Gene and Cell Therapy

Researchers are also exploring other possible HIV cure approaches that focus on gene and cell therapies. The goal of gene therapy is to deliver therapeutic genes into a patient that will treat the disease. In cell therapy,  living cells are transplanted into a patient to treat the disease. 

One cell therapy approach involves engineering HIV target cells to render them resistant to HIV entry. Another approach is to modify cytotoxic T cells to selectively target and eliminate infected cells. Generally, these therapies rely on genetic modification to “edit” the blood cells of the patient so that they become resistant to HIV or become better at targeting and eliminating HIV and infected cells.

In gene therapy, anti-HIV genes are introduced into cells using a viral vector or an engineered nanoparticle. Gene therapies use different approaches to target HIV. In some cases, target genes are edited either by inserting a therapeutic sequence or by disrupting DNA sequences of proteins that are important in the HIV life cycle. Examples of gene editing methods include the use of TAL-effectors or zinc fingers with nuclease, and/or CRISPR-Cas9. With these techniques, a specific sequence of DNA is recognized and cut, and (in some cases) new DNA is introduced at the cut site.

A primary target for many gene therapy approaches is the CCR5 gene. CCR5 is a receptor found on the surface of white blood cells, including T cells, and is required by HIV to enter T cells. When this protein is absent (such as in individuals with a naturally occurring deletion, such as one called CCR5-Δ32), HIV cannot infect cells. An individual known as the “Berlin Patient” was cured of his leukemia and of HIV when he received a stem cell transplant from a donor who has a double CCR5-Δ32 deletion mutation. This mutation, however, is very rare. Many current cure approaches focus on introducing CCR5 deletions or mutations. One possible complication, however, is that a similar receptor to CCR5, called CXCR4, exists in white blood cells, and it is possible that HIV may be able to adapt in order to use CXCR4 to gain entry into cells in the absence of CCR5.

Gene Therapy using engineered CD8+ cells

In an effort to improve the design of CAR-T cell therapy for HIV patients, researchers engineered a receptor that fused the binding domain of a monoclonal antibody (called scFv) that can specifically recognize HIV Env protein with the T cell receptor’s signaling domain.

Unfortunately, this bNAb-based CAR was not found to be effective therapeutically, and researchers are continuing to engineer new CARs that have started to show promising results. Using multiple antigen-recognizing domains in a single CAR, for example, has been shown to improve protection in animal studies. Researchers have recently designed a receptor with two CAR molecules created out of multiple receptors that can bind HIV — called duoCAR. In animal models, duoCAR therapy was able to successfully eliminate HIV-infected cells and resist HIV infection. This may be a viable approach for controlling viral loads and eliminating latent cells in HIV patients.