The researchers identify broad inhibitors that could be used for HIV prevention and therapy

March 27, 2021

2 min read

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Glögl M et al. Abstract 85LB. Presented at: Conference on Retroviruses and Opportunistic Infections; 6-10 March 2021 (virtual meeting).

Disclosure:
Glögl does not report any relevant financial information.

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Using molecules called engineered ankyrin repeat proteins, or DARPins, researchers identified variable loop 3 structures on the HIV-1 envelope that could be used as a vaccine blueprint and target for therapeutics.

The results were presented at the virtual conference on retroviruses and opportunistic infections.

Matthias EqÖgl

“It has been a recognized fact for decades: while the variable loop 3 (V3) on the trimer of the HIV-1 envelope (Env) is an ideal target for broad neutralization – as it is essential for virus entry – the V3 shielded The Env-Trimer prevents access for strong neutralization. ” Matthias EqÖgl, A doctoral student at the Institute for Medical Virology at the University of Zurich told Healio. “As a result, the massive antibody response to V3 in natural infections is weak or non-neutralizing, and broad neutralization involving the V3 is limited to antibodies that recognize glycans surrounding the V3 on screened env.”

He added, “What drove our current study was some interesting evidence from previous studies in our laboratory with DARPin-based inhibitors that indicated that broad neutralization via the V3 crown might indeed be possible. Given the abundance of data that spoke against it so far, it would be a paradigm shift if the V3 itself could actually be accessed to achieve broad neutralization. “

Glögl and colleagues used DARPin technology to select DARPins targeting HIV-1 Env through ribosome display. They also examined hits on V3 binders with a broad neutralization capacity to define V3-specific DARPins with broad neutralization activity, and used them to define entry- and neutralization-relevant V3 conformations.

According to the study, the researchers identified eight different V3-specific DARPins with an “exceptional neutralization range of up to 93%”.

“With these special molecules, the DARPins, they identified some special structures of the V3 loop on the envelope glycoprotein.” Richard Pair, MD, The deputy director of the vaccine research center at the National Institute of Allergies and Infectious Diseases said during a press conference.

“These can open up new targets for vaccines, but there are also companies developing DARPins and these specific DARPins could be used prophylactically or as therapeutics,” said Koup, who was not involved in the study.

Glögl explained that the broad inhibitors identified in the study attack the V3 on open Env trimers after CD4 binding, which means that a presumed short-lived intermediate entry conformation of V3 is sufficient to allow broad neutralization. In addition, the study revealed a novel, neutralization-relevant conformation of V3 called V3C. According to Glögl, V3C is attacked by the largely neutralizing inhibitors, which indicates a “high functional relevance”.

“Based on our findings, a renewed examination of the V3 antibody responses in the case of an HIV-1 infection is justified, since a V3 neutralization acting after CD4, which corresponds to the largely neutralizing DAARPins identified, may have been overlooked,” concluded Glögl.

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Conference on Retroviruses and Opportunistic Infections (CROI)