Immune to HIV: How Do They Do It?

Individuals with HIV immunity have intrigued scientists for over a decade. How is it that the immune systems of some seem impervious to a virus that kills 2 million people around the globe each year?

Researchers have focused on a few proteins – called CCR5, CD4 and human leukocyte antigen – that may hold the key to this puzzle as well as offer the potential for new HIV treatments.

A new study at the University of Southern California shows mice with a mutation in the gene that encodes CCR5 have immunity to HIV. According to the researchers' report in the July issue of Nature Biotechnology, their work provides "proof of concept for a new approach to HIV treatment."

CCR5 is found on the surface of human immune-system cells. Essentially, CCR5 works as a lock that HIV, the virus that causes AIDS, opens in order to enter the cells.

The researchers took mice already infected with HIV and injected them with stem cells containing a specific mutation in the CCR5 gene. They found the injected cells were able to fight and destroy HIV, and the mice were able to fight off other infections, too.

Because stem cells reproduce indefinitely, these mutant stem cells could provide a permanent supply of HIV-resistant immune cells, according to the researchers.

The procedure — developed in collaboration with scientists at biotech company Sangamo BioSciences — is currently being tested in humans in Phase 1 clinical trials. It was inspired by a 2009 New England Journal of Medicine case report that described a patient with both HIV and leukemia. After undergoing a bone marrow transplant from a donor with the CCR5 mutation — known as the CCR5-delta 32 mutation — the patient became HIV-free and no longer required anti-AIDS drugs.

Tracking a mysterious mutation

This mutation in CCR5 is associated with natural immunity to HIV in about 10 percent of Caucasian people. Scientists suspect that its commonness comes from being spared by deadly plagues in the distant past. However, there is disagreement over which disease or diseases influenced the mutation over time.

Much research has shown that the mutation may have given some people immunity to the waves of bubonic plague that swept through Europe during the 12th through 15th centuries.

But University of Berkeley researchers suggest smallpox is a likely cause for the mutation's spread. In a 2003 report in the Proceedings of the National Academies of Science, the scientists explained that smallpox was around far longer than the plague and killed far more people. And smallpox especially affected younger children, who were not yet old enough to reproduce.

In a 2006 study, Johns Hopkins University researchers found that the mutation reduced infection by the hepatitis B virus, as well. They concluded that "a diverse group of infectious disease, rather than a single, deadly pathogen," may have been the driving force behind the mutation's prevalence.

Other factors

Because the CCR5 mutation does not provide HIV immunity in all populations, researchers have looked at other proteins that may bestow a natural advantage in fighting off the virus.

A protein called cystatin may be at work. In 2008, researchers at the University of Manitoba studied Kenyan women who were still HIV-free after working as prostitutes for at least three years. The scientists found increased levels of cystatin, which is known to interfere with the ability of HIV to reproduce.

Studies of Zambians have highlighted the influence of the protein HLA, or human leukocyte antigen. So-called "elite controllers" – people whose cells are able to effectively attack and destroy HIV – often possess certain types of HLA. They may never experience symptoms even though they are infected with the virus.

Another protein that has garnered attention from scientists is called CD4. As with CCR5, HIV must interact with CD4 in order to enter person's immune cells, and some say it may make a better drug target than CCR5.

Recently Peter Kwong, a scientist at the National Institute of Allergy and Infectious Diseases, led a team that investigated a protein produced by people immune to HIV that binds to HIV and to CD4. The researchers concluded that fully understanding how this protein binds to both the virus and the human cells could lead to the creation of an HIV vaccine.

"The CCR5 binding site is only revealed to the virus after it binds to CD4," Kwong said. "So although CCR5 is an extremely good drug target, the CD4 site is much better because it must always be accessible for HIV to get into the cell."

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