HIV inserts into human genome using a DNA-associated protein

November 27, 2005

A human DNA-associated protein called LEDGF is the first such molecule found to control the location of HIV integration in human cells, according to a new study from researchers at the University of Pennsylvania School of Medicine. This study, published in this week's early online edition of Nature Medicine, describes the first clear target for modulating where viruses insert into the human genome, which has implications for better design of gene-therapy delivery. Retroviral vectors are often used to introduce therapeutic genetic sequences into human chromosomes, such as in the delivery of Factor VIII for hemophilia patients.

HIV integrates into active transcription units on chromosomes within the nucleus of human cells. These units are sites that lead to efficient expression of the viral genome. Most HIV-infected cells in a patient will have a very short life span, a day or less. "We surmise that this strategy helps the virus make hay while the sun is shining, as it were, producing lots of viral copies during a short time, so that the virus can maximize production of daughter virions," says Frederic Bushman, PhD, Professor of Microbiology at Penn.

This present study demonstrates the first piece of a mechanism that dictates where HIV integration takes place. Previous studies at other institutions showed that LEDGF binds tightly to HIV integrase, the enzyme that's important for the integration reaction. Now, Penn researchers showed in this study that the way LEDGF binds to HIV integrase and to specific sites on chromosomes suggests that HIV targets integration using a molecular tether.

Retroviruses contain RNA in their particles. They enter a cell and convert RNA into DNA by the enzyme reverse transcriptase and then integrate that DNA copy into the DNA of the host, using the integrase enzyme. The new viral particles are made by transcription of the viral genome, as with any cellular genes. If the cell divides, the viral DNA is copied and inherited, along with cellular human genes.

Bushman and his team made cells that were depleted of LEDGF and found that integration was less frequent in transcription units and in genes regulated by LEDGF. "This implies that LEDGF is part of the machinery that helps dictate the placement of retroviral integration sites within chromosomes," says Bushman.

Bushman notes that finding that LEDGF is part of the cellular apparatus necessary for HIV replication is important to the field of gene therapy. Controlling where gene-therapy vehicles insert in the human genome could help make the delivery of new therapeutic sequences safer. The new findings about LEDGF suggest that engineered tethering interactions might some day allow control over integration site selection during gene therapy. According to Bushman, this finding is of particular importance in light of recent cases where integration of gene-therapy vectors near cancer genes contributed to the development of leukemia in gene-therapy patients.

"This is first example of a cellular factor that's a clear player in target site selection," says Bushman. "This isn't engineering yet, but it's a key piece of information on the way."
-end-
This research was funded in part by the National Institutes of Health, the J.B. Pendleton Charitable Trust, and the F.B. Burns Foundation. Other co-authors in addition to Bushman are: Angela Ciuffi, Christian Hoffman, and Jeremy Leipzig, all from Penn, as well as Manuel Llano and Eric Poeschla from the Mayo Clinic College of Medicine, Rochester, Minn., and Paul Shinn and Joseph R. Ecker from The Salk Institute, La Jolla, Calif.

This release and related images can also be found at: www.uphs.upenn.edu/news.

PENN Medicine is a $2.7 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 #4 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.

Penn Health System comprises: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health 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.