Is Genetic Diversity Key to HIV Immunity?

According to The Guardian  the team responsible for curing the Berlin patient is closing in on a one-shot HIV cure. And he’s not the only one using gene therapy to fight HIV.

“I believe it’s possible to develop a mass-market single-shot treatment for HIV,” Dr. Gero Hütter told The Guardian. “If we can overcome a few problems, our approach is closer to a complete cure than anything in the last 30 years.”

Seven years ago Hütter and his team at the Charité hospital in Berlin were treating a 40-year-old HIV-positive patient who was also fighting leukaemia when they tried an experimental procedure that not only stopped the cancer but seemed to eliminate HIV from his body.

After chemotherapy treatments killed cancerous cells they were replaced with a donor’s bone marrow. The twist: this donor’s genes carried a natural immunity to HIV.

About 1 percent of the population has the rare gene mutation that prevents HIV from binding to white blood cells, by disabling its typically receptor target, CCR5.

When the Berlin patient, Timothy Ray Brown, was tested for two years after the transplant, all trace of HIV had been eliminated from his body. At the time, the Berlin patient case was lauded as the biggest breakthrough in the history of HIV research—and people expected to see more patients cured.

(Brown remains HIV free. Read a recent interview with him and Hütter  here.)

Since then, six more HIV patients have been treated with similar transplants. None have survived longer than twelve months.

Naturally HIV experts have been debating for years about why these transplants failed when Brown’s succeeded. And, since these patients also had cancer it can be difficult to discern what role their terminal illness played in the process.

Some researchers have argued that disabling the CCR5 receptor through gene therapy resulted in the HIV virus mutating to invade cells through other receptors. But that clearly did not happen with Brown. And understanding why is the million dollar question.

“If we can understand this,” Hütter told The Guardian, “we may be able to translate his cure into something feasible for all patients.”

Unfortunately, exactly how Brown was cured remains a bit of a mystery.  Potential explanations include that chemotherapy destroyed the HIV reservoir or that transplanted donor cells may attacked the HIV positive cells as foreign and eliminated them.

Since 2009, donor sites have begun screening for the CCR5 mutation but the kind of transplant Brown underwent is not feasible on a large scale. And patients not facing death from cancer might not be willing to undergo chemotherapy and its potential side effects.

“Gene therapy has its own risks,” added Hütter. “And current trials are at a very early stage.  You can permanently disable a gene but this only works if you change the DNA code. The risk is that you change the DNA strand at critical places where the replication and proliferation is encoded. If you accidentally manipulate the wrong part, there’s a risk of inducing cancer.”

Another influential HIV researcher also believes the CCR5 gene mutation is the answer. Dr. Michael Farzan,  the Harvard University professor famous for discovering the benefits of CCR5 mutation 16 years ago, told The Guardian he’s close to developing an HIV vaccine based on this genetic immunity.

Farzan said that his potential vaccine would bind to the HIV virus and prevent it from invading the white blood cells. For those who are already poz, Farzan said the vaccine would “prevent [HIV] from spreading to further cells and replicating.”

But, Farzan was also quick to point out, “This isn’t a cure. A cure would remove all evidence of the virus from the body and we don’t have that ability.”

Still, the vaccine would offer people with HIV a chance “reach a state called biologic remission, which means they can live without drugs.”

Some of the previous attempts at developing an HIV vaccine have focused on stimulating the body’s immune response. In typical vaccines, a small portion of the virus is injected into a patient, whose body generates immunity in response.

But Farzan’s approach is to prevent the virus from attaching by blocking all cell receptors it can attach to. Farzan did admit that the virus could find additional access points, but he maintained, “Those strains of HIV are extremely rare so if it moves away from the common receptors, this will come with what we call a fitness cost for the virus. Because there are fewer strains, they are less replicative and transmissible.”

The CCR5 mutation is not the only form of genetic immunity that exists. For example, there are what researchers call “elite controllers,” patients who test positive for HIV but who remain symptom free. Their immune systems remain healthy and vigorously attack HIV-infected cells before they can replicate. (Read more about one elite controller here.)

Meanwhile University of Minnesota scientist Reuben Harris is studying serodiscordant couples who’ve retained their mixed HIV status without medication.

“These instances are extremely interesting,” Harris told The Gaurdian, “because you have an infected person and their partner who remains HIV-negative despite many opportunities for the virus to be transmitted.”

He said finding out why these couples maintain their discordant status isn’t an easy task, but, “by taking blood samples, we can play around with the virus and work out what changes would need to be made in order for it to infect cells from the partner. And from that we can work out what’s protecting them.”

Harris said he believes he has found the answer and it lies with a family of genes called APOBEC3. These genes produces antiretroviral enzymes, which the immune system depends on to fight viral infections. Harris discovered that a specific variation to the gene APOBEC3H produces stronger and more stable enzymes; which appear to impede the replication of HIV. Those with the gene variation aren't immune, but they are less likely to catch the disease.

“Understanding what happens at the point of transmission is the key to successful intervention,” Harris explained. “It’s where the virus is most vulnerable. When HIV is transmitted, it’s maybe one single virus or at most a very small number. If those viruses don’t take root, then the infection can’t get going and amplify.”

Harris said that researchers are considering gene therapy based on the APOBEC3H variant, which could be used to make populations less susceptible to HIV. In this case, studies show that few Caucasians naturally have the optimal version of the gene so would benefit from such treatments.

“These enzymes are really powerful virus inhibitors,” Harris said. “And it may be possible to suppress infection completely by unleashing them to a greater extent.  The APOBEC3H gene could become part of the donor screening progress for future bone marrow transplants. If a donor has a stable version of APOBEC3H and the CCR5 mutation, then they have a double shot at protection from infection.”

Genetic variation that hinders HIV transmission certainly isn’t the same thing as a cure or even a vaccine, but they can dramatically alter the odds of infection.

“If you took 20 billion viruses,” Harris told The Guardian, “some of them would undoubtedly be resistant to APOBEC3H enzymes and maybe even to the CCR5 deletion. But at the point of transmission, you’re only exposed so a few virus strains. So there we have the advantage and the virus has the disadvantage, and any little genetic advantage we can give people, then the odds are in their favor.”

Harris also said he believes there may be other forms of natural immunity yet to discover.

“There are probably lots of different ways that people can resist infection,” he said. “I guess it’s a perfect example of why we don’t want homogeneity in the human race,” Harris concluded. “If we were all the same then it would be too easy for a super-virus to sweep through and wipe us all out.”