amfAR HIV Cure Summit: Locating and Understanding Viral Reservoirs

On Monday, November 17 at 7 World Trade Center in New York City, Paula Cannon of University of Southern California, and Eileen Scully, MD, PhD, of Harvard Medical School and Massachusetts General Hospital, talked about one of the biggest barriers to curing HIV: Locating and understanding HIV's viral reservoirs, including differences that exist between male and female patients.

"Sometimes when HIV infects a cell, instead of making more HIV, it kind of goes to sleep, and this is what we call a latently infected cell -- call it Sleeping Beauty," said Cannon. "If it did nothing else, we'd be fine. Unfortunately, there are some princes out there in the body that can wake it up, and if you've stopped taking your antiretroviral drugs, what's going to happen is the infection is going to flare right back up. An HIV cure must eliminate or suppress it."

One place that HIV can hide is in the brain, where it can move via CD4 cells into the brain's microglia cells, which constantly check and prune the brain's nerve cells. This complicates things, because it's difficult to look at what's happening in the brains of living things (although some PLWHAs have discussed establishing an HIV brain bank for PLWHA to donate their brains to science).

"If you're infected with HIV and can't suppress the viral with antiretroviral medications, you can end up with neurological complications," said Cannon. Figuring out how to eliminate or suppress the latent reservoir of HIV-infected microglia would be very useful in finding the cure.

To that end, Cannon has teamed up with Dr. Jonathan Karn of Case Western University to create a mouse model with human microglia in its brain. They call these "humanized mice," because scientists replace some of the mouse's immune system with human bone marrow stem cells and then wait about two months, when about 50 percent of its white blood cells will be human. Then, they can infect these humanized mice with HIV and test different drugs in a small animal model that isn't a primate.

At Case Western, scientists are looking for drugs that will wake up and purge latent HIV from the brain. This meshes well with the work being done over at Harvard Medical School, where Scully is working to understand how HIV viral reservoirs persist and what wakes them up, be it a change in the body's environment, the stimulation of a cell or just random chance.

"When HIV infects a cells, it actually becomes a part of the DNA" said Scully. Viruses like influenza or the common cold don't do this, but "the problem with HIV is in the cells it gets into, it integrates itself and becomes part of the DNA in the body."

The virus will create new viruses that will go into the body and infect other healthy cells, and will eventually die out. But these sleeping cells can hide HIV for years and years, a ticking time bomb of HIV.

"If it's not making any HIV parts, there's no way the immune system can see it," said Cannon. "The problem is when something wakes it up."

Cannon and her team (including scientists at Case Western) are working on identifying the impact of sex-based differences that activate this latent HIV. This can be through infections; through environmental triggers like smoking, drugs, or nutrition; or through environmental changes, like hormones like estrogen, cortisol or progesterone, which differ between men and women.

"When it comes down to it, the only genetic difference between men and women is an X and a Y chromosome," said Cannon. "But on top of that is the hormones that are different between men and women. It's important to figure out what those differences are."

Researchers have seen different responses between men and women in response to vaccines for influenza, hepatitis A and B and dengue, but women are much less likely to be included in clinical trials. More than 26 percent of studies had no women, and they were largely absent from clinical trials, because scientists worried that they would skew the results.

With HIV, women have a lower viral load, but still progress at the same speed as men. They have higher level of immune activation, a lower level of HIV-1 DNA from women who are fully suppressed, and may see a longer time for the virus to bounce back.

Cannon suggested that this is partially attributed to the fact that when women become pregnant, the body represses its own immune system so that it won't attack the baby. Still, women account for more than half of HIV infections in low- and middle-income countries, and 58 percent of HIV infections in sub-Saharan Africa. Finding out how HIV functions in women is imperative to halting the rate of infection, and to discern whether hormones effect how HIV is controlled.

To this end, the University of California, San Francisco is currently recruiting 50 women of reproductive age who are not on hormones like birth control, for large blood draws. The problems are that women are hesitant to enroll in these trials because of problems with scheduling and childcare and domestic responsibilities.

"Our end hope is to have a comprehensive comprehension of both men and women, including a sensitive measure of the reservoir, immune outreach and responsiveness to reactivation," said Cannon. "Cure strategies need to be clinically relevant for both men and women."