World AIDS Day: Stepping up the search for a cure - Fred Hutch News Service

Inclusion is critical for HIV-cure research

As prospects improve for research on cures for HIV, advocates are urging that women and transgender people be included in any future clinical trials.

Women and girls make up roughly half of the 38 million people in the world living with HIV, but participation in clinical trials skews heavily toward males, said Brian Minalga, project manager for the Women’s HIV Research Collaborative, a National Institutes of Health-funded advisory group housed at Fred Hutch.

 

“A cure would be huge. It would change everything, and women and transgender people need to be involved in that,” Minalga said. “It is their human right.”

 

At a recent conference of the Association of AIDS Care Nurses in Portland, Oregon, Minalga presented results of an analysis by the New York-based Treatment Action Group of 128 HIV-cure studies. Of the only 44 studies that reported enrollment by sex, 18 (40%) were all male, one was all female, and 25 included males and females.

 

“There’s a problem here, systemically, about what research questions are asked and about how women and transgender people are enrolled,” Minalga said. “Why does this matter? It is because men and women are different, and transgender and cisgender people (those whose gender identity matches the sex they were assigned at birth) are different.”

 

The NIH Revitalization Act of 1993 requires that women and minority groups be included in all NIH-funded medical research, but the guidance only applies to late-stage clinical trials. As a result, Minalga said, females tend to be left out of early-stage studies, even in preclinical studies involving mice.

Brown and his doctors thought it would be worth a try. It was a brutal procedure that almost killed him, but he was cured of both HIV and leukemia. For more than a decade, he was the only person believed cured of HIV. This year, two more patients, in London and Dusseldorf, Germany, appear to have been cured with similar procedures.

Kiem and Jerome have co-hosted five scientific conferences in Seattle since 2014 to discuss research on ways to understand how and why Brown — and now two others — were cured by transplants, and how more cures could follow. The successful transplants essentially swapped out the patients’ immune systems for new, HIV-resistant ones. The long-term goal is to expand and vastly simplify the process of modifying the human immune system without transplantation by transferring genetic traits that block HIV or command immune cells to destroy other cells where HIV quietly hides.

In current gene therapy experiments, a patient’s own blood stem cells are removed and genetically modified ex vivo — outside the body — in a laboratory setting. Snippets of DNA that confer resistance to HIV, such as the CCR5 mutation, are inserted into genes of the patient’s cells. This is a cut-and-paste process called gene editing, which is made possible by new generations of precision gene-cutting tools, such as the enzyme CRISPR/Cas9. The edited stem cells are then returned to the patient.

'Gene therapy in a syringe'

Blood stem cells are the mother cells of the immune system, and when these modified cells divide, their HIV-resistance genes are passed down to their progeny: a whole family of diverse blood cells, including the T cells that HIV normally likes to infect. Kiem said he and his colleagues are currently studying how to modify stem cells so they are not only resistant to HIV but also generate immune cells that can seek out and destroy any remaining infected cells in the patient.

Kiem is taking this curative process one big step further. A mixture containing all the ingredients for gene transfer — DNA and the gene-editing enzymes — is packaged into a syringe and injected into the body. The gene-transfer process takes place “in vivo,” or inside the body. He calls it “gene therapy in a syringe.” It has the potential to be safe, effective and relatively inexpensive. 

Dismissed as “pie in the sky” by some leading HIV researchers, the approach has nevertheless inspired a cadre of scientists who see a path forward and continue to carry out studies aimed at overcoming the many barriers that remain.

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