Making inroads toward eliminating latent HIV reservoirs

h.i.v. infected t cell
HIV reservoirs hide throughout the body, posing an ongoing risk to patients even when they respond well to antiretroviral treatments. (NIH)

As successful as antiretroviral therapy has been in suppressing HIV, the virus that causes AIDS, many patients are left with latent viral “reservoirs” that hide in the body and can resurge at any time. Two recent advances are focused on using new technology to combat these HIV reservoirs.

Last week, scientists at Case Western Reserve University received an $11 million grant from the National Institutes of Health to study gene-edited T cells in HIV. The Case Western team is working with Sangamo Therapeutics to design a study in 20 patients, which they anticipate will begin this year, according to a press release.

The feasibility of taking infection-fighting T cells from patients and engineering them to recognize and eradicate illnesses from the body has already been proven in oncology with two FDA-approved blood cancer treatments: Novartis’ Kymriah and Gilead’s Yescarta. While those treatments are designed to train T cells to recognize and target an antigen on cancer cells, the Case Western-developed technology works by disrupting HIV's ability to enter cells.

The technology is centered on eliminating a gene called CCR5, which is responsible for ushering HIV into host cells. The technique, called zinc finger nuclease gene editing, employs specially engineered proteins to create precise breaks in DNA, knocking out CCR5.

Sangamo had shown in earlier trials that T cells edited in this manner can be expanded outside the body, and that they persist and grow after being infused back into patients. They also documented increases in CD4+ T cells, which helped break down the HIV reservoirs. During the new trial, 10 patients will receive gene-edited T cells and the other 10 will be given unmodified T cells, according to the statement.

"For patients with HIV, new treatments to permanently eradicate latent HIV reservoir and increase CD4+ T cell counts—potentially leading to a cure—are an important unmet need," said Rafick-Pierre Sekaly, Ph.D., a professor of immunopathogenesis at Case Western Reserve School of Medicine, in the statement.

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CAR-T cells' success in cancer has spurred interest in applying the technology to infectious diseases, particularly HIV. In December, for example, scientists at the University of California in Los Angeles announced that they are developing an engineered T cell that binds to CD4, a protein that HIV hijacks in order to infect host cells.

Scientists at the University of Nebraska Medical Center announced last week that they are taking a different tack, modifying an existing antiviral drug to improve its ability to penetrate and attack hidden HIV reservoirs. They’ve taken HIV drug Tivicay (dolutegravir), from GlaxoSmithKline subsidiary ViiV, and enclosed it in nanocrystals, according to a statement. The nanocrystals were designed to be able to withstand temperature variations in the body and persist for months.

In mouse models and HIV-infected human cells, the University of Nebraska team showed that the nanocrystals extended the life of Tivicay and facilitated its entry into lymph nodes, bone marrow and other “hidden body compartments,” according to the statement. Once they enter macrophages, the drug becomes active and is released into the surrounding tissue, they reported in the journal Nature Communications.

ViiV and the University of Nebraska have filed patents on the technology, and the college is planning to build a nanomedicine production plant so it can produce the drug on campus. The researchers hope the nanocrystal technology proves useful in other diseases as well, such as cancer and neurodegenerative disorders.