Targeted bacteriophage T4 nanoparticles reverse HIV-1 latency in human T cell line models

Himanshu Batra; Jingen Zhu; Swati Jain; Neeti Ananthaswamy; Marthandan Mahalingam; Pan Tao; Camille Lange; Shawn Hill; Chaojie Zhong; Mary F Kearney; Haitao Hu; Frank Maldarelli; Venigalla B Rao

doi:10.1016/j.isci.2025.114006

Targeted bacteriophage T4 nanoparticles reverse HIV-1 latency in human T cell line models

iScience. 2025 Nov 12;28(12):114006. doi: 10.1016/j.isci.2025.114006. eCollection 2025 Dec 19.

Authors

Affiliations

¹ Bacteriophage Medical Research Center, Department of Biology, The Catholic University of America, Washington, DC, USA.
² National Cancer Institute, National Institutes of Health, Frederick, MD, USA.
³ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Abstract

A major barrier for HIV-1 eradication is the latent virus reservoir containing stably integrated and silent proviruses in CD4⁺ T cells. Targeted reactivation and removal of this latent reservoir is a potential strategy for HIV-1 cure, but remains a major challenge. Here, we investigated whether CD4-targeted bacteriophage T4 capsid nanoparticles that mimic the HIV envelope can reactivate HIV-1 latency. The nanoparticles were arrayed with CD4-binding CD4-DARPin, or the HIV-1 gp140 envelope trimer. When exposed to J-Lat T cell model of HIV-1 latency or primary T-lymphocytes from human PBMCs, these nanoparticles activated CD4⁺ T cells without causing global T cell activation, which led to the activation of HIV-1 proviral transcription, viral protein production, and release. Intriguingly, the observed T cell activation and HIV-1 latency reversal do not involve the classic PKC or NFAT pathways and did not lead to cytokine storm. These studies indicate that engineered non-infectious bacteriophages can be exploited for HIV-1 cure and targeted T cell therapies.

Keywords: Immunology; Virology.