One the one hand, it binds to CD3 receptors that stud T cells, both helper T cells latently infected with HIV, as well as killer T cells. On the other hand, it binds to HIV proteins that are expressed on the surface of previously dormant helper T cells. The “it” here is VRC07-αCD3, an ambidextrous protein that was developed to eliminate T helper cells latently infected with HIV.
The protein, which was developed by scientists at the National Institutes of Health (NIH), can rouse latent HIV out of sleepy helper T cells and prod killer T cells to send helper T cells with active HIV to their final rest. Now that these scientists have used the protein to facilitate the destruction of latently infected T cells in a laboratory setting, they are hopeful that it could contribute to a cure for HIV infection.
The scientists anticipate that their protein could help deplete the reservoir of long-lived, latently HIV-infected cells that can start making the virus when a person stops taking anti-HIV drugs. To determine the viability of this approach, it will be necessary to advance from evaluations of cell cultures to studies in animals and people.
In the current study, the NIH scientists found that VRC07-αCD3 triggered the activation and killing of latently HIV-infected helper T cells when the cells were taken from patients on antiretroviral therapy and then incubated in the lab with the patients’ own killer T cells. In addition, the scientists found a monkey-adapted version of the protein to be safe and well-tolerated when given to monkeys infected with a simian form of HIV and receiving antiretroviral therapy.
These findings appeared October 20 in the journal Nature Communications, in an article entitled, “Activation and lysis of human CD4 cells latently infected with HIV-1.”
“An immunomodulatory protein was created that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor,” wrote the authors. “CD3 engagement by the protein can stimulate T-cell activation that induces proviral gene expression in latently infected T cells. It further stimulates CD8 T-cell effector function and redirects T cells to lyse these previously latent-infected cells through recognition of newly expressed Env.”
VRC07-αCD3, which powerfully binds to more than 90% of HIV strains, facilitates the killing of latently HIV-infected cells in three steps:
- The CD3-binding end attaches to a resting, HIV-infected helper T cell, activating the cell so it starts making HIV and displaying pieces of virus on its surface.
- The HIV-binding end of the protein latches onto those pieces of virus while the CD3-binding end attaches to a killer T cell, activating it and bringing it close to the helper T cell.
- The activated killer T cell destroys the HIV-infected helper T cell.
If HIV, which persists in reservoirs of latently HIV-infected cells, could be cleared and not just held at bay, it would be possible to reduce the duration of treatments such as combination antiretroviral therapy. At present, such treatments must be sustained throughout a patient’s lifespan.
To advance their work, the NIH researchers are now conducting animal studies. Specifically, they are studying the effectiveness of monkey-adapted VRC07-αCD3.
In addition, the Nature Communications included recommendations for developing even more effective versions of their basic approach: “It is likely that the efficacy of these proteins can be improved, either by addition of specificities directed to other highly conserved Env domain, modulating CD3 affinity, or including a third specificity directed to T-cell co-stimulatory molecules such as PD-1, CD28, or CD137.”
Finally, the authors noted that their protein or similar proteins could be used in combination with other therapeutics: “HDAC inhibitors have also shown promise in activating HIV-1 from latency. Bispecific activating and targeting proteins could potentially be used in combination with such drugs to better activate and eliminate such infected cells in reservoirs of latent infection.”