, the vector puts a wrench in the HIV replication process." Instead of chemical- or protein-based HIV replication blockers, this approach is genetic and uses a disabled AIDS virus to carry an anti-HIV genetic payload. The modified AIDS virus is added to immune cells that have been removed from the patients' blood by apheresis, purified, genetically modified, and expanded by a process June and Levine developed. The modified immune cells are then returned to the patients' body by simple intravenous infusion.

This approach enables patients' own T cells, which are targets for HIV, to inhibit HIV replication - via the HIV vector and its anti-viral cargo. The HIV vector delivers an antisense RNA molecule that is the mirror image of an HIV gene called envelope to the T cells. When the modified T cells are given back to the patient, the antisense gene is permanently integrated into the cellular DNA. When the virus starts to replicate inside the host cell, the antisense gene prevents translation of the full-length HIV envelope gene, thereby shutting down HIV replication by preventing it from making essential building blocks for progeny virus. VRX496 was designed and produced by the Gaithersburg, Md. biotech company VIRxSYS Corp.

A New Field
The new vector is based on a lentivirus, a subgroup of the well-known retroviruses. The study and its safety profile to date have now opened up the field of lentiviral vectors, which have potential advantages over other viral vectors currently being studied because they infect T cells better than adenoviruses, a commonly used viral vector. Lentiviruses also infect non-dividing or slowly dividing cells, which improves delivery to cells such as neurons or stem cells, thus enabling the evaluation of gene therapy in an even wider array of diseases than before. Furthermore, lentiviral vectors insert into cellular DNA in such a way that may be safer than other gene therapy vectors. This is because lentiviruses appear to insert differently from other retroviruses that have caused side effects in other trials involving stem-cell therapy. In addition, gene insertion by lentiviral vectors is attractive for potential therapeutics since it enables long-term gene expression, unlike other viral vectors where expression is lost over time.

Penn researchers are now recruiting for a second trial using the VRX496 vector with HIV patients whose virus is well controlled by existing anti-retroviral drugs, a group of patients who are generally healthier and have more treatment options available. This trial will use six infusions rather than one and is designed to evaluate the safety of multiple infusions and to test the effect of infusions on the patients' ability to control HIV after removal of their anti-retroviral drugs. The hope is that this treatment approach may ultimately allow patients to stay off antiretroviral drugs for an extensive period, which are known to have significant toxicity, especially after long-term use.

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The research was supported by the National Institute of Allergy and Infectious Disease; the Abramson Family Cancer Research Institute; and VIRxSYS Corp. In addition to June, Levine, and MacGregor, co-authors on the paper are: Jean Boyer and Frederic Bushman from Penn; Laurent M. Humeau, Tessio Rebello, Xiaobin Lu (now with US Pharmacopeia), Gwendolyn K. Binder (now with Penn), Vladimir Slepushkin, Frank Lemiale, and Boro Dropulic (now with Lentigen Corp, Baltmore) from VIRxSYS; and John R. Mascola from the National Institutes of Health.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors (Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center); a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

Contact: Karen Kreeger
University of Pennsylvania School of Medicine

When it going to ends, Iraqi Sunnis kill 10 Shiites, kidnap 50 others,- Sunni gunmen ambushed a convoy of minibuses Saturday night at a fake checkpoint on a highway south of Baghdad, killing 10 Shiite passengers and kidnapping about 50.

Across the country at least 52 other people were killed in violence or were found dead, five of them decapitated Iraqi soldiers.

Police said the mass kidnapping and killing was near Latifiyah, about 20 miles south of Baghdad in the so-called Triangle of Death.

Shiite Muslims, a minority in that district, have routinely come under attack from Sunni insurgents who control the territory. The highway passing through the region from Baghdad leads to Najaf, the holiest Shiite city in Iraq.

Shiite pilgrims have become a favorite target of Sunni gunmen, although it was not immediately known where the victims of Saturday night's assault were headed.

Sectarian revenge killings, many thought to involve police and Iraqi troops, have left morgues full across a wide swath of the country.

There were no reported deaths among America's 152,000 service men and women in Iraq on Saturday. U.S. Ambassador Zalmay Khalilzad and Gen. George Casey, the top commander in Iraq, oversaw a Veterans Day ceremony at which 75 members of the armed forces from 33 countries were sworn in as American citizens.

In Baghdad, eight people died and at least 38 were wounded when two bombs hidden under parked cars exploded among noontime shoppers in downtown Baghdad's Hafidh al-Qadhi square. Police and a medical workers said at least 38 others were injured in the explosion at the formerly bustling area on the eastern bank of the Tigris River.

