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Pitt researchers develop promising advances for HIV cure

| Monday, Aug. 8, 2016, 9:00 p.m.
Stephanie Strasburg | Tribune-Review
Research assistant professor John Alvarado, 44, of Raccoon Township, shows fellow research assistant professor Lori Sedlak, right, 38, of Cranberry, HIV-1 Nef protein crystals through a microscope at a University of Pittsburgh lab in South Oakland on Wednesday, Aug. 3, 2016.
Stephanie Strasburg | Tribune-Review
Graduate student Ravi Patel, 23, of Regent Square, performs cell culture experiments in the lab of University of Pittsburgh HIV specialist Thomas Smithgall in South Oakland on Wednesday, Aug. 3, 2016. Smithgall is contributing to a new effort that harnesses new advances in cancer immunotherapy to try to cure HIV and AIDS.
Stephanie Strasburg | Tribune-Review
University of Pittsburgh HIV specialist Thomas Smithgall draws cell diagrams at his lab in South Oakland on Wednesday, Aug. 3, 2016. Smithgalls is contributing to a new effort that harnesses new advances in cancer immunotherapy to try to cure HIV and AIDS.
Stephanie Strasburg | Tribune-Review
University of Pittsburgh HIV specialist Thomas Smithgall stands for a portrait in his lab in South Oakland on Wednesday, Aug. 3, 2016. Smithgall is contributing to a new effort that harnesses new advances in cancer immunotherapy to try to cure HIV and AIDS. Behind him in the photo, research assistant professor John Alvarado, 44, of Raccoon Township, works.
Stephanie Strasburg | Tribune-Review
Visiting scholar Kecey Shen, left, 21, of Shadyside via Beijing, and research assistant professor John Alvarado, 44, of Raccoon Township, work in the lab of University of Pittsburgh HIV specialist Thomas Smithgall in South Oakland on Wednesday, Aug. 3, 2016.
Stephanie Strasburg | Tribune-Review
Research assistant professor John Alvarado, right, 44, of Raccoon Township, talks with visiting scholar Kecey Shen, 21, of Shadyside via Beijing, in the lab of University of Pittsburgh HIV specialist Thomas Smithgall in South Oakland on Wednesday, Aug. 3, 2016.

The ability of HIV to silence the cells it infects, cutting off communication with the body's immune system, has helped the virus elude efforts to cure it over the past three decades.

University of Pittsburgh researchers think they might have found a way to restore that communication, a discovery that could play a key role in reinvigorated attempts to eradicate the virus.

“It's still an enormous public health problem, especially internationally,” said Thomas Smithgall, chairman of the Department of Microbiology and Molecular Genetics at Pitt's School of Medicine. “And the reason is that while we do have many drugs that are very good at suppressing viremia — keeping the virus at bay — they are not curative.”

Pitt is one of 18 institutions participating in a recently announced $5.7 million project led by Washington, D.C.-based George Washington University to advance the search for a cure over the next five years.

Even as people with HIV live long lives, thanks to anti-retroviral drugs that suppress the virus, infected cells linger in latent reservoirs throughout the body, springing back to life if people stop taking the medication.

The project, known as BELIEVE, targets the latent reservoirs, drawing on recent discoveries in cancer treatment that show how powerful the body's immune system can be when bolstered against disease.

When a cell in the human body is newly infected with HIV, the cell attempts to communicate with killer immune cells by extending through the cell's membrane a protein containing information about the infection.

But, as Smithgall says, HIV is clever. One of the first things the virus does after infecting a cell is to deploy its own protein, known as nef, to stop the host cell from signaling to immune cells that it is infected.

Smithgall's team has developed a synthetic molecular compound that inhibits the nef protein, restoring the infected cell's ability to communicate with the killer immune cells.

Or at least that's what it does in lab tests. Hurdles remain before the compound could be part of an HIV treatment, he said, including safety and efficacy testing in animal and human trials and then finding a way to administer it, ideally in pill form.

To be part of a cure, the compound would need to be accompanied by other major advances, he and other HIV specialists said. Other groups in the 18-institution collaborative are focused on those advances.

“We think that to make a real dent in the HIV reservoir, you have to overcome a lot of obstacles in parallel,” said Brad Jones, one of the BELIEVE leaders and an assistant professor of microbiology, immunology, and tropical medicine at GW's School of Medicine and Health Sciences.

Two central objectives are to strengthen the killer immune cells and find a way to reliably “wake up” cells with latent infection so the immune system can kill them.

Jones is working on both those objectives. He is trying to find the immune cells that are most effective at killing HIV and expand their numbers in people who have the virus.

Children's National Health System, another participant, has the ability to grow the enhanced immune cells and reinfuse them into study participants, he said.

In both cancer and HIV, affected cells communicate with immune cells by displaying information in proteins on their surfaces, Jones said. Immunotherapy in both cancer and HIV involves tinkering with the proteins in ways that boost the immune system to fight the diseases.

To wake up latent cells, Jones is working with a cancer drug from Altor Bioscience known as ALT-803. The drug has been shown to wake up HIV from the places where it lies latent in the body — researchers think it might be in lymph nodes, peripheral blood and the brain — and to enhance the immune system's ability to kill infected cells.

The overlap between cancer and HIV therapies may help with testing drugs, Jones said. Because HIV patients can live near-normal lives with the virus, few may be interested in clinical trials of drugs; cancer patients may be more willing because their disease is deadlier.

The prevalence of untreated HIV indicates better, or more convenient, treatments could still be needed, Jones said. Of the estimated 1.2 million people living with HIV in the United States in 2011, only 40 percent were engaged in treatment, and only 30 percent had viral suppression through treatment, according to the Centers for Disease Control and Prevention.

The National Institutes of Health has dedicated about $30 million over the next five years to six research collaborations, including the BELIEVE project, that aim to develop a cure or a vaccine for HIV as part of the second round of the Martin Delaney Collaboratory program, according to an NIH news release.

Researchers have tried cell-therapy treatments for HIV before, but the BELIEVE participants think the combination of an enhanced immune response, a nef inhibitor and an effective agent to wake up cells from latency represents promise.

“There's been a resurgence of optimism for the concept of a cure in general,” Jones said.

Smithgall and Jones hesitate to talk about when HIV might be cured.

Smithgall's team spent 18 months and tested about 250,000 compounds before finding the one that seems to stop HIV from hiding itself from the immune system. They are now preparing to test it in mice that have been engineered so they can be infected with HIV.

They said they hope to have found a way to reduce HIV reservoirs by the end of the five-year grant. Another accomplishment would be to reach the same level of suppression with immuno-therapeutic methods that has been reached with anti-retroviral therapy, they said.

“There's always a lot of hope and promise,” Smithgall said, “but it's a slow process.”

Wes Venteicher is a Tribune-Review staff writer. Reach him at 412-380-5676 or wventeicher@tribweb.com.

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