Engineered molecules targeting both killer T cells and HIV-infected cells containing the viral envelope protein (Env) can kill HIV-infected cells and work to reduce the levels of detectable HIV expression in HIV-positive patients on antiretroviral therapy, according to research published in PLOS Pathogens.
Led by Scott Koening of MacroGenics in Rockville, MD, and Tomas Cihlar from Gilead Sciences in Foster City, CA, a team of researchers developed Dual-Affinity Re-Targeting (DART) bispecific molecules: the first arm of the molecule binds specifically to the HIV Env protein, while the second binds to CD3 – a molecule found on cytotoxic T cells. The DART CD3-binding arm has the potential to recruit and activate any kind of cytotoxic T cell, carrying out a much larger attack on Env-expressing target cells.
To develop the DART CD3 molecules, the researchers generated a set of DART molecules that were tested on a mix of resting CD4 T cells – isolated from donors and infected with wild-type HIV isolates – and unstimulated CD8 T cells from the same individuals.
“These cells may better approximate the resting state and corresponding low levels of surface Env expressed on reservoir cells from HIV-infected individuals on antiretroviral therapy,” the researchers wrote.
The researchers were also able to show that DART molecules are capable of reducing the level of HIV expression ex vivo in isolated blood cells from HIV-infected participants on suppressive antiretroviral therapy.
“Ultimate proof of reservoir reduction would have to be obtained by in vivo testing of DART molecules,” the researchers added.
- Sloan DD, Kao Lam C-Y, Irrinki A, et al. Targeting HIV reservoir in infected CD4 T cells by dual-affinity retargeting molecules (DARTs) that bind HIV envelope and recruit cytotoxic T cells. PLOS Pathog. 2015; doi: 10.1371/journal.ppat.1005233