How HIV adapts when a critical building block Is missing

Cryo‑EM shows how a single mutation restores HIV infectivity without IP6

HIV‑1 depends on the host molecule IP6 at two key stages:

Early assembly – IP6 stabilises the six‑helix bundle (6HB) in the immature Gag lattice.
Maturation – IP6 binds to charged residues (R18, K25) in the capsid, enabling formation of the mature, cone‑shaped shell needed for infection.

Viruses carrying mutations that prevent IP6 binding (the K158A/K227A “KAKA” mutant) can assemble immature particles but fail to form stable mature capsids, making them non‑infectious.

Researchers at the Wellcome Trust Centre for Human Genetics, along with international collaborators, used cryo‑EM, at Diamond's eBIC to investigate how HIV‑1 adapts when deprived of IP6. Cryo‑EM allowed them to visualise HIV particles and capsid proteins at near‑atomic resolution.

The group found that during forced evolution experiments, the virus acquired a single compensatory mutation in the capsid protein, G225R, which:

Restores mature capsid formation without IP6
Recovers infectivity
Allows capsid proteins to assemble more easily in low‑IP6 conditions

Cryo‑EM revealed that G225R stabilises a normally flexible part of the capsid, strengthening the structure in a way unseen by other techniques. This discovery highlights how HIV can adapt and uncovers a previously unknown structural role of the capsid protein, offering new insights relevant to antiviral drug development.

Read the paper to find out more.

How HIV adapts when a critical building block Is missing

Cryo‑EM shows how a single mutation restores HIV infectivity without IP6

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