The past year has seen a notable expansion of efforts to apply gene therapy approaches to HIV cure research, and several online events have highlighted progress in the field. In parallel, work is underway that aims to make gene therapies more affordable and accessible globally.
Two papers published early in the year (one in the Journal of Clinical Investigation, the other a preprint in bioRxiv) reported that a small number of participants in trials of a gene therapy developed by Sangamo Therapeutics showed evidence of partial control of HIV viral load after antiretroviral therapy (ART) interruption. Importantly, the enhanced control of HIV replication was associated with improved HIV-specific immunity. These publications were highlighted by researcher Danny Douek in an excellent plenary presentation on HIV cure research at the virtual IAS 2021 conference in July.
The Sangamo Therapeutics approach applies gene editing to CD4 T cells to prevent expression of the CCR5 co-receptor used by most HIV strains to enter cells. Large volumes of CD4 T cells are sampled from participants, gene edited in the laboratory, and then reinfused. The reported results suggest that strategies that protect CD4 T cells from HIV infection may also have the capacity to bolster HIV-specific immunity, particularly HIV-specific CD8 T cell responses (at least in some cases).
This idea is being explored further by the biotech company American Gene Technologies, which is currently conducting a trial that focuses on genetic modification of HIV-specific CD4 T cells (rather than CD4 T cells in bulk). The goal is to protect the CD4 T cells that should be leading the immune response against HIV. The company has reported that initial infusions appear safe and preliminary results are anticipated next year.
Sangamo Therapeutics aren’t pursuing commercial development of their candidate but are supporting a large trial in people with HIV that is ongoing in Cincinnati. Led by Rafick-Pierre Sekaly and Carl Fichtenbaum, the study will evaluate the factors associated with improved HIV-specific immunity and HIV reservoir reductions in greater detail.
Another approach to enhancing HIV-specific immunity with gene therapy is to equip cells with receptors that are adept at recognizing the virus and triggering the killing of infected cells. T cells are sampled from the intended recipient, gene modified in the laboratory to give them what is known as a “chimeric antigen receptor” (CAR), and then reinfused. Several CAR T cell gene therapies are licensed for the treatment of cancers (in that setting, the CAR is designed to target the cancer).
In August, a preliminary study from Bingfeng Liu and colleagues in China was published in the Journal of Clinical Investigation reporting that delivery of CAR T cells targeting HIV was associated with modest reductions in the viral reservoir. The intervention was not able to promote control of viral load after an analytical treatment interruption (ATI), but rebounding viruses showed evidence of mutations suggesting that the CAR T cells were exerting anti-HIV activity. The researchers are continuing to work on improving the potency of the CAR T cells and note in their paper the possibility of combining with gene therapies that protect CD4 T cells from HIV infection.
Steve Deeks and colleagues at UCSF are working with the company Lentigen to study a duoCAR T cell gene therapy in people with HIV. The technology has shown promise in preclinical humanized mouse studies. A phase I/IIa clinical trial, which includes an ATI, is now recruiting.
Scientists involved in founding Lentigen are also key players in a global initiative to bring gene therapies to resource-limited settings, starting with India and Uganda. The initiative is coordinated by a non-profit company, Caring Cross, and involves many partners. The ultimate goal is to make gene therapies accessible and affordable globally. Dr. Boro Dropulić of Caring Cross provided an overview of the effort at the virtual Pre-CROI Community HIV Cure Research Workshop in March of this year.
Gene therapies may also have the potential to target HIV directly, with several groups of researchers developing technologies that aim to remove the virus from persistently infected cells or disable it in ways that prevent viral load rebound when ART is interrupted.
The most well publicized gene editing technology is CRISPR/Cas9. The laboratory of Kamel Khalili at Temple University in Philadelphia has published a series of preclinical studies indicating that CRISPR/Cas9 can excise (or otherwise disable) HIV from the latently infected cells that make up the persistent viral reservoir. The group has published evidence of variable reservoir reductions in a small number of macaques infected with SIV, the simian counterpart of HIV (TAG covered this study when it was presented at CROI in 2019).
Excision Biotherapeutics, a company founded by Khalili to commercially develop the technology, recently announced a major milestone: The US Food and Drug Administration has authorized the first clinical trial in people with HIV. The CRISPR/Cas9 construct (named EBT-101) will be delivered using an adeno-associated virus (AAV) vector, which is a commonly used platform for gene therapies.
Media coverage of the preclinical research results has been guilty of overhyping near term prospects (see entries to TAG’s Cure Research Media Monitor). Eradication of HIV is not considered likely due to the difficulty of reaching all the intact viruses in the body, but the hope is to reduce the amount of HIV to a level the immune system might be able to contain in the absence of ongoing ART.
Safety will be carefully monitored as there are concerns about the potential for off-target edits to human genes. No such problems have been documented in extensive preclinical studies, but there are technological limitations to how extensively off-target edits can be analyzed. It will also be important to assess whether the Cas9 protein (which is derived from bacteria) is targeted by the human immune response. Encouragingly, a preliminary report on the use of CRISPR/Cas9 to treat a small number of people with transthyretin amyloidosis was published in August, describing evidence of safety and activity.
On a webinar hosted by the European AIDS Treatment Group on October 26, Joachim Hauber presented plans for a clinical trial involving a different gene editing approach that directly targets HIV. The editing is accomplished by an enzyme from bacteria dubbed Broad Range Recombinase 1 (Brec1).
The researchers intend to sample hematopoietic stem cells from people with HIV requiring stem cell infusions to treat diffuse large B cell lymphoma, then introduce Brec1 into the cells via a lentiviral vector. The stem cells will be reinfused with the goal of generating a population of cells equipped with Brec1 and able to fend off HIV infection. The estimated start date for the trial is the fourth quarter of 2022.
Future studies involving direct delivery of Brec1 with AAV vectors are also under consideration. The EATG webinar recording isn’t posted yet, but Joachim Hauber discussed the work in a presentation at the IAS 2021 meeting which is available online.
The vulnerability of CD4 T cells to HIV has led some scientists to believe that genetic modifications will be essential to cure strategies, so it’s encouraging to see gene therapy research now progressing on multiple fronts.
HIV Gene Therapy Meetings and Presentations in 2021
Pre-CROI Community HIV Cure Research Workshop Session #2, March 5, 2021
Overview of gene therapy in HIV cure research
Christopher Peterson, PhD, Fred Hutch
Anti-HIV duoCAR-T cells: Preclinical studies leading to a Phase I/IIa clinical trial and a model for affordable access of gene-modified cell therapy products
Kim Antony-Gonda, PhD, MB ASCP
Boro Dropulić, PhD, MBA
Bringing safe, effective, and accessible curative interventions for HIV to all
Joseph (Mike) McCune, MD, PhD, Head, HIV Frontiers, Global Health Innovative Technology Solutions
IAS 2021 HIV Cure & Gene Therapy Forum, July 19-21, 2021
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