Thirty years ago, contracting HIV was a death sentence.
The virus attacks the immune system, specifically T-cells, until immunity breaks down completely. Patients would eventually develop AIDS, and ultimately succumb to opportunistic infections.
The development of highly active antiretroviral therapies or HAART changed all that, converting a deadly disease into a chronic one. As long as patients stayed on the drug regimen, they could live normal lifespans. Their immune systems would recover and viral levels would decline to nearly zero.
But there’s a catch. Nearly zero is not the same as zero. HIV has a latency mode, during which the virus is dormant – evading both HAART and the body’s immune system. Remove HAART treatment, and the virus comes roaring back.
That means a lifetime consuming powerful and expensive treatments – if one’s body and health status can tolerate them in the first place. And no one knows how the drugs will affect patients after 20, 30 or 40 years.
“We’ve made great progress, but at the end of the day you still have more than 30 million people living with HIV,” says Satya Dandekar, professor and chair of the UC Davis Department of Medical Microbiology and Immunology. “Without drugs, the virus can come back at the same threat level for patients.
“Actually eradicating HIV is extremely critical.”
For decades, UC Davis researchers have worked with that ultimate goal in mind. Scientists have learned important details about how HIV operates along the way; for example, that it first attacks immune cells in the gut.
But now we’ve reached a new stage in the battle against HIV. The goal is no longer to control the disease, but to cure it. Two UC Davis groups are beginning clinical trials in hopes of doing just that.
Shock and kill
It would be hard to overstate the significance of HIV latency. The virus’s ability to evade treatment has made it difficult, if not impossible, to cure. The challenge for clinicians is to identify a two-pronged strategy: shock the latent virus out of hibernation, and hit it with immune treatments to kill it.
Dandekar, along with dermatologist Emanual Maverakis, are about to test the first part of that strategy. Just a few months ago, the Dandekar lab identified several agents that “wake up” HIV. One in particular, PEP005, has shown striking results. Even better, the drug is already approved by the U.S. Food and Drug Administration.
“We found this was really effective at reactivating HIV and works beautifully with other latency reactivating agents,” says Dandekar. “The thing that’s really exciting is that the molecule is in the drug PICATO, which treats skin cancer. It’s already approved and being used by patients.”
Now the UC Davis group hopes to extend PICATO’s uses to attacking HIV latency as well, and is launching a small clinical trial to test the drug’s safety in HIV patients. If the trial is successful, the team hopes to combine PICATO, and other drugs that reactivate HIV, with immunotherapies that would destroy the virus as it comes out of hiding.
“It will have to be a combination,” says Dandekar. “Just reactivating HIV from latency won’t be enough. We need to position the patient so those reactivated cells can be cleared.”
Reboot the system
UC Davis researchers are moving another promising approach into clinical trials as well. It involves taking blood stem cells from patients, genetically engineering them with anti-HIV genes, and returning them to the patients – essentially “rebooting” their immune systems and empowering them to eradicate or adequately suppress remaining HIV on their own over the long term.
“We are using our understanding of basic HIV biology to engineer each patient’s own stem cells to fight the virus,” says Joseph Anderson, an assistant adjunct professor who researches infectious diseases at the UC Davis Institute for Regenerative Cures, the university’s main stem cell research center. “We’re hoping that by reintroducing these cells in a bone marrow transplant, we can rebuild the immune system to resist HIV.”
Anderson and Mehrdad Abedi, a hematology professor and stem cell transplant specialist, are trying to replicate the treatment that cured Timothy Brown, also known as the “Berlin Patient.” Brown received a stem cell transplant from a donor whose genome contained an HIV-resistant mutation. That was seven years ago – and Brown remains HIV-free.
Anderson, who has been investigating anti-HIV genes since he was a Ph.D. student, is using three different genes to attack the virus, each one hitting a different mechanism associated with HIV infection. Like the drug cocktails used for HAART, multiple attack vectors may reduce the virus’s ability to evade treatment.
But a new key to the UC Davis team’s gene therapy strategy is also an improved viral vector that Anderson developed to help boost the treatment’s potency. The vector contains a gene that “tags” the surface of the stem cells that are HIV-resistant, allowing researchers to maximize their volume and potential power by culling out non-resistant cells before transplantation.
Anderson and Abedi have received an $8.5 million grant from the state’s stem cell agency, the California Institute for Regenerative Medicine or CIRM, to conduct the trial. The study will test the engineered stem cells in patients with HIV-related lymphoma, since they already require bone marrow transplants to treat their cancer. This trial will also test the therapy’s safety.
The team hopes the treatment will be a complete cure, but even a partial response would be great news for HIV patients.
“Maybe we won’t be able to eradicate it in some patients,” said Anderson, “but hopefully we are giving them enough of an HIV-resistant immune system that they can live the rest of their lives without having to take the antiretroviral drugs.”