CAR Therapies Could Offer New HBV, HIV Treatments

Early evidence related to the use of chimeric antigen receptor T-cell (CAR-T) and natural killer-cell (CAR-NK) therapies suggests they hold promise as potential treatments for chronic hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections.

However, a new systematic review suggests the existing scientific evidence remains heterogeneous and limited in scope. Thus, the report argues, larger studies are warranted to more accurately optimize and design chimeric antigen receptor (CAR) therapies for these viruses. The review was published in Frontiers in Medicine.¹

CAR therapies were originally developed to treat cancer, and they have proven successful at treating some types of hematologic malignancies. That success, the authors explained, led scientists to investigate other possible applications for the technology.²

“During the last twenty years, an extensive arsenal of cell types, such as first-generation CD3ζ CARs and second-generation co-stimulated CARs (CD28 or 4-1BB), as well as next-generation CAR constructs incorporating safety switches, armored cytokine secretion, or bispecific targeting techniques, have been produced to treat viral infections,” they wrote.¹

Among the new types of CAR therapies under development are CAR-NK cells, which the authors explained are seen as a potentially safer alternative to other types of CAR therapies, given their natural resistance to graft-versus-host disease and a reduced risk of cytokine release syndrome (CRS).

The authors wrote that they were driven to conduct a systematic review of the potential use of CAR-T and CAR-NK therapies in the settings of HIV and HBV because the existing reviews are narrative in nature and not comprehensive.

The investigators searched scientific databases for studies including in vitro, in vivo, and clinical trials of virus-directed CAR-T lymphocytes. They found a total of 43 studies, of which 21 were in vitro, 14 were in vivo, and 8 were clinical trials.

Taken together, the studies suggested both CAR-T and CAR-NK therapies hold promise. For instance, preclinical CAR-T models directed at HIV led to statistically significant HIV p24 antigen reductions (standardized mean reduction [SMD], –1.15, 95% CI, –1.50 to –0.80). CAR-T therapies directed at HBV led to decreases in HB surface antigen (HBsAg) and HBV DNA (SMD, –1.30, 95% CI, –1.70 to –0.90).

CAR-NK therapies led to similar results, along with potentially improved safety profiles, they said.

The same was true of in vivo analyses of the immune-cell therapies, which consistently suppressed HIV RNA (SMD = -0.92, 95% CI, -1.26 to -0.58) and moderately reduced HBV DNA levels (SMD = -1.05, 95% CI, -1.52 to -0.63).

Early phase 1/2 clinical trials found CAR-T therapies directed at HIV led to “modest” decreases in circulating HIV RNA and HBV-directed therapies led to “small but detectable” antiviral responses, the investigators said.

As a whole, the studies showed these new therapies hold significant promise, the authors said.

“CAR-modified lymphocytes exhibited similar sustained antiviral activity in vitro and in vivo and reduced HIV p24, HIV RNA, HBsAg, and HBV DNA across 43 studies included,” they said. They added that these early trials indicate the therapies have manageable and mild side effects, though the antiviral benefits patients experienced were “modest and short-lived.”

Still, the authors said translating this early research into meaningful, clinically useful therapies remains a challenge. Part of the problem is the risk of toxicities, particularly with CAR-T therapies, they noted.

The investigators said future studies should focus on how to make the effects of CAR therapies more persistent, which they said could include potential combination strategies with latency-reversing or immune-modulating agents. They said larger and longer-term trials are also needed in order to better understand the long-term impacts of the therapies.

The authors concluded that virus-directed CAR immunotherapies represent, “a promising approach towards a functional cure of chronic viral infections.”

References

1. Sleman S, Ameen MB, Abid OI, Abdullah BJ, Abass ZA. Virus-directed CAR immunotherapies for chronic HBV and HIV: a systematic synthesis of preclinical and early clinical evidences. Front Med (Lausanne). 2026;13:1768365. doi:10.3389/fmed.2026.1768365

2. Cao D, Khanal S, Wang L, et al. A matter of life or death: productively infected and bystander CD4 T cells in early HIV infection. Front Immunol. 2021;11:626431. doi:10.3389/fimmu.2020.626431