Gene-editing technique

The human body cannot naturally defend itself against HIV—not usually, at least. But in very rare cases, infected individuals generate broadly neutralizing antibodies, or bNAbs, that fight the virus. Now, Rockefeller scientists have devised a way to grant this HIV-fighting power to otherwise average immune cells. Michel C. Nussenzweig, whose work on bNAbs has produced new HIV treatments showing promise in early clinical trials; has now set his sights on a second goal: immunization against the virus.

CRISPR/Cas9 to express mature bNAbs

A small number of HIV-1–infected individuals develop broadly neutralizing antibodies to the virus (bNAbs). These antibodies are protective against infection in animal models. However, they only emerge 1–3 yr after infection, and show a number of highly unusual features; including exceedingly high levels of somatic mutations. It is therefore not surprising that elicitation of protective immunity to HIV-1 has not yet been possible. Here we show that mature; primary mouse and human B cells can be; edited in vitro using CRISPR/Cas9; to express mature bNAbs from the endogenous Igh locus.

Moreover, edited B cells retain the ability to participate in humoral immune responses. Immunization with cognate antigen in wild-type mouse recipients of edited B cells; elicits bNAb titers that neutralize HIV-1 at levels associated with protection against infection. This approach enables humoral immune responses; that may be difficult to elicit by traditional immunization.

Technique used as an immunization tool

In a recent study, described in the Journal of Experimental Medicine, Nussenzweig and his colleagues used CRISPR-Cas9 gene editing technology to modify B cells, a type of white blood cell that secretes antibodies. Specifically, the researchers engineered mouse B cells to make human bNAbs on their own. Cells altered in this way, the researchers found, produced antibody levels sufficient to protect the animals against HIV—suggesting that this technique could eventually be used as an immunization tool.

While this research is still in an early stage, it demonstrates the feasibility of enhancing immune response via gene editing. Importantly, the technique does not affect germline cells and therefore evades the ethical concerns sometimes raised by CRISPR interventions. If realized, this novel approach to immunization could be useful not only against HIV, but against any disease that is sensitive to a specific antibody.