Immunizing the well and flushing the reservoir may be ways to HIV cure

Print 09 March 2016
Anette Breindl / BioWorld

Somewhat like a vaccine for HIV, a cure has been on the horizon yet out of reach for a frustratingly long time.

"I think it's fair to say that the score card is not very impressive," Mario Stevenson, chief of the division of infectious disease at the University of Miami Medical School, told the audience at a the plenary session of the Conference on Retroviruses and Opportunistic Infections (CROI), which is going on in Boston this week. He cited "40 million or so infected individuals worldwide and one documented cure" in form of "Berlin patient" Timothy Ray Brown.

In a CROI plenary talk on "Progress in Gene Therapy for HIV Cure," Paula Cannon, professor of molecular microbiology and immunology at the University of Southern California, traced the origin of the idea of an HIV cure using gene therapy back to 1988, when molecular biologist and Nobel Prize winner David Baltimore wrote about the possibility of "intracellular immunization" against HIV.

That, Cannon said, set off a golden age of HIV gene therapy, when "anyone could be an armchair gene therapist."

Tangible success with the concept, however, awaited progress on multiple fronts, including integrating gene transfer vectors, adoptive T-cell therapy, autologous hematopoietic stem cell transplants – first for cancer patients, and then gentler regimens that were appropriate for wider use – and targeted nucleases that have enabled more precise gene editing.

One advantage of gene therapy, Cannon said, is that "in many ways, it's the opposite of a daily pill – if we can get it to work well enough, it could be kind of a single pill approach."

That remains an important goal because although the development of single-tablet regimens has greatly simplified what used to be much more complex dosing regimens, toxicity remains a concern with the simpler regimens.

And sometimes adherence remains a concern, too. The case of the Mississippi baby, for example, a child who experienced an extraordinary 27 months of remission after early aggressive treatment followed by a treatment interruption, came to light not because the child went off of antiretroviral treatment (ART) in a planned way, but because her parents stopped seeking medical care for her for several months. (SeeBioWorld Today, Aug. 8, 2014.)

And even for those who do diligently take their daily pill or pills, it is fair to say that many wish they did not have to.

Successful gene therapy offers one avenue to long-lasting or even permanent treatment, and in her talk, Cannon gave an overview of academic institutions and biopharmas involved in the space.

Furthest along is Sangamo Biosciences Inc., which is in phase II with its gene edited SB-728-T in T cells for the treatment of HIV, and in phase I with SB-728-T in stem cells. (See BioWorld Today, March 6, 2014.)

Also in the clinic is Calimmune Inc., which published preclinical primate data this week on its gene therapy Cal-1, which is in phase I/II trials in patients who are not taking ART.

Cal-1-treated cells are engineered to resist HIV in two ways. Treatment inhibits the expression of CCR5, a co-receptor that HIV uses to enter cells and that is also the target of SB-728-T. Engineered cells also express a fusion inhibitor on their surface.

The treatment is used to engineer not only T cells, but also hematopoietic stem cells isolated from patients. That approach has two advantages. First, engineering stem cells can potentially provide patients with a lifetime of resistant cells.

Second, though T cells make up the bulk of infected cells, HIV can also infect other cell types, and resistance of those cells decreases HIV's hiding spots. Latently infected cells – the so-called reservoir – are a major obstacle to an HIV cure.

In their paper, which was co-authored with researchers from the Fred Hutchison Cancer Research Center and published online in Molecular Therapy – Methods & Clinical Development on Feb. 24, 2016, the team described treating pigtail macaques and then infecting them with SHIV, a version of HIV that can infect primates besides humans.

The study, Calimmune's senior vice president of research and development, Jeffrey Bartlett, told BioWorld Today, was not directly analogous to the situation in patients, where gene therapy follows infection rather than preceding it; however, the work gave new insights into the interplay between T-cell counts and viral load.

After being infected with SHIV, treated animals showed an acute rise in viral levels and drop in CD4 T cells that was similar to the course of infection that would be expected from historical control data.

During chronic infection, he said, though the viral loads were lower than those of historical controls even at the beginning of the chronic phase, a precipitous drop in viral load came only after T-cell levels had recovered into the normal range, which took several months. "It shows the importance of immune function before we could have an impact on the virus," he said.

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