Radioimmunotherapy and antiviral therapy: An elimination strategy for HIV-infected cells

Abstract

While antiretroviral therapy (ART) has dramatically improved life expectancy for people infected with HIV/AIDS, it cannot kill infected cells. These cells persist in cellular and anatomical reservoirs, leading to disease resurgence. Radioimmunotherapy (RIT) utilizes antibodies as vehicles to deliver cytocidal radiation to cells and successfully killed HIV infected cells using the 2556 monoclonal antibody to HIV-1 gp41 protein. However, both ART-treated cells and latently infected cells have decreased gp41 expression, which may decrease RIT efficacy. The aim of this work is to assess the ability of RIT to bind and kill infected cells using latent cell line models, simian lymphocytes, and primary human lymphocytes co-treated with ART. We hypothesized that the surface gp41 expression in all three models would be reduced compared to actively infected cells but sufficient to permit preferential binding and killing of infected cells by RIT.;Cells were treated with Bismuth-213 (213Bi) conjugated to 2556. Cell survival, viral load, and gp41 expression were assessed using chronically infected cell lines or peripheral blood mononuclear cells (PBMCs) isolated from monkeys or humans. ART-treated infected PBMCs continued to express gp41 in sufficient quantity to be killed by RIT, and 213Bi-2556 eliminated more than 90% of detectable virus in 13 of 15 patient samples. ART and RIT co-treatment was consistently more effective at reducing viral load in vitro than either therapy alone. Both latent and activated cell lines were killed by RIT in a dose-dependent manner, although the inability of RIT alone to eliminate all latently infected cells in the sample suggests that, for maximum efficacy, an accompanying latency reactivation strategy should be considered to maximize surface gp41 expressed by these cells. 2556 competed with the endogenous anti-gp41 antibodies present in simian/human immunodeficiency virus (SHIV) infected macaque serum, and 213Bi-2556 preferentially bound to and killed SHIV infected PBMCs in numbers twice as high as PBMCs from control monkeys. Taken together, these data show proof of concept that 213Bi-2556 may represent a novel and effective targeting method for killing persisting HIV-infected cells, and demonstrate that SHIV infected macaques are a potential model for investigating RIT efficacy in future studies.