AIDS Treatment Breakthrough: Novel Dual-CAR-T Immunotherapy Promising for Targeting HIV Reservoir

The global HIV epidemic affects more than 35 million people worldwide. Antiretroviral therapy (ART) is a routine treatment that can control but not cure HIV (human immunodeficiency virus) infection. However, access and lifelong adherence to daily regimens is a major challenge for many people living with HIV. A major barrier to an HIV cure is the viral reservoir, the copy of HIV hidden in the genome of infected cells. If ART treatment is stopped, this virus can rapidly make new copies of HIV, ultimately leading to the onset of Acquired immunodeficiency syndrome (AIDS).

In a new study, researchers from the Ragan Institute, the University of Pennsylvania and Massachusetts General Hospital describe a novel dual CAR T cell (Dual-CAR-T ) immunotherapy that could help fight HIV infection. The findings were published online on Aug. 31, 2020, in the journal Nature Medicine, titled "Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo".

CAR-T cells are a powerful immunotherapy currently used in cancer treatment: the patient's own immune T cells are genetically modified to express chimeric antigen receptors (CARs). The expressed CAR reprograms the T cells so that they recognize and eliminate specific diseased or infected cells, such as cancer cells or potentially HIV-infected cells.

The research team designed a new HIV-specific CAR-T cell. They set out to design Dual-CAR-T cells that can target and rapidly eliminate HIV-infected cells and, once they survive and proliferate in vivo, are able to resist infection by HIV itself, due to the fact that HIV's primary target is these T cells.

As a new type of CAR-T cell design, the Dual-CAR-T cells are genetically modified to express two CARs from the same T cell, each carrying a CD4 protein that allows it to target HIV-infected cells, and each having a co-stimulatory structural domain that signals the CAR-T cells to increase their immune function. The first CAR contains a 4-1BB costimulatory structural domain that stimulates cell proliferation and persistence, while the second CAR has a CD28 costimulatory structural domain that increases the ability of these T cells to kill HIV-infected cells.

Since HIV frequently infects T cells, they also added a protein called C34-CXCR4, which prevents HIV from attaching to T cells and thus prevents the virus from infecting them. The resulting Dual-CAR-T cells are long-lived, replicate in response to HIV infection, effectively kill infected cells, and develop partial resistance to HIV infection.

When the protected Dual-CAR-T cells were administered to HIV-infected mice, these researchers observed that HIV replication became slower and that they had fewer HIV-infected cells compared to mice that were not given the same cells. They also observed that the number of HIV viruses in the blood of these mice was reduced and CD4+ T cells were preserved. In addition, when they used a combination of Dual-CAR-cells and ART in HIV-infected mice, this virus was suppressed more rapidly, which resulted in a smaller HIV viral reservoir than in mice treated with ART only.

Dual-CAR-T cells were shown to reduce HIV load in a variety of tissues and cell types, including long-lived memory CD4+ T cells. This would support the use of CAR-T cell therapy as a novel tool for targeting the HIV viral reservoir in order to achieve a functional cure for HIV infection.

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