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New study reveals why some people may be immune to HIV-1

Natural genetic variation in a protective antiviral enzyme holds promise for new therapies

University of Minnesota – WEBWIRE

Doctors have long been mystified as to why HIV-1 rapidly sickens some individuals, while in others the virus has difficulties gaining a foothold. Now, a study of genetic variation in HIV-1 and in the cells it infects reported, by University of Minnesota researchers in this week’s issue of PLOS Genetics, has uncovered a chink in HIV-1’s armor that may, at least in part, explain the puzzling difference — and potentially open the door to new treatments.

HIV-1 harms people by invading immune system cells known as T lymphocytes, hijacking their molecular machinery to make more of themselves, then destroying the host cells — leaving the infected person more susceptible to other deadly diseases. T lymphocytes are not complete sitting ducks, however. Among their anti-virus defense mechanisms is a class of proteins known as APOBEC3s that have the ability to block the HIV-1’s ability to replicate. However, HIV-1 has a counter-defense mechanism — a protein called Vif that cons the T lymphocytes into destroying their own APOBEC3.

Suspecting differential susceptibility to HIV-1 might be related to genetic variations in this system, a research team led by Professor Reuben Harris of the University’s College of Biological Sciences and Medical School and doctoral student Eric Refsland, took a closer look. First, the researchers found that HIV-1 infection boosts the production of one kind of APOBEC3, APOBEC3H — suggesting it’s a key player in fighting back. Then, using an experimental technique known as separation of function mutagenesis, they discovered that different people have different strengths/potencies of APOBEC3H, with some proteins expressed stably and others inherently unstable.  The stable variations, the researchers found, were able to successfully limit HIV-1’s ability to replicate if the infecting virus had a weak version of Vif — but not for HIV-1 viruses that had strong Vif.

“This work shows that the competition between the virus and the host is still ongoing,” Refsland says. “The virus hasn’t completely perfected its ability to replicate in humans.”

Armed with this clearer picture of the multifaceted interactions between Vif and APOBEC3, Harris says. The next step is to figure out how to stop Vif from disabling the APOBEC3 enzymes. “One could imagine drugs that stop Vif from binding with APOBEC,” he said. “This is a bonafide HIV killing pathway, and we just have to devise clever ways to activate it in infected persons. Such an approach could indefinitely suppress virus replication, and even result in curing it.”

About the College of Biological Sciences
College of Biological Sciences (CBS) faculty conduct research in all areas of biology, from molecules to ecosystems, which supports applications in medicine, renewable energy, agriculture and biotechnology. The college offers degree programs in biochemistry, molecular biology and biophysics; genetics, cell biology and development; ecology, evolution and (animal) behavior; plant biology; microbiology and neurosciences. Admission to undergraduate programs is highly competitive. Visit the CBS site to learn more.

About the University of Minnesota Medical School
The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school’s 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Click here to learn more.

About the Masonic Cancer Center
Masonic Cancer Center, University of Minnesota is part of the University’s Academic Health Center. It is designated by the National Cancer Institute as a Comprehensive Cancer Center. For more information about the Masonic Cancer Center, click here or call (612) 624-2620.


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