A team led by researchers from Weill Cornell Medicine and Children’s National Hospital has developed a unique preclinical model that allows the study of long-term HIV infection and the testing of new therapies aimed at curing the disease.
Ordinary mice cannot be infected with HIV, so previous HIV mouse models used mice carrying human stem cells or CD4 T cells, a type of immune cell that can be infected with HIV. But these models tend to have limited utility because human cells quickly perceive the tissues of their host mice as “foreign” and attack – making mice seriously ill.
In contrast, the new mouse model, described in an article in Journal of Experimental Medicine on May 14, avoids this problem by using a subset of human CD4 cells that primarily excludes cells that would attack mouse tissue. Researchers have shown that mice can usefully model the dynamics of long-term HIV infection, including the virus’s response to experimental therapies.
“We expect this to be a valuable and widely used tool for studying the basic science of HIV infection and for accelerating the development of better therapies,” said co-first author Dr Chase McCann. During the study, Dr McCann was a student at Weill Cornell Graduate School in the laboratory of senior author Dr Brad Jones, Associate Professor of Immunology in Medicine in the Division of Infectious Diseases at Weill Cornell Medicine. . Dr McCann, who was supported at Weill Cornell by a TL1 Training Fellowship from the Clinical and Translational Science Center (CTSC), is now head of the Cell Therapy Laboratory at the Center for Cancer and Immunology Research at Children’s National Hospital in Washington, DC. . The other co-first authors of the study are Dr Christiaan van Dorp of the Los Alamos National Laboratory and Dr Ali Danesh, senior medical research associate at Weill Cornell Medicine.
The invention of the new mouse model is part of a larger effort to develop and test cellular therapies against HIV infection. Cellular therapies, such as those using the patient’s own T cells, are increasingly common in the treatment of cancer and have achieved remarkable results. Many researchers hope that a similar strategy can work against HIV and can potentially be curative. But the lack of good mouse models has hampered the development of such therapies.
Drs. Jones and McCann and their colleagues showed in the study that the cell-attack-host problem found in earlier mouse models is mainly due to so-called “naive” CD4 cells. These are CD4 cells that have not yet been exposed to targets and apparently include a population of cells that can attack various mouse proteins. When the researchers excluded naïve CD4 cells and used instead only “memory” CD4 cells, which circulate in the blood as sentinels against infection following exposure to a specific pathogen, the cells survived indefinitely in them. mice without causing major damage to their hosts.
The researchers observed that human CD4 cells could also be infected and killed by HIV, or protected by standard anti-HIV drugs, in much the same way they are in humans. Thus, they showed that mice, which they called “participant-derived xenograft” or PDX mice, served as a viable model for long-term HIV infection. This term is related to the “patient-derived xenograft” PDX models used to study cancer therapies, while recognizing the contributions of people living with HIV as active participants in research.
Finally, the researchers used the new model to study a new prospective therapy based on T lymphocytes, very similar to the one currently being tested against cancers. They memorized CD4 T cells from a human donor in the mice to allow HIV infection, and then, once the infection was established, treated the mice with another infusion of human T cells, these ones. these being CD8-type T cells, also called “killer T” cells. cells. “
The killer T cells came from the same human donor and could recognize a vulnerable structure on HIV – so they attacked the virus wherever they found it in mice. To increase the effectiveness of the killer T cells, the researchers supercharged them with a T cell stimulating protein called IL-15.
The treatment powerfully suppressed HIV in the mice. And although, as often seen in human cases, the virus eventually evolved to evade recognition by killer T cells, the ease of use of the mouse model allowed researchers to monitor and study these infections in detail. long-term and viral escape dynamics.
“I think the major impact of this model will be its acceleration in the development of T cell-based therapies that can overcome this problem of viral leakage,” said Dr Jones.
He and his lab continue to study such therapies using the new mouse model, with modified T cells from the lab of Dr. McCann and others.