Enhancing Innate Immunity Against HIV

Clues from elite controllers suggest possible cure strategies

By Jeffrey Laurence, M.D.

Research question
The control of HIV to undetectable levels without ART (antiretroviral therapy)—a “functional HIV cure”—is characteristic of about 0.5% of all people living with HIV (PLWH). amfAR grantees Drs. Mathias Lichterfeld and Xu Yu have been among the researchers studying these “elite controllers” (ECs). A few years ago, Drs. Lichterfeld and Yu studied the case of Loreen Willenberg, an elite controller diagnosed in 1992 who has never taken ART, and published their findings: They were unable to find any intact HIV in her body despite searching in more than one billion cells. The researchers have since expanded their investigations into elite control in order to understand what might be needed to cure HIV.

Insight into the mechanisms enabling elite control has so far been limited. For example, it was known that natural killer (NK) cells, part of the innate immune system, capable of killing HIV-infected cells are twice as prevalent as in non-controller PLWH, but how these cells arise and are maintained was unknown.

Xu Yu, MD, and Mathias Lichterfeld, MD, PhD, of the Ragon Institute of MGH, MIT and Harvard and Brigham and Women’s Hospital. Dr. Lichterfeld is also a researcher at the Broad Institute of MIT and Harvard.

Drs. Lichterfeld, Yu, and colleagues from Harvard and MIT examined 40 elite controllers who had

undetectable levels of HIV-1 replication for a median of five years in the absence of ART, along with 33 people living with HIV who required ART to maintain undetectable levels of virus. Healthy HIV-negative controls were also studied.

The scientists uncovered unique profiles of gene activation among NK cells from ECs, including changes leading to high levels of the immune hormone IL-15. IL-15 enhanced the killer function of these cells and prolonged their survival. The types of genetic modifications uncovered facilitated a heightened state of what is known as innate “trained immunity.”

The authors emphasize that this work “may lead to actionable interventions designed to induce natural control of HIV-1.”

amfAR’s role
amfAR was a funder of this research.

Original article

Dr. Laurence is amfAR’s senior scientific consultant.

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