A Slovak and Polish soldier were reported killed overnight by a roadside bomb. Slovakian defense ministry spokesman Vladimir Gemela said the two died when their vehicle was hit by a roadside bomb near Kut, 100 miles southeast of Baghdad where coalition troops have fought fighters with the Mahdi Army militia loyal to the radical anti-American cleric Muqtada al-Sadr.

The deaths marked the 18th among Polish troops and fourth among those from Slovakia, which has about 100 troops in Iraq operating jointly with the 900 Polish troops in the country.

Slovakia's Prime Minister Robert Fico has said his country will pull its troops out of Iraq in February.

Baghdad police 1st Lt. Thayer Mahmud said his men found 25 corpses dumped in several parts of the capital in the 24 hours from 6 p.m. Friday.

A Samarra police captain, who spoke on condition of anonymity because he feared retribution, said the city morgue had received the beheaded bodies five soldiers who were kidnapped last week in the Meshahda area, 20 miles north of the capital.

New Zealand students may 'text-speak' in exams, New Zealand's high school students will be able to use "text-speak" -- the mobile phone text message language beloved of teenagers -- in national exams this year,.

Text-speak, a second language for thousands of teens, uses abbreviated words and phrases such as "txt" for "text", "lol" for "laughing out loud" or "lots of love," and "CU" for "see you."

The move has already divided students and educators who fear it could damage the English language.

New Zealand's Qualifications Authority said Friday that it still strongly discourages students from using anything other than full English, but that credit will be given if the answer "clearly shows the required understanding," even if it contains text-speak.

The authority's deputy chief executive for qualifications, Bali Haque, said students should aim to make their answers as clear as possible.

Confident that those grading papers would understand answers written in text-speak, Haque stressed that in some exams, including English, text abbreviations would be penalized.

Post Primary Teachers' Association President Debbie Te Whaiti said the authority's move reflects the classroom situation.

Teachers would have concerns if text slang became acceptable in everyday written language in classrooms, she said.

Critics said the National Certificate of Educational Achievement or NCEA, the main qualification for high school students, would be degraded by the authority allowing text speak use in exams.

Internet blogger Phil Stevens was not amused by the announcement. "nzqa[New Zealand Qualifications Authority]: u mst b joking," Stevens wrote. "or r u smoking sumthg?"

Chirac meets Hong Kong Chief Executive.French President Jacques Chirac said on Thursday in Paris that he was delighted with the constant progress of the business relations between France and Hong Kong.

Chirac made the remarks when meeting with the visiting Chief Executive of the Hong Kong Special Administrative Region (HKSAR) Donald Tsang at the Elysee Palace.

"The President of the Republic hailed the remarkable economic performances of Hong Kong and was delighted with the constant progress in the business relations between France and Hong Kong," French President spokesman Jerome Bonnafont said.

The president was also glad to see the investment progress that French enterprises have made in Hong Kong, he said.

Tsang is expected to attend a conference for promoting business exchanges between Hong Kong and France on Friday.

France is the third leg of Tsang's European tour.

Source: Xinhua

US vetoes motion on Gaza attack, The US has vetoed a UN Security Council resolution condemning an Israeli attack in Gaza that killed 18 civilians, including women and children.
The draft, which also condemned Israeli military operations in Gaza, followed Wednesday's attack in Beit Hanoun.

The US ambassador at the UN, John Bolton, described the text as unbalanced and politically motivated.

Ten of 15 Security Council members backed the resolution. Four abstained - Denmark, Japan, Slovakia and the UK.

This was the second time this year the US used its veto on a draft resolution on Israeli military operations in Gaza.

The US has a history of vetoing resolutions condemning Israel which it feels are biased against the country, says the BBC's Laura Trevelyan at the UN in New York.

'Not even-handed'

The draft resolution - backed by Arab, Islamic and non-aligned states and formally proposed by Qatar - called for a withdrawal of Israeli troops from the Gaza Strip.

It also asked the UN secretary general to set up a fact-finding mission into the deaths in Beit Hanoun.

The draft urged the Palestinian Authority to act to end violence - including rockets fired at southern Israel.

The US ambassador said he regretted the Palestinian loss of life, but disagreed with the language used in the resolution.

"This resolution does not display an even-handed characterisation of the recent events in Gaza, nor does it advance the cause of Israeli-Palestinian peace to which we aspire and for which we are working assiduously," he said.

Qatar's ambassador said the credibility of the Security Council had been called into question by the vote and the cycle of violence in the Middle East would continue.

Israel launched its operation in and around Beit Hanoun last month in an effort to root out militants firing rockets.

The deaths were caused when what witnesses described as a volley of tank shells hit a built-up civilian area. Many of the dead were from one extended family, and included several women and children.

Israeli Prime Minister Ehud Olmert apologised for the attack, describing it as a "technical failure".