Mimicking CD4: A Bait and Switch Approach to Immunotherapy
By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
Last month we highlighted research on genetically modified blood-forming stem cells that can generate T cells capable of killing HIV-infected cells. This month we focus on another form of immunotherapy, also with the potential to facilitate eradication of HIV reservoirs as part of an HIV cure strategy.
One potential method of eliminating this reservoir is “shock-and-kill,” by which HIV is provoked out of latently infected cells by drugs known as latency-reversing agents. This strategy requires a potent immune response to eliminate those infected cells. Most studies have focused on using T cells; new research involves natural killer (NK) cells, which can kill HIV-infected cells when combined with HIV-specific antibodies.
The research team previously found that agents called CD4mc, so named because they mimic the entry receptor CD4, can make HIV-infected cells susceptible to killing by an antibody-dependent process known as ADCC. CD4mc jams open the envelope protein on the surface of infected cells. In this open, vulnerable conformation, antibodies already present in bodily fluids and tissues can also bind to the envelope protein. Once these naturally occurring antibodies are bound, they recruit killers, such as NK cells, to the scene so that those killers can eliminate the infected cells.
Using “humanized” mice capable of supporting an HIV infection, the researchers now show that treatment with CD4mc plus either antibodies derived from the plasma of HIV-infected individuals, or the plasma itself, can suppress HIV replication and keep the latent HIV reservoir in check. It can also decrease HIV rebound in antiretroviral-treated mice that were then taken off therapy.
The authors concluded that “CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure.”
amfAR was a funder of this research, which was performed by amfAR Mathilde Krim Fellow Dr. Jonathan Richard and his mentor Dr. Andrés Finzi at the Centre de Recherche du CHUM, Montreal, and colleagues.
Dr. Laurence is amfAR’s senior scientific consultant and Dr. Johnston is VP and director of research.