Tracing the Unique Immune Footprints of Elite Controllers

By Jeffrey Laurence, M.D.

Research Question 

“Elite controllers (ECs)” are individuals capable of suppressing HIV without antiretroviral therapy (ART). ECs are critical proof that the human immune system itself can control HIV. But the mechanisms that permit this distinct profile in perhaps 0.5% of all HIV-infected individuals are unclear.


Sequences of latent HIV from 58 ECs and 42 ART-treated individuals with undetectable viral loads were examined. The ECs harbored defective latent viruses in gene locations from which those viruses could easily be activated. In contrast, fully intact latent HIV appeared restricted to “gene deserts,” which are much more resistant to viral activation. ECs also had lower levels of HIV mutations permitting evasion of host immune responses. In stark contrast, individuals requiring ART to control HIV lacked these immune signatures.

Dr. Xu Yu 
Dr. Xu Yu


The authors, led by Drs. Xu Yu of the Ragon Institute of MGH, MIT and Harvard, and Mathias Lichterfeld of Brigham and Women’s Hospital in Boston, concluded that immune pressures common to elite controllers may eliminate many intact latent viruses before escape mutations can predominate. In addition, viral proteins generated by defective latent viruses may serve as a built-in HIV vaccine in ECs, maintaining effective anti-HIV defenses.

The net result is a small “skeleton reservoir” of intact latent viruses that are susceptible to elimination by the immune system, but are buried deep in genes, and thus protected against such targeting. But what does this mean for the >99% of HIV-infected individuals whoare not natural ECs?

Dr. Mathias Lichterfeld 
Dr. Mathias Lichterfeld 

The authors emphasized that immune processes characterizing ECs “are only gradually but not fundamentally different from ART-treated individuals. It remains possible that intensification of antiviral host immune activity through strategies such as therapeutic vaccines…may approximate an EC-like profile.”

amfAR’s Role 

amfAR was a funder of this research. The findings and their potential significance were discussed in detail by researchers, including Drs. Yu and Lichterfeld, at an amfAR think tank in December 2021.

Original Article

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