Pre-Clinical Model Could Enable the Study of HIV-Curing Therapies

Investigators from Weill Cornell Medicine and Children’s National Hospital have developed a unique pre-clinical model using a specific subset of CD4 cells that could allow the study of long-term HIV infections and the testing of new curative therapies.

Ordinary mice cannot be infected with HIV, so most HIV mouse models use human CD4 T cells that can be infected. However, the researchers said these human cells tend to have limited utility because they soon perceive the tissues of the mice as foreign and attack, making the mice incredibly sick.

To avoid these problems, the new model utilizes a subset of human CD4 cells that mostly exclude the cells that would attack mouse tissue. The investigators found that the mice can successfully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies, according to the study.

“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection, and for speeding the development of better therapies,” said co-first author Chase McCann, MS, PhD, in a press release.

In the study, the researchers demonstrated that the cell-attacks-host problem found in prior mouse models is primarily due to naïve CD4 cells, which have not yet been exposed to targets and include a subset of cells that can attack various mouse proteins. When they excluded these naïve CD4 cells and only used memory CD4 cells, the investigators found that the cells survived indefinitely in the mice without causing major damage.

In these models, the team found that the human CD4 cells could also be infected and killed by HIV or protected by standard anti-HIV drugs. Therefore, they demonstrated that the mice, called participant-derived xenograft (PDX) mice, served as a functional model for long-term HIV infection. This model works similarly to patient-derived xenograft models used to research cancer therapies, according to the study.

Finally, the investigators used the new model to research a prospective new T-cell based therapy, which is similar to one being investigated in cancers. The team put memory CD4 T cells from a human donor into the mice to create an HIV infection, and then treated the mice with another infusion of CD8-type T cells, also called killer T cells.

The CD8-type cells were from the same human donor and recognized a vulnerable structure on the HIV cells, thereby attacking the virus wherever they found it in the mice. To improve the cells’ effectiveness, the investigators supercharged them with a T cell-stimulating protein called IL-15.

According to the study, the treatment significantly suppressed HIV in the models. Although it eventually evolved to escape recognition by the killer T cells, the researchers noted that the ease of use of the mouse model allowed them to monitor and study these long-term infections and viral escape dynamics.

“I think that the major impact of this model will be its acceleration of the development of T cell-based therapies that can overcome this problem of viral escape,” said senior author Brad Jones, PhD, in the press release.

The investigators are continuing to study potential therapies using the new mouse model, as well as engineered T cells obtained from McCann’s laboratory and others, according to the press release.

REFERENCE

New Pre-Clinical Model Could Hold the Key to Better HIV Treatments [news release]. Weill Cornell Medicine; May 14, 2021. https://news.weill.cornell.edu/news/2021/05/new-pre-clinical-model-could-hold-the-key-to-better-hiv-treatments. Accessed May 20, 2021.