Should HIV Cure Research, Inspired by Advances in Fighting Cancer, Aim for Remission Not Eradication?

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Learning From Oncology

Although HIV and cancer might seem to be two distinct diseases, they are both products of a malfunctioning immune system. While a true cure remains elusive for both diseases, HIV researchers are looking at new advances in immuno-oncology for clues on how to achieve durable HIV remission.

"Much of the work we are doing should be informed and inspired by work in cancer," said Steven Deeks, M.D., professor of Medicine at the University of California, San Francisco, speaking at the New York State 2016 HIV Cure Symposium, organized by Mount Sinai's Institute for Advanced Medicine. Dr. Deeks told the audience that it's time to reframe our thinking about an HIV cure and to start focusing on the achievable goal of "HIV remission." Instead of finding and killing every single infected cell, the goal of HIV remission treatment is allowing patients to live years and even decades without taking any antiretroviral medication.

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"Shock and Kill"

One of the central problems with HIV, as with cancer, is that it takes only one renegade cell for the disease to come roaring back. In HIV cure research, "shock and kill" has been the main thrust. Shock and kill is a two-phased treatment concept in which patients are first given a drug to revive all dormant HIV cells hiding in reservoirs, then given immunotherapy to encourage their immune systems to kill those cells.

Yet, it's extremely difficult to completely eradicate the HIV reservoir, Dr. Deeks said. Instead, HIV researchers should learn from oncologists, who have realized that even if every single cancer cell cannot be found and eliminated, therapeutic vaccines work much better if the amount of cancer is reduced. Similarly, shock and kill approaches could improve the health of people living with HIV by dramatically reducing (rather than completely eliminating) the HIV reservoir, Dr. Deeks said.

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Promising Solutions: The CMV Vaccine

One promising vaccine-based approach targets HIV genes packaged within the shell of a virus called cytomegalovirus (CMV), a cousin of herpes. CMV made headlines in 2013 when a simian version of the vaccine helped eliminate the SIV virus from 50% of monkeys tested. Next year, Louis Picker, M.D., at Oregon Health and Sciences University will move this work into a Phase 1 human trial in Portland.

While most CMV work has focused on pre-exposure prevention rather than treatment, a post-exposure treatment option could also work to thwart HIV infection, Dr. Deeks said. In his view, CMV is a "very clever vaccine approach," and Picker's work in monkeys is the first strong piece of evidence that a retrovirus could be cured with a vaccine.

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Promising Solutions: DNA Vaccines

In 2015, a group of researchers proved that a DNA vaccine could eradicate precancerous cervical lesions caused by the human papilloma virus (HPV) in about half of women treated. The work, led by David Weiner, Ph.D., the "father of DNA vaccines," demonstrated that injecting the vaccine into the muscle (rather than the bloodstream) yields a powerful T-cell response. According to Dr. Deeks, the 2015 HPV study is an "inspiring story" because it is the first strong evidence that vaccines can stimulate CD8 T cells to specifically identify and kill virus producing target cells.

"That's exactly what we need in HIV," said Dr. Deeks. DNA vaccine technology is generating interest not only for cancer, but also for viruses such and HIV and Ebola. A Phase I study is of DNA vaccines for HIV is underway.

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Promising Solutions: TLR Agonists to Boost Vaccine Effectiveness

Immuno-oncologists have realized that vaccines often work best when paired with a booster to help stimulate the immune system. Many companies, including Gilead and others, are working on a type of adjuvant drug called a toll-like receptor (TLR) agonist. Earlier this year, Gilead released promising results from research done in monkeys. The company's TLR7 agonist helped reduce SIV DNA in some infected monkeys and helped extend viral suppression in monkeys that had stopped antiretroviral treatment.

"Although it's controversial, my read of the data ... is that you got enhanced capacity of the immune system to control the virus," Dr. Deeks said. According to Dr. Deeks, the bottom line is that powerful HIV vaccines may be on the horizon, and some drugs such as TLR agonists may make them even more effective.

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Checkpoint Inhibitors

HIV leads to chronic inflammation, fibrosis and tissue dysfunction. In fact, HIV researchers now know that more inflammation is correlated with a larger latent reservoir. Cancer patients are also victims of harmful inflammation, which essentially causes the immune system to work overtime.

"Oncologists figured out a long time ago that inflammation is bad for you because it results in a counter regulatory response," Dr. Deeks said. Today, cancer researchers have found remarkable success with drugs that "downregulate" immune response, such as PD1/L1 and CTLA 4 inhibitors. And one case study from Australia offered a tantalizing glimpse of how this approach might benefit HIV-positive patients. In 2013, an Australian melanoma patient with HIV started cancer treatment with a CTLA 4 inhibitor. Although he was being treated for cancer, over time the size of his HIV reservoir decreased.

"We're in an era of experimental medicine," Dr. Deeks emphasized, but current cure research promises a "viable pathway to achieving remission."

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