Fighting HIV with HIV

November 06, 2006

(Philadelphia, PA) -- 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.
-end-
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.

Editors Note: For more information on the current HIV clinical trial, contact Larissa Zifchak at 215-349-8091 or Larisa.Zifchak@uphs.upenn.edu.

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.

University of Pennsylvania School of Medicine

Related HIV Articles from Brightsurf:

BEAT-HIV Delaney collaboratory issues recommendations measuring persistent HIV reservoirs
Spearheaded by Wistar scientists, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies.

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.

Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.

The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.

The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.

Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.

NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.

Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.

Read More: HIV News and HIV Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.