Bowman Gray Scientists Find Novel Way To Block AIDS Virus

September 30, 1997

WINSTON-SALEM B In what could be the most exciting advance in the treatment of AIDS to date, Bowman Gray School of Medicine scientists today reported a novel way to block the deadly HIV virus from ever invading white blood cells.

This new strategy, described in the Oct. 1 issue of the journal Nature Medicine, points to a fundamental new way to treat patients with HIV-1 infection or patients with Acquired Immune Deficiency Syndrome (AIDS).

This study, by Si.-Yi Chen, M.D., Ph.D., assistant professor of cancer biology, and his colleagues at Bowman Gray School of Medicine, describes how a critical co-receptor on the surface of particular white blood cells called lymphocytes is blocked, making the cells immune to infection by HIV-1.

HIV-1 virus causes AIDS by invading and destroying the white blood cells whose functions are essential to maintain the human immune system.

Chen's advance is based on the recent discovery of the critical role of chemokine receptors on the surface of the lymphocyte, as the doorway B or co-receptor B for the HIV invasion into lymphocytes.

After virus invasion, the now familiar steps in the development of AIDS follow: multiplication of the virus in the infected cells and the killing of the infected cells, progeny virus spreading to other normal lymphocytes, the decline of the disease-fighting CD4 lymphocytes and the progression to AIDS, and its ultimate downward spiral.

Last year, in another dramatic discovery, a genetic defect in a chemokine coreceptor was found to protect individuals with this defect from HIV-1 infection. These genetically defective individuals remain healthy, because the usual functions of a defective chemokine receptor can be taken over by other receptors because of redundancies in the chemokine family.

So, Chen reasoned, "genetic inactivation of the chemokine co-receptors should protect lymphocytes from HIV-1 infection and have therapeutic implications."

Chen and his colleagues set out to mimic the natural resistance of the genetically defective individuals. They designed a novel approach, termed "intracellular chemokine" ? intrakine for short ? to genetically inactivate a CXC-chemokine coreceptor, or CXCR4 for short. This CXCR4 co-receptor plays a critical role in HIV-1 fusion and entry into permissive cells, especially for T-cell line tropic HIV-1 viruses that are frequently isolated in late stages of HIV-1 infection and AIDS.

In their studies, Chen and his colleagues were able to inactivate CXCR4 through a series of steps B steps that prevent newly-produced CXCR4 deep within the lymphocyte from ever reaching the cell surface. The key is the alteration of what is known as the SDF-intrakine, which binds to the CXCR4 and traps the molecules inside the lymphocyte.

Hence there is no place on which the HIV-1 virus can land to infect the cell.

"The genetically modified lymphocytes are immune to T-tropic virus infection but appear to maintain normal biological activities," he said.

Chen said that in treating people with AIDS or HIV infection, if the process proves out, human lymphocytes would be removed from an infected patient, genetically modified with intrakine, and periodically reinfused back into patients to delay or prevent the disease progression.

"This intrakine strategy likely is superior to currently described anti-HIV approaches," said Chen, for two main reasons: He said that since genetically modified lymphocytes can live for many months or years, "this gene-based intrakine therapy should have a potent and long-lasting anti-HIV effect."

In contrast to Chen's approach, the best current HIV treatment is with combinations or "cocktails" of drugs. While these combinations of medications shows promise of extending the lives of patients with HIV-1, Chen said, "such an approach induces toxic side effects, selects for resistant mutants, and is unlikely to completely eliminate HIV-1 from infected individuals."

Chen said, "A strategy of genetic modification of host cells, the lymphocytes or stem cells, for resistance to HIV-1 infection, together with drug therapy, may hold the ultimate hope for HIV treatment."

His group is now in the stage of pre-clinical study to further evaluate the efficacy and safety of this intrakine approach. But he said clinical trials in people are a year or more away.

The research scientists in Chen's team include Jidai Chen, M.D., Ph.D. and An-gang Yang, M.D., Ph.D. both post-doctoral fellows, and Xuefai Bai, Ph.D., a research fellow.
-end-



For further information, contact Robert Conn, Mark Wright or Jim Steele at 910-716-4587. Dr. Chen may be reached directly on email at SiChen@bgsm.edu.

Wake Forest Baptist Medical Center

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.