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Two New Papers Highlight North Carolina’s Race to an HIV Breakthrough

North Carolina has always been a research hotspot, but in the past few years, a stunning number of breakthroughs in HIV have been coming out of the state.

By Stephanie Soucheray

Over the last 20 years, the Research Triangle has become an epicenter for American research concerning the treatment, prevention and cure of HIV. Now two papers have the Triangle racing toward a new understanding of how to end HIV as we know it, 30 years after it came to the attention of medical professionals.

A paper authored by UNC-Chapel Hill professor Victor Garcia-Martinez, published in PloS Pathogens, describes how Garcia-Martinez and colleagues used the first “humanized” mouse models to kill, or deactivate, the HIV virus.

HIV on a white blood cell

This scanning electron micrograph revealed the presence of the human immunodeficiency virus (HIV-1), (green, spherical in appearance), which had been co-cultivated with human white blood cells (lymphocytes). HIV-1 virions can be seen on the surface of this lymphocyte. Photo courtesy CDC/ C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus

Using humanized mouse models is a major breakthrough for HIV research. For years, researchers were limited to using the rhesus monkey for HIV research, but monkeys are expensive and in short supply.

“If you use mice, you have many more subjects,” explained Myron Cohen, director of the Center of Infectious Diseases at UNC, who collaborates with Garcia -Martinez and others at the UNC Center for AIDS Research.

Cohen also said that when developing a novel treatment or vaccine, a rhesus monkey takes up more of the experimental drug because of its weight, leaving little wiggle room for scientists.

“Remember, we can never think about doing it in the human without an animal model,” said Cohen. “So using mice is invaluable.”

Garcia-Martinez’s work with mice began six years ago at the University of Texas Southwestern Medical Center, where he and colleagues saw that the HIV virus could be killed in test tubes by a protein, APOBEC3, present in human cells.

But HIV has evolved to contain a gene called vif, or viral infectivity factor gene, that destroys the human immune system’s innate ability to control HIV. HIV antivirals kill vif, but Garcia-Martinez postulated that if the gene itself could be targeted it could be important for drug discovery.

But proving something in a test tube means little in the battle against HIV. Garcia-Martinez and colleagues needed an animal model: enter the humanized mouse, an animal whose immune system reflects the human system when confronted with HIV. The humanized mice are created by placing human bone marrow, liver and thymus tissues into animals that don’t have an immune system.

“The results were amazing,” Garcia-Martinez said. “If you remove vif from HIV and you challenge humanized mice, the virus did not grow at all. In some instances, you could not find it in the animal. It was eradicated from the body. It was a vestige of the original virus that had been mutilated so much by human oration that it was dead.”

Curing people

Garcia-Martinez said the next step will be probing this axis to test new drugs that will target vif and APOBEC3.

mouse on a gloved hand

“Humanized” mouse. Photo credit: UNC School of Medicine.

“We can literally heal the virus if we can develop drugs that target this pathway,” he said. “The virus will be dead in its tracks. We can find a way we can actually cure people.”

Using words like “cure” is not something to be taken lightly, but Cohen said it’s not an impossible goal for researchers in the Triangle, especially if they work together.

In 2011, Cohen led a team of researchers in the HPTN 052 trial, which successfully used antiretroviral medications to prevent HIV transmission in healthy people exposed to the disease. His work used RTP’s FHI 360, and was named Science magazine’s breakthrough of the year.

“That was the first time in 17 years that HIV was part of the breakthrough of the year,” said Cohen.

More recently, Cohen collaborated with scientists at Duke’s Center for HIV/AIDS Vaccine Immunology (CHAVI) for a paper published in Nature this week. The study looked at HIV in one patient, identified by Cohen, and the antibodies present in the patient after infection. The antibodies may help researchers at CHAVI in their quest for an HIV vaccine.

“What that paper does is give us a big clue about an alternative way to make an HIV vaccine; it gives us another direction,” said Cohen. “And we learned it from one patient.”

The paper, co-authored by Hia-Xin Liao, research director of Duke Human Vaccine Institute, follows a Malawian man infected with HIV who had a strong immune response to the disease.

Researchers followed the man for three years, watching how his immune system used broadly neutralizing antibodies (BnAbs) to fight the infection. BnAbs usually develop two to four years after infection, but if they can be harnessed before a patient is exposed to HIV they could become valuable tools for an immunization.

“This is a very important glimpse at the co-evolution of BnAbs and HIV,” said Liang. “The work will help us identify the vaccine candidate, and eventually develop a vaccine.”

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