amfAR Rolls Out Its “Next Generation” of Funded HIV Cure Research
by Chip Alfred
On December 3, 2020 in honor of World AIDS Day, amfAR held its annual Meet the Scientists panel discussion livestreamed on YouTube. Moderated by Rowena Johnston, PhD, amfAR’s Vice President and Director of Research, the panel included Timothy Schacker, MD, Vice Dean for Research and Director of the Program in HIV Medicine at the Medical School of the University of Minnesota; and Jerome A. Zack, PhD, Distinguished Professor and Chair of the Department of Microbiology, Immunology and Molecular Genetics at UCLA.
Both research projects discussed in the program borrow from cancer research and employ the use of natural killer (NK) cells. The only known cases of HIV cure to date occurred in people living with HIV—Timothy Ray Brown, also known as the Berlin patient, and the London patient—whose blood cancer was treated with a stem cell transplant. Both received stem cells from donors with a genetic mutation that left them with no functional CCR5 protein—the main gateway that enables most types of HIV to enter and infect cells.
“While we learned a great deal from these cases, it just isn’t possible to apply or adapt this type of procedure to cure everyone who’s living with HIV,” states amfAR Chief Executive Officer Kevin Robert Frost. “Though a number of different avenues are currently being pursued in the search for a cure, we sought research projects that could seed the next generation of potential interventions.”
The new grant initiative seeks out novel ideas and technologies, and it explores an HIV cure approach that has previously shown promise in cancer therapy. Natural killer cells are the foot soldiers of the innate immune system, delivering an immediate and potent attack against infectious agents such as HIV, but naturally-occurring NK cells are not as efficient in attacking HIV as CD8+ T cells.
Dr. Schacker recently completed an amfAR-funded project exploring transplantation of NK cells between close relatives as a means of reducing the reservoir in HIV-positive recipients. He says the study posed the question: “What would happen if we gave an HIV-infected person on antiretrovirals who was well-suppressed healthy NK cells?” The NK cells were amplified so that more cells could be put into each HIV-positive recipient. NK cells are the first responders to viral emergencies, but they only stay on the job a few days as our bodies constantly produce more of them. Another question this study sought to answer was if the NK cells could be more effective at targeting HIV cells if they could remain viable in the body longer. After treating the NK cells with Interleukin 15 (IL-15), researchers tracked NK cells in the reservoirs of patients for at least eight days; in one patient viable NK cells were detected after twenty-one days. Although the data from this project have not yet been published, Dr. Schacker says the preliminary results are very promising.
Dr. Zack is just beginning his clinical trial applying new therapeutic approaches with NK cells on mice. Since mice can’t contract HIV, this study uses humanized mice with human immune systems that are then infected with HIV. “The rationale we’re planning to take is to engineer into NK cells a molecule that will add greater ability of the NK cells to see HIV in the target,” he explains. So far Dr. Zack and his colleagues have tested the effects of unaltered NK cells. Infected mice were given antiretroviral therapy (ART), achieved viral suppression, then ART was stopped to determine how long it would take for resurgence of viral replication in the body, also called rebound. Dr. Zack reports his model found that rebound was delayed with this method.
The next step will be to engineer CAR-NK (chimeric antigen receptor) cells to enhance their ability to find and destroy HIV-infected cells. To compare the ability of unaltered and CAR-NK cells to eliminate cells harboring reservoir virus from the body and affect the rebound of virus when ART is withdrawn, the researchers will employ several novel technologies developed by Dr. Zack. These include the insertion of a barcode into viruses so that the fate of each individual virus can be tracked, and the use of a latency reversing agent developed in his lab. Latency reversing agents reactivate latent HIV within CD4 cells so that infected cells can be recognized and targeted.
Kudos to amfAR for presenting an informative, accessible discussion about this groundbreaking new initiative. The moderator and panelists did an excellent job of taking their time to break down complex principles and terminology for the non-scientists who participated. The program kicked off with a powerful video about the global impact of amfAR and the organization’s unwavering commitment to finding a cure. I left the conversation feeling inspired and hopeful that a cure may in fact be within our reach.
Chip Alfred is A&U’s Editor at Large, a public speaker, and a media and public relations consultant based in Philadelphia. Follow Chip on Twitter @ChipAlfred